Factors In£uencing the Bioavailability of PeroralFormulations of Drugs for Dogs

S. SabnisFort Dodge Animal Health, POBox 400, Princeton, NJ 08543-0400, USAE-mail: sabniss@pt.cyanamid.com

Sabnis, S., 1999. Factors in£uencing the bioavailability of peroral formulations of drugs for dogs.Veterinary Research Communications, 23(7), 425^447

ABSTRACT

The oral route is presently the preferred route of drug delivery. Poor oral bioavailability results invariable concentrations of drugs in the plasma and variable pharmacological responses, in addition tohigher product costs. The unique canine physiology, anatomy and biochemistry makes designing caninedosage forms a challenging exercise. This article reviews the physicochemical, physiological, pharma-cokinetic, pharmacological and formulation factors that can in£uence the drug availability of the oralformulations in dogs in an e¡ort to provide a source of data to aid development of canine drug productswith superior bioavailability.

Keywords: absorption, bioavailability, dog, elimination, intestine, oral administration, stomach

Abbreviations: AUC, area under the plasma concentration^time curve; Cmax, maximum plasmaconcentration; kel, elimination rate constant; Tmax, time from administration to Cmax; V, volume ofdistribution

INTRODUCTION

Despite intense interest in alternative dosage routes, the oral route is still the preferredroute of drug administration from practically every point of view and will probablycontinue to be so. Currently, approximately 340 oral forms of dosage are available inthe US, speci¢cally for the treatment of dogs (Arrioja-Dechert, 1998) with severalmore in development. During the process of drug discovery, `oral bioavailability' isoften a prerequisite when considering a candidate drug for further development. Poororal bioavailability has the consequences of more variable drug e¡ects and possiblyhigher product costs, and as a result the marketing potential of the drug declines. Sinceeach new candidate drug is expected to o¡er unique physicochemical characteristics,the study of its absorption and bioavailability marks a critical step in the developmentof a new drug. Canine physiology o¡ers many unique features that must be consideredin developing e¡ective forms of canine dosage. This article identi¢es various factorsthat de¢ne the oral bioavailability of a canine drug candidate and reviews the recentadvances in improving drug absorption.

Veterinary Research Communications, 23 (1999) 425^447# 1999 Kluwer Academic Publishers. Printed in the Netherlands

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DEFINITION OF BIOAVAILABILITY

A consensus statement on bioavailability/bioequivalence testing was developed at aworkshop of the Drug Information Association in Barcelona, Spain (Cartwright et al.,1991). The de¢nition of bioavailability adopted for that statment is that bioavailabilityis `the rate at which and extent to which the drug substance and/or its metabolitesreach(es) the systemic circulation' (Block, 1992).

BIOAVAILABILITY DETERMINATION

Drugs following linear kinetics

A drug is said to follow linear kinetics when a change in its dosage does not a¡ect itsclearance or elimination rate constant (kel), as illustrated in Figure 1A. On the otherhand, an increase in the dose of a drug undergoing nonlinear kinetics (Figure 1B)causes a reduction in its clearance and kel. As a result of the change in clearance, thereis an increase in the area under the plasma concentration^time curve (AUC). For drugsundergoing linear kinetics, the determination of absolute or relative bioavailability isbased on the following principles. First, the amount of active substance reaching thesystemic circulation is equal to the amount of drug eliminated from the systemiccirculation. Second, clearance of the active substance following intravenous or oraladministration is the same.

Figure 1. Plasma concentration pro¢les of a drug following (A) linear and (B) nonlinearkinetics

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Absolute bioavailability: It is generally well accepted that the absolute bioavailabilitycan only be determined by comparison with an intravenous dose and is calculated asfollows:

Absolute bioavailability �Fabs� �

8>>:R10 C dt

9>>;oral� Dosei:v:8>>:R10 C dt

9>>;i:v:� Doseoral

�1�

Relative bioavailability: In many instances, intravenous dosing is not practical. In suchcases, the bioavailability of a drug is established by comparing it to a secondarystandard (oral solution). This parameter is termed relative bioavailability and iscalculated as follows:

Relative bioavailability �F rel� �

8>>:R10 C dt

9>>;oral8>>:R10 C dt

9>>;oral standard

�2�

The above methods of determination are based on the premise that the overallclearance, de¢ned as the amount of drug eliminated divided by AUC, is the same forboth doses. When elimination of a drug follows nonlinear kinetics, as with phenytoin,this premise is violated, producing an error in the estimate of bioavailability (Tozer andRubin, 1988).

Bioavailability determination of drugs following nonlinear kinetics

Various methods of determining the bioavailability of drugs with Michaelis^Mentenkinetics or other forms of nonlinear elimination have been proposed. Martis and Levy(1973) have proposed a model-dependent method that can be used for drugs exhibitingparallel ¢rst-order elimination:

Fest � 1Dpo

Z 10

8>>:Vmax � CKm � C

� k � V � C9>>;dt �3�

In this equation, Fest is the estimated value of bioavailability, Dpo is the oral dose,Vmax is the maximum rate of metabolism, C is the systemic drug concentration, k is the¢rst-order elimination rate constant,V is the volume of distribution and Km representsthe concentration at which the rate is one-half the maximum value.

Tozer and Rubin (1988) have indicated that the method of Martis and Levy (1973) ismore suitable for drugs for which saturable elimination occurs in an organ other than

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the liver. Since the concentration of drug entering the liver following oral absorption isthe sum of the systemic concentration and that derived from oral absorption (¢rst-pass), the e¡ective concentration of the drug entering the liver is underestimated,resulting in an overestimation of bioavailability.

Veng-Pederson (1985) suggested that, when elimination is nonlinear, an empiricalfunction describing the concentration dependence of elimination could be used toestimate bioavailability. Equation (4) employs this clearance function CL(t) todetermine the bioavailability:

F est � 1Dpo

Z 10

CL�t� � C dt �4�

When elimination does occur by Michaelis^Menten kinetics, an empirical functionmay not describe elimination as well as the Michaelis^Menten equation. The methodof Veng-Pedersen may be used for nonlinear disposition due to saturable plasmaprotein binding.

Rubin and colleagues (1987) and Waschek and colleagues (1984) used anotherinteresting approach for estimating the bioavailability of drugs with nonlinear kinetics.This involved administration of an intravenous reference dose as a labelled tracer at thetime of administration of the oral dose. The same degree of saturation would beencountered by the drug from an oral as well as from an intravenous dose, resulting inequal values of clearance. This method o¡ers the advantages of requiring fewerassumptions about the appropriate pharmacokinetic model. It also avoids the e¡ectsof changes in clearance that may occur between separate administrations of oral andintravenous doses.

Òie and Jung (1979) have proposed another model-independent method that isappropriate for drugs with nonlinear renal excretion. For drugs with no renalmetabolism, the amount of drug eliminated by the nonlinear route can be measureddirectly in the urine and the bioavailability can be calculated as:

F est � CLxr �AUCpo � Aex

Dpo�5�

where, CLxr is the extrarenal clearance, AUCpo denotes the area under the drugconcentration curve following oral dosing, and Aex is the amount of drug excreted inthe urine. This method bypasses the problem of using clearance to estimate the amountof drug eliminated by the nonlinear pathway (Tozer and Rubin, 1988).

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FACTORS AFFECTING BIOAVAILABILITY

Physicochemical factors

Chirality of the drug: The concept of stereochemistry was introduced by Louis Pasteurin 1848, when he proposed that the optimal activity of solutions of organic molecules isdetermined by their molecular asymmetry, which produces non-superimposablemirror image structures (Mayersohn, 1996). Stereoisomers have very similar physico-chemical properties, so it is di¤cult to distinguish between them in achiral environ-ments. However, in the highly chiral environment of the body, they exhibit cleardi¡erences. For example, the drug absorption process is likely to be stereospeci¢cwhen mediated by carrier molecules. On the other hand, passive processes such asdi¡usion across the gastrointestinal or other membranes are not governed by anyenantioselective mechanisms. The importance of stereochemical aspects in consideringthe bioavailability of drug molecules has been well emphasized by Jamali andcolleagues (1989) and by Jamali (1992). Many enantioselective drugs are usuallymarketed as racemates, although their therapeutic bene¢ts are ascribed only to speci¢cenantiomers. For example, the area under the curve of the therapeutically bene¢cialenantiomer of etodolac (S) is only one-tenth that of the inactive enantiomer (R) when itis administered as a racemate (Brocks et al., 1991). The di¡erences in the bioavail-abilities of the stereoisomers may be due to any of the following: (1) stereoselectivemetabolism during the absorptive phase, (2) dissimilar pharmacokinetic rate con-stants, (3) conversion of one isomer to the other in the body, or (4) stereoselectiverelease from the dosage formulation due to interaction of enantiomers of the drug witha chiral excipient in the formulation (Duddu et al., 1993). Delatour and colleagues(1993) have reported considerable interspecies di¡erences in the pharmacokinetics ofthe enantiomers of ketoprofen and carprofen after administration of the racemates tohumans, dogs, cats, sheep, dwarf goats, dwarf pigs and horses. The implications ofchirality for the development of drugs of use in animals have been reviewed by Landoniand colleagues (1997).

Partition coe¤cient and pKa: Most drug molecules are either weak acids or weak basesthat will be ionized to an extent determined by the compound's pKa and the pH of thebiological £uid in which it is dissolved (Mayersohn, 1996). The importance ofionization in drug absorption is based on the observation that the non-ionized formof the drug has a greater n-octanol^water partition coe¤cient (Ko/w) than the ionizedform. Since Ko/w is a major determinant of membrane penetration, the degree ofionization would be expected to in£uence absorption (Navia and Chaturvedi, 1996).Ideally, e¡orts to improve bioavailability can be initiated at the drug design stage offormulation development (Yoshimura and Kakeya, 1983). The compound's partitioncoe¤cient and consequently its bioavailability are in£uenced by the structural changesbrought about by the substitution of di¡erent chemical groups. Mayersohn (1996) hastabulated the in£uence of various substituent groups on the membrane permeability ofnonelectrolytes. Since an alteration in the chemical structure of a drug molecule mayadversely a¡ect its pharmacological activity, other avenues, such as the formation of

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derivatives or prodrugs, have also been exploited. These approaches to improvingbioavailability will be discussed next.

Complex formation: The complexes of interest in pharmaceutical systems may bebroadly divided into three categories based on the energy of attraction between thecomponents of the complexes. They are (1) covalently linked complexes, (2) ioniccomplexes and (3) inclusion complexes. While the energy of attraction of covalentlylinked complexes is about 100 kcal/mol, that of the latter two types of complex isapproximately410 kcal/mol. The constituents of ionic complexes are held together byweak forces of the donor^acceptor type or by various other secondary forces such aselectrostatic, Coulombic, charge-transfer, etc. As a result, these complexes exhibit alabile, unsaturated, and strained coordination structure susceptible to dynamicchanges in their con¢guration. Therefore, these interactions ^ often referred to as `soft'or `dynamic' ^ occur rapidly and can readily be reversed (Tsuchida, 1991). Complexesformed by covalent linkages, on the other hand, can be dissociated into separatecomponents only by a chemical or an enzymatic reaction. For example, prodrugs areprepared by chemical modi¢cation of the drug by the addition of a labile moiety, suchas an ester group (Hussain et al., 1987), so as to improve the solubility, absorption oruptake by the target organ (Lai et al., 1987). Such a moiety can also serve to reduce thedrug molecule's presystemic metabolism (Murata et al., 1989) or to suppress theadverse e¡ects associated with this (Olkkola et al., 1994). In a prodrug, the ester groupor other moiety is chemically removed in the gastrointestinal tract or at the target site,usually by enzymatic action, and the parent drug is freed to produce its pharmacolo-gical action (Hansen et al., 1992; Lokind and Lorenzen, 1996). The prodrug approachhas been utilized in the development of bacampicillin (Bodin et al., 1975) andpivampicillin (Ensink et al., 1992) ^ prodrugs of ampicillin. Hussain and colleagues(1987) reported on the development of prodrugs of naltrexone by synthesizing itsanthranilate, acetylsalicylate and benzoate esters to improve its oral bioavailability.Enro£oxacin is a £uoroquinolone that is widely used in veterinary medicine. Cesterand Toutain (1997) have shown that enro£oxacin is largely metabolized in vivo to themore active cipro£oxacin, thus making enro£oxacin a prodrug of cipro£oxacin.Inclusion compounds, which form the third category of complexes, result more fromthe architecture of molecules than from their chemical interaction. One of theconstituents of the complex is trapped in the open lattice or cage-like molecularstructure of the other to yield a stable arrangement. Cyclodextrins have been mostwidely used for this purpose, since they can trap lipophilic drugs in their molecularenvelope and form a complex having a comparatively more hydrophilic character(Albers and Mu« ller, 1995). A complex formation of a drug with cyclodextrin is knownto enhance its solubility (Ja« rvinen et al., 1995) or dissolution rate (Brewster et al.,1997), and thereby the bioavailability of the drug.The drug molecules can also form complexes that may adversely a¡ect their

bioavailability. Such situations arise as a result of drug^drug, drug^excipient or drug^food interactions. These possibilities are discussed in later sections.

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Physiological factors

Gastrointestinal pH: The pH of the medium a¡ects the extent of ionization of the drug,which in turn in£uences its absorption. The unionized form of a drug permeatesmembranes better than its ionized form, so that acidic drugs are more rapidly absorbedfrom acidic solution, whereas basic drugs are more rapidly absorbed from a relativelyalkaline solution. The pH in the stomach may a¡ect drug dissolution from varioussolid forms of dosage. The acidic environment formed as a result of the secretion ofgastric £uid favours the non-ionized forms of drugs such as carbamazepine andphenytoin (Sriwatanakul and Weintraub, 1983; Jacknowitz, 1987), thereby enhancingtheir absorption. It must be noted at this point that the intestine still serves as thepredominant site of absorption of the drug from most peroral dosage forms owing tothe larger surface area available for drug absorption (Mayersohn, 1996). The secretionof hydrochloric acid responsible for the low gastric pH occurs from the parietal cellslining the proper gastric mucosa. Three phases of gastric secretion are generallyrecognized: (1) cephalic phase, (2) the gastric phase, and (3) the intestinal phase. Thecephalic phase occurs as a result of central stimulation such as sight, smell, taste andchewing or swallowing. The gastric phase begins when the food enters the stomach,while the intestinal phase of secretion occurs as a result of the food entering theduodenum. The secretion of various gastrointestinal enzymes and ions is a¡ected bygastric pH. For example, Elwin and Andersson (1972) have shown that the release ofgastrin in dogs is inhibited at pH below 2, while Grossman and Konturek (1974)showed the dependence of the secretion of pancreatic bicarbonate ion (HCO3

^) ongastric pH. At an intragastric pH of 7, secretion of the pancreatic HCO3

^ ion was lowand did not change much when the pH decreased to 4.5. Between 4.5 and 3.0, secretionof the HCO3

^ ion rose sharply but did not continue to change with further acidi¢cation.An increase in pancreatic protein secretion was also observed in the same range of pHthat caused the HCO3

^ responses. Great inter- and intra-subject variability in gastro-intestinal pH has been reported. For example, pH values of 1.5 to 8.5 were reported inthe gastric region of dogs by Ogata and colleagues (1985). Since gastric pH in£uencesthe overall gastrointestinal activity, considerable variability in bioavailability can occuras a result of di¡erences in the pH in the stomach.

Gastric emptying: Most drugs are best absorbed from the small intestine, so any factorthat delays the movement of a drug from the stomach to the small intestine willin£uence the rate of absorption. Gastric emptying and the factors a¡ecting gastro-intestinal motility have been widely studied in attempts to improve bioavailability, sincegastric emptying may represent the limiting factor in the process of drug absorption.Gastric emptying has been quanti¢ed by a variety of techniques that use liquid or solidmarkers (Mayersohn, 1996; Tanaka et al., 1997). Gastric emptying patterns aredependent on the presence or absence of food. In the absence of food, the emptystomach and intestinal tract undergo a sequence of repetitious events referred to as theinterdigestive migrating motor complex, MMC (Minami and McCallum, 1984). TheMMC results in the generation of contractions, beginning in the proximal stomach andextending to the ileum. These contractile activities are divided into four stages, which

431

are marked by progressively intense contractions that decrease in duration. The thirdstage, referred to as the housekeeper wave, lasts for about 10^20 min (Gleysteen et al.,1985) and is responsible for emptying the gastric contents into the pylorus: the entirecycle lasts for about 2 h. Thus, the residence time for a dose taken on an empty stomachdepends on the time of dosing relative to the occurrence of the housekeeper wave(Gleysteen et al., 1985). Langguth and colleagues (1994) studied the in£uence ofvarious fasting-state gastrointestinal parameters on the variability in absorption ofcimetidine, using simulation and cimetidine administration to mongrel dogs. Theyconcluded that gastric emptying increased the variability of cimetidine concentrationin blood and that it played a role with respect to double-peak occurrence in theconcentration^time pro¢les (Langguth et al., 1994). Lipka and colleagues (1995)reported similar ¢ndings with respect to celiprolol. They observed that the fasted-statemotility phases in£uenced the rate and extent of drug absorption and caused theoccurrence of a double peak in the concentration^time pro¢les of celiprolol.

The interdigestive MMC is interrupted in the presence of food.Various mechanical,hormonal and neural mechanisms are involved in controlling gastric emptying in thepresence of solid or liquid food (Kelly, 1974; Sarna, 1985). The receptors lining thestomach, duodenum and jejunum that assist in controlling gastric emptying includemechanical receptors, acid receptors, osmotic receptors and l -tryptophan receptors(Stephens et al., 1976). Arguably, the neural control is associated with the inhibitoryvagal system, although the exact controlling mechanism is unknown (Gleysteen et al.,1985; Lenz, 1989). Several hormones, such as cholecystokinin (Jin et al., 1994), gastrin(Lenz, 1988), secretin (Lafontaine et al., 1983) and motilin (Debas et al., 1977) areknown to be involved in the gastric emptying process. The biological activities,including gastric emptying and intestinal motility, of various gastrointestinal hormoneshave been summarized well in a tabular form by Argenzio (1984).

Besides the presence or absence of food in the gastrointestinal tract, other factorsthat in£uence the gastric emptying include the size and state of the ingested meal. Infact, Dressman (1986) has elicited a direct relation between the cyclic activity of thegastric contractions and meal size. Solid meals of 30, 60 and 90 kcal/kg energy contentresulted in contractile activity cycles of 324, 561 and 799 min, respectively. Further-more, Meyer and colleagues (1985) have shown that the state of the ingested food, i.e.solid or liquid, also a¡ects gastric emptying. Accordingly, a dose ingested along with aliquid nutrient meal may experience a faster emptying rate than a dose taken with asolid meal, owing to the overall faster emptying rate of liquid meals. Multiparticulatedosage forms usually fall in the size range between ¢ne particles, which empty with£uid, and those that are too large to empty except in conjunction with stage III(housekeeper wave) activity. In a systematic study investigating the emptying ofnondigestible spheres in dogs, Meyer and colleagues (1985) observed that particles ofa density of 1 and a diameter of 1.6 mm emptied faster than the meal, while particleslarger than 2.4 mm in diameter emptied more slowly than the meal. As expected, alarge di¡erence in the gastric emptying is observed amongst di¡erent dosage forms.Niazi and colleagues (1983) reported that the absorption half-life was higher whennitrofurantoin was administered in a solid dosage form compared to administration asa solution. The elimination half-lives following oral administration ranged from 19 to

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87 min, with signi¢cantly prolonged elimination when solid dosage forms wereadministered compared to those when solutions were given. These observations agreewith those made by Kaniwa and colleagues (1988), who also observed an inverserelationship between the size of dosage forms and the gastric emptying rates. Davis andcolleagues (1986) observed that the time required for gastric emptying by di¡erentpharmaceutical dosage forms increased in the following manner: solutions5pellets5tablets and capsules. In contrast to ¢ndings on gastric motility, they observed that theintestinal transit time was much more consistent and independent of the dosage form(Davis et al., 1986).

Intestinal transit: For most non-ruminant animals, especially dogs, the intestinal transittime constitutes mainly the time required for small-intestinal transit as the smallintestine occupies 480% of the total intestinal length. Argenzio (1984) has made acomparison of the physiological attributes of gastrointestinal tracts of various animals(Table I).

The intestinal tract of the dog is relatively short and simple compared to that ofruminant animals, consisting of the small intestine, which is linked by the ileocaecalvalve to the caecum, which in turn is connected to the colon. Transit through the smallintestine appears to be quite di¡erent in a variety of ways from movement through thestomach. The time taken by the material to reach the ileocaecal valve, once emptiedfrom the stomach, is relatively consistent. Apparently, transit through the smallintestine is less dependent on the size or state of the matter, and the presence of fooddoes not in£uence the intestinal transit (Davis et al., 1986). Therefore, it is duringintestinal transit that the maximum opportunity exists for drug absorption from mostdosage forms. To illustrate the possible roles of gastric emptying and intestinal transitin the absorption of drugs, various formulation scenarios are compared in Table II.

TABLE IComparative length of small intestine to intestine of di¡erent animals

Relative length of Average absolute Ratio of body lengthAnimal small intestine (%) length (m) to intestinal length

Dog 85 4.14 1:6Cat 83 1.72 1:4Sheep 80 26.2 1:27Pig 78 18.3 1:14Horse 75 22.4 1:12Rabbit 61 3.56 1:10

Modi¢ed from Argenzio (1984)

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TABLE IIE¡ect of gastrointestinal activities on drug absorption from formulations

Probable e¡ect on drug absorption of

Hastened Delayed Rapid SlowDosage Drug gastric gastric intestinal intestinalform characteristic emptying emptying transit transit References

Liquid Readily soluble Complete Complete No e¡ect No e¡ect Kelly (1980)absorption absorption

Solid More soluble Rapid onset, Rapid onset, Complete Complete Horowitz (1987)at low pH incomplete complete absorption absorption Ganley et al. (1984)

absorption absorption

Solid More soluble Rapid onset, Delayed onset, Incomplete Complete Schurizek et al. (1988)at high pH complete complete absorption absorption Rinetti et al. (1982)

absorption absorption

Non-disintegrating dosage formsSustained Controlled No e¡ect No e¡ect Incomplete Complete Sako et al. (1996)release release rate absorption absorption Davis et al. (1986)

Sagara et al. (1992)

Delayed Drug not Onset not Onset not Incomplete Complete Davis et al. (1988)release available for a¡ected, a¡ected, absorption absorption Wilding et al. (1991)

some time incomplete complete Sako et al. (1996)absorption absorption

Enteric Drug available Rapid onset Delayed onset Incomplete Complete Gamst (1992)coated only at pH46 absorption absorption Chapron et al. (1994)

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Good membrane permeability is assumed in the situations considered in Table II,wherein the rate at which the drug is presented to the site of absorption is the rate-limiting step in the absorption process.

In general, gastric emptying in£uences the bioavailability of rapidly absorbed drugs,while intestinal transit time a¡ects the absorption of drugs requiring carrier-mediatedtransport for systemic uptake (Leesman et al., 1988).

Age and sex of the animal: To date, the only study reporting any sex-related di¡erencesin the bioavailability in dogs involved four di¡erent oral dosage forms of digoxin(Gastauer et al., 1979). Reportedly, digoxin was eliminated more rapidly from femaledogs. These results may be attributed to the higher digoxin biotransformation capacityof females as compared to males (Gault et al., 1984; Kitani et al., 1985). The studiesperformed by Adusumalli and colleagues (1992, 1993) are some of the few thatevaluated age and sex of the animal as possible factors in£uencing the bioavailabilityof dosage forms. They observed no sex-related di¡erences in the pharmacokineticsfollowing azelastine hydrochloride administration.When comparing age-related di¡er-ences, they observed a higher maximum systemic concentration of the drug (Cmax) anda lower volume of distribution at steady state (Vss) in paediatric dogs (4^6 weeks old),although the bioavailability was not a¡ected. Therefore, the same dosages wererecommended for paediatric as well as adult (1^2 year old) dogs.When evaluating thepharmacokinetics of felbamate, Adusumalli and colleagues (1992) did observe age-related di¡erences in the bioavailability. Five-week-old dogs exhibited much lowerbioavailability than adults, possibly owing to much more rapid overall elimination offelbamate in the younger dogs. The authors attributed these di¡erences to fasterhydroxylation (p-hydroxy and 2-hydroxy metabolites) pathways for felbamate in youngdogs (Adusumalli et al., 1992; Yang et al., 1992). Also, it has been reported that veryyoung animals have a relatively high activity of the hepatic mixed-function oxidasesystem compared to adult animals (Dvorchik, 1981).

In general, since acid secretion is related to the development of the gastric mucosa,neonates may present a less acidic environment compared to adults, thus a¡ectingdissolution and/or absorption in the gastric region. On the other hand, the enzymaticprocesses in elderly dogs may not be identical to those in young or adult dogs. As aresult, the uptake of actively absorbed drugs and clearance rates may be a¡ected.

Breed of animal: Beagles and mongrels are the most widely used breeds of dogs forpharmacokinetic studies, but very few studies have been documented that involvecomparative evaluations of these two breeds. Robinson and colleagues (1986) showedthat thiobarbiturates produced di¡erent sleep patterns in Greyhounds from those inmixed-breed dogs. Signi¢cantly higher drug concentrations were observed in theGreyhounds. These observations could be attributed to decreased tissue distributionor metabolic clearance owing to a di¡erence in plasma protein binding in theGreyhounds (Sams et al., 1985; Baggot and Brown, 1998). Di¡erences in response topropofol in Greyhounds and mixed-breed dogs were demonstrated by Zoran andcolleagues (1993). Signi¢cant di¡erences were noticed in the volumes of distribution inthe two groups. The di¡erences in the basic parameters were attributed to variations in

435

body fat content and in the rate of hepatic metabolism of propofol (Baggot and Brown,1998).

Diet: By several mechanisms, food may reduce, delay or enhance the absorption ofdrugs from the gastrointestinal tract.Williams and colleagues (1993) have listed severaldrugs and the mechanisms by which their absorption may be a¡ected by food. Otheruseful reviews on this subject include those by Welling (1977), Melander (1978) andToothaker andWelling (1988). Ku« ng and colleagues (1995) have illustrated the e¡ect ofthe period between feeding and drug administration on the absorption of oralampicillin in dogs. Generally, the longer times between feeding and drug administra-tion yielded greater AUCs (Watson et al., 1987a). A comparison between dry food andcanned food was also made by Ku« ng and colleagues (1995) when they administeredampicillin 2 h after feeding either dry or canned food. A more pronounced food^druginteraction was observed with dry food than with canned food. Slower gastricemptying of the dry food was suggested as the possible cause. In another instance, thebioavailability of bropirimine in dogs from tablets was 100% more under postprandialconditions than under fasted conditions. The authors, Emori and colleagues (1995),surmised that a longer gastric residence time due to presence of ingesta may have led tobetter dissolution of the drug in the stomach, so yielding better bioavailability.

Besides its e¡ect on absorption, food may also a¡ect the metabolism of drugs andin£uence their bioavailability in this way. For example, a high-protein low-carbohy-drate diet can accelerate the metabolism of several drugs by the liver, while a low-protein high-carbohydrate diet can have the opposite e¡ect (McKellar et al., 1993;Williams et al., 1993). The fat content of the diet or lipid-based formulations, such assoft gelatin capsules and emulsions, may have a varied e¡ect on drug bioavailability,including changes in Cmax, Tmax, AUC, V, etc. The fat content of most commerciallyavailable dog-foods ranges from 6% to 20% (Thorpe-Vargas and Cargill, 1998). Ahigh-fat diet may reduce bioavailability by delaying gastric emptying as shown by Paoand colleagues (1998) in the case of the antiarrhythmic drug bidisomide. It may alsoprovide a barrier to absorption as a result of drug partitioning into the oil phase.Changes in the distribution and elimination processes may occur, since oleaginouselements are likely to circulate through the lymphatics (Charman, 1997).

The presence of fat may increase the solubility of a poorly water-soluble drug such asgriseofulvin and increase its absorption (Khalafalla et al., 1981). In other cases, drugpartitioning into the oil phase may provide protection from stomach acids or e¡ectslower transit through the gastrointestinal tract, so resulting in greater bioavailability(Charman, 1998). As mentioned earlier, the e¡ect of fat on bioavailability is varied; it isgreatly in£uenced by the properties of the drug as well as the formulation.

Circadian rhythm: Diurnal changes in the disposition of various drugs have beenevidenced in dogs. Diurnal changes in the gastric motor activity in conscious dogswere observed by Itoh and colleagues (1977). They also observed that regularity in thepattern was maintained by diet, time of feeding and the health of the animals. Nightlycyclical increases in the volume of distribution of pentazocine were observed byRitschel and colleagues (1980). Theophylline concentration was found to alter in a

436

circadian manner, which was paralleled by changes in the pH of the urine. Computersimulations performed by Rackley and colleagues (1991) indicated a rhythmic patternto theophylline renal clearance and the metabolism of the drug to 3-methylxanthine.

Pharmacokinetic factors

First-pass e¡ect: When the drug is released from an oral dosage form, it traverses thegastrointestinal mucosal barrier and is carried by the splanchnic circulation thatperfuses the gastrointestinal tract into the portal vein. It is then conveyed through theliver to reach the systemic circulation. When a drug is extensively metabolized by theliver prior to its reaching the systemic circulation, the process is called the ¢rst-passe¡ect or presystemic elimination, and has important implications on the bioavailabilityof the drug. Baggot and Brown (1998) noted that, as a result of the generally highercapacity of the liver of herbivorous species, such as horses and ruminant animals, tometabolize lipid-soluble drugs by microsomal metabolic pathways, the ¢rst-pass e¡ectis likely to decrease the systemic availability of rapidly metabolized drugs to a greaterextent in herbivorous than in non-herbivorous species. Yet a large number of drugs areknown to undergo a ¢rst-pass e¡ect in dogs. Besides the liver, the gastrointestinal tractwall is the other major site of presystemic elimination of orally administered drugs.Table III lists drugs relevant to veterinary medicine whose bioavailability is primarilya¡ected by presystemic elimination.

TABLE IIISome drugs that undergo signi¢cant presystemic elimination

Bioavailability DosageDrug (%) form Reference

Nalbuphine hydrochloride 5.6 Solution/capsules Aungst et al. (1985)Dopamine 3.0 Solution Murata et al. (1988)Enro£oxacin 83.5 Tablets Cester and Toutain (1997)Nomifensine 48.3^49.5a Solution Lindberg et al. (1985)Naftopidil 8.6 Solution Peter et al. (1991)Naltrexonehydrochloride 15.8 ^ Li et al. (1996)

Idazoxan 60^88 Capsules Valle© s et al. (1989)Meperidinehydrochloride 11.0 Solution Ritschel et al. (1987)

Mosapride citrate 8.0 Suspension Sakashita et al. (1993)Diazinon 35.5 in rats Emulsion Wu et al. (1996)Lacidipine 32.0 Suspension Pellegatti et al. (1990)Salicylamide 22.0 Solution Waschek et al. (1985)

aCalculated from reported AUC

437

Drug recirculation: The primary mode of drug recirculation is enterohepatic recircula-tion, also termed biliary recycling. It is a phenomenon in which drugs are emptied viathe bile into the small intestine and are then reabsorbed into the systemic circulation,so a¡ecting their bioavailability. Other modes of recirculation include excretion of thedrug in saliva followed by its reabsorption. These phenomena are pharmacokineticcharacteristics of individual drugs and occur irrespective of the formulation or route ofadministration used. There is some evidence that ingestion of food in£uences the extentof recirculation, since the secretion of saliva and that of bile are linked to the intake offood (Polli et al., 1996). Also, it is known that protein and fat increase the £ow of bile.Some of the drugs known to take part in biliary recirculation are digitoxin, rifamycin,stilboestrol, glutethimide, chloramphenicol, indomethacin, morphine, rigomycin andpiroxicam (Ritschel, 1986).

Altered elimination/dose dependence: For a given drug, a dose-dependent change inbioavailability may be observed as a result of factors such as (1) renal insu¤ciency, (2)saturable metabolism, and (3) concentration-dependent serum protein binding.Furthermore, drug interaction and certain disease states are among other factors thatmay cause renal insu¤ciency. A saturable or capacity-limited metabolism is typical ofenzymatic reactions. Greater bioavailability is obtained for doses that exceed thesaturation threshold dose. Conversely, if a drug undergoes carrier-mediated transportfor its movement from the gastrointestinal tract into the systemic circulation, thenreduced bioavailability may result from doses that exceed the saturation thresholddose. Some drugs, such as ce¢xime (Bialer et al., 1987), exhibit concentration-dependent serum protein binding. Decreases in binding increase the fraction of theunbound form of the drug in the plasma. Consequently, both hepatic and renalelimination processes are a¡ected, yielding reduced bioavailability at higher doses ofthe same drug. Bialer and colleagues (1987) reported that, when ce¢xime wasadministered orally at various doses from 6.25 to 200 mg/kg, the bioavailability forthe lower doses (6.25^50 mg/kg) was 55%. However, it decreased to 44% at a dose of100 mg/kg and to 27% at the highest dose. The fraction of unbound drug in the bloodwas reported to increase from 7% to 25%. Multiple dosing regimens must be selectedcarefully for drugs whose bioavailability is a¡ected by a dose-dependent eliminationprocess. Dose titrations may be necessary to maintain the drug concentrations withintheir therapeutic windows.

Drug interaction: Drug interactions may be indirect, by virtue of the action of one drugon the gastrointestinal tract a¡ecting the absorption of another drug, or perhaps ofitself. Interactions may also be direct, wherein two compounds interact physically orchemically and so cause an alteration in their absorption characteristics. Majorindirect interactions that have been reported include altered gastrointestinal motility,caused by such agents as metoclopramide, diamorphine and diphenhydramine, causingaltered absorption of other compounds (Welling, 1988). An increase in the contractileactivity of the gastrointestinal tract caused by macrolide antibiotics, such as erythro-mycin, roxithromycin, clarithromycin and oleandomycin, was noted by Nakayoshi andcolleagues (1992). Erythromycin is known to be a motilin receptor agonist (Peeters et

438

al., 1989). Also, therapeutic agents such as omeprazole, picoprazole and cimetidine areknown to possess gastric antisecretory properties that may alter the bioavailability of aconcurrently administered drug (Larsson et al., 1983). Besides alterations in gastro-intestinal activity, indirect interactions may also occur owing to altered metabolicfunctions. For example, Abramson (1988) showed that phenobarbital signi¢cantlyenhanced the metabolic processing of antipyrine, and so reduced antipyrine's bioavail-ability from 73% to 20%. Some of the major direct interactions are known to occurwith antacid preparations (Remon et al., 1983; Deppermann and Lode, 1993). Forexample, Deppermann and Lode (1993) studied the bioavailability of 4-£uoroquino-lone antimicrobials such as cipro£oxacin, o£oxacin, nor£oxacin and lome£oxacin inthe presence of antacids. They reported a signi¢cant decrease in the bioavailability ofall these drugs when coadministered with aluminium hydroxide-based antacids.Reportedly, the probable mechanism of interaction is chelation between quinolonemolecules and the metallic cations of the antacids (e.g. Al3+ and Mg2+). Whencoadministered with £uoroquinolones, multivitamin products are known to decreasethe drugs' bioavailability owing to direct interaction with ferrous as well as othercations in the multivitamin preparations (Polk et al., 1989). Although an increasingnumber of `New Animal Drug Application' submissions contain some interactionstudies, it is impossible to anticipate the enormous variety of interactions that mayoccur in the clinic.

Pharmacological factors

Disease states and acute-phase response: In mammals, tissue damage, in£ammation orinvasion of pathogenic microorganisms induces systemic changes, collectively knownas the `acute-phase response'. Some of the varied alterations that together produce thisresponse are fever, inhibition of gastric function, lack of appetite, increased lassitude,synthesis of hepatic acute-phase proteins, changes in blood £ow to various organs,tachycardia, activation of lymphocytes, mobilization of phagocytes, decreased ironand zinc levels, and changes in the metabolism of carbohydrates, lipids and proteins(van Miert, 1990). The intensity of these di¡erent reactions may vary depending on thecausative organism or the toxin involved. Therefore, the e¡ect of the acute-phaseresponse on the pharmacokinetic behaviour of a drug is not standardized (Eckersalland Conner, 1988). Many of these factors, in turn, produce changes in the absorptioncharacteristics of therapeutic agents. The intensity of these di¡erent reactions may varydepending upon the type of invading microorganism (Koj, 1996). Meyer and Carlson(1917) were apparently the ¢rst to report on the acute-phase response in dogs. Theyobserved a lack of gastric secretions as well as hunger contractions associated withanorexia in presence of distemper or pneumonia. Although the stomach does notconstitute a primary drug absorption site, as discussed earlier, the rate of gastricemptying and gastric pH may considerably a¡ect the bioavailability of drugs. Thechanges in the plasma protein concentrations during the acute-phase response alsoa¡ect the bioavailability of several protein-bound drugs. A decrease in albumin levelsand an increase in a1-acid glycoprotein (AGP) in response to in£ammatory diseases

439

may increase the free fraction of albumin-bound drugs and decrease the free fraction ofAGP-bound drugs (Perucca, 1980; Belpaire et al., 1987). It has been generally acceptedthat the acute-phase response is bene¢cial in that it aids in the restoration ofhomeostasis, but the mechanism of the initiation of the acute-phase response is stillpoorly understood. Besides a¡ecting the absorption and distribution phases of activecompounds, the acute-phase response may also a¡ect the metabolism and excretion ofdrugs. For example, the activity of cytochrome P450, which plays an important role inthe metabolism of many drugs, may be depressed as a result of the acute-phaseresponse to endotoxins, resulting in reduced biotransformation of many drugs (Ghezziet al., 1986). Besides the acute-phase response, several disease states may alter thepharmacokinetics of many drugs. For example, disorders that a¡ect gastrointestinalactivity include post-surgical e¡ects, non-ulcer dyspepsia, muscular dystrophy, post-viral gastroparesis, intestinal pseudo-obstruction, etc. As with nutrients, such asvitamin B12, calcium and iron, there is regional speci¢city within the small intestinefor absorption of some orally administered drugs, e.g. pafenolol and cipro£oxacin.Any signi¢cant changes to the normal function of the bowel brought about by agastrointestinal disorder produces alterations in the absorption characteristics (Heb-bard et al., 1995). For more insights into this subject, the author recommendscomprehensive reviews by Kushner and Mackiewicz (1993) and by van Miert (1990).

Formulation factors

Types of formulation: The variety of oral dosage forms for use in dogs includessolutions, emulsions, suspensions, gels, pastes, powders, granules, capsules and tablets.Of these dosage forms, solution is most likely to yield a high bioavailability, since thereare no physical processes involved before the drug is available for absorption throughthe biological membranes.With other dosage forms, additional processes are involved,of which dissolution of the drug is common to all. As seen from Figure 2, solid dosageforms, such as tablets, involve more physical processes prior to absorption ascompared to dispersed systems such as emulsions and suspensions. As a result, greaterbioavailability is generally to be expected from dispersed systems than from soliddosage forms (Watson et al., 1987b; Ku« ng and Wanner, 1994).

Excipients: Although dispersed systems generally yield higher bioavailabilities, they arenot as convenient to administer as the solid dosage forms. Therefore, severalformulation approaches are used on the solid dosage forms to improve theirbioavailability, one of which is the selection of excipients. Owing to the size of thistopic, the reader is referred to the extensive articles by Stavchansky and McGinity(1990), Tabibi and Rhodes (1996) and Augsburger (1996) for in-depth discussion of theformulation approach to improving bioavailability. However, one of these approachesinvolves the inclusion of absorption enhancers, which is discussed in the nextsubsection.

440

Absorption enhancers: In order to lower the physical barrier of the structural elementsof the intestinal mucosa towards poorly absorbed drugs, the potential of coadministra-tion of absorption-enhancing agents has been investigated extensively in recent years.Because of the hydrophilic characteristics, ionic charge and high molecular weight ofseveral drug molecules, the absorption-limiting barriers to these drugs are likely to bein the mucous layer, the cell membrane and the intercellular spaces (Van Hoogdalem etal., 1989). Absorption enhancers increase the absorption of drugs by penetrating thelipid-rich region and protein-¢lled environment of the mucous barrier in the gastro-intestinal tract and interacting with them. Many enhancers entering the lipid bilayer ofthe absorption membrane cause disruption of its organization and decrease its £uidity(Muranishi, 1990). The absorption enhancers belong to widely di¡ering chemicalcategories, some of which are listed in Table IV.

Figure 2. Processes controlling the availability of drugs for absorption from di¡erent dosageforms following oral administration

441

The available data indicate that absorption enhancement is frequently associatedwith morphological changes to the intestinal epithelium, indicating the need for a closeinvestigation into the e¡ects of absorption promoters and the mechanisms involved inthe process.

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TABLE IVSome prevalently used absorption enhancers

Category Example References

Surfactants Nonionic: polyoxyethylene ethersAnionic: sodium lauryl sulphate Florence (1981)Cationic: quaternary ammonium

compounds

Bile salts Sodium deoxycholate Fagundes Neto et al. (1981)

Mixed micelles Glyceryl monooleate, sodium Muranishi (1985)taurocholate

Fatty acids Oleic acid Tokumura et al. (1987)

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(Accepted: 28 June 1999)

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