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Pharmacokinetics, bioavailability and dosage regimen ofsulphadimidine in camels (Camelus dromedarius) under

hot, arid environmental conditionsRajiv Kumar, Awadesh Pratap Singh, Ashutosh Kumar Rai

To cite this version:Rajiv Kumar, Awadesh Pratap Singh, Ashutosh Kumar Rai. Pharmacokinetics, bioavailability anddosage regimen of sulphadimidine in camels (Camelus dromedarius) under hot, arid environmentalconditions. Veterinary Research, BioMed Central, 1999, 30 (1), pp.39-47. �hal-00902555�

Original article

Pharmacokinetics, bioavailability and dosage regimenof sulphadimidine in camels (Camelus dromedarius)

under hot, arid environmental conditions

Rajiv Kumar Awadesh Pratap Singh Ashutosh Kumar Raic

a Department of Pharmacology, College of Veterinary and Animal Science,Rajasthan Agricultural University, Bikaner-334001, Rajasthan, Indiah Department of Medicine, College of Veterinary and Animal Science,Rajasthan Agricultural University, Bikaner-334001, Rajasthan, India

‘National Research Centre on Camel, Jodbeer, Bikaner - 334003, Rajasthan, India

(Received 15 May 1998; accepted 29 October 1998)

Abstract-A two-way crossover study was conducted in young Bikaneri camels (aged between 12 2and 18 months) during the hot summer season to determine the bioavailability, pharmacokinetics anddosage regimens of sulphadimidine (SDM). A dose of 100 mg.kg-I of SDM was used to study boththe intravenous and oral pharmacokinetics of the drug. Analysis of the intravenous data according toa two-compartment pharmacokinetic model revealed that SDM was well distributed in the body(Vdt.«e!t: 0.862 L.kg-1), had an overall body clearance of 0.035 ±0.019 L.h-1.kg-1 and the elimina-tion of half-lives was in the range of 14.2 to 20.6 h. The mean maximum plasma SDM concentrationfollowing oral administration was 63.23 ± 2.33 pg.mL-1, which was achieved 24 h after the oraladministration. The mean bioavailability of SDM following oral administration was approximately100 %. To achieve and maintain the therapeutically satisfactory plasma sulphadimidine levels of

> 50 pg.mL-1, the optimum dosage regimen for camels following either intravenous or oral admin-istration would be 1 10 0 ing.kg!’ as the priming dose and 69 nig.kg-I as the maintenance dose, to berepeated at 24 h intervals. © lnra/Elsevier, Paris.

bioavailability / camel / dosage regimen / pharmacokinetics / sulphadimidine

* Correspondence and reprintsTel.: (91 ) 151 527 603

Résumé - Pharmacocinétique, biodisponibilité et posologie de la sulphadimidine chez le chameau(Camelus dromedarius) dans un environnement chaud et aride. Une étude croisée double a été réa-lisée chez des jeunes chameaux Bikaneri (âgés de 12 à 1 8 mois) pendant la saison sèche d’été afin dedéterminer la biodisponibilité, la pharmacocinétique et la posologie de la sulphadimidine (SDM). Unedose de I 00 mg.kg- de SDM a été utilisée pour étudier la pharmacocinétique de la drogue administréepar voie orale ou intraveineuse. L’analyse des données obtenues après injection intraveineuse selonun modèle pharmacocinétique bi-compartimental révèle que la SDM été bien distribuée dans le

corps (V d (area : 0,862 L.kg-1), a eu une clairance corporelle globale de 0,035 ± 0,019 9 L.h!’ .kg!’ etles demi-vies d’élimination étaient réparties entre 14,2 et 20,6 h. La concentration maximale moyennede SDM dans le plasma après administration orale a été 63,23 ± 2,33 !tg.mL-1 ; elle a été atteinte 24 haprès l’administration orale. La biodisponibilité moyenne de la SDM près administration orale a étéapproximativement 100 %. Pour atteindre et maintenir des niveaux thérapeutiques satisfaisants de SDMdans le plasma supérieurs ou égaux à 50 pg.mL-1, la posologie optimale après administration oraleou intraveineuse devrait être pour le chameau 110 mg.kg-1 comme dose initiale et 69 mg.kg-1 comme

dose d’entretien administrée à 24 h d’intervalle. © Inra/Elsevier, Paris.

biodisponibilité / chameau / posologie / pharmacocinétique / sulphadimidine

1. INTRODUCTION

Sulphadimidine is one of the most exten-sively used drugs in veterinary medicine.In India, it is mainly used to treat coccidio-sis and respiratory infections in camels. Thepharmacokinetics and metabolism of sul-phadimidine have been extensively inves-tigated in the following ruminant species;cattle [16, 20, 24, 25], buffaloes [7, 29],sheep [30, 43], goats [35] and camels [14,42]. All these studies indicate that a markedspecies difference exists in the metabolismand pharmacokinetics of sulphadimidine inanimals, suggesting the importance of inves-tigating the pharmacokinetic data in the ani-mal species and environment in which thedrug is clinically used. Furthermore, in viewof the conflicting data available on the kinet-ics disposition of sulphadimidine in camels[14, 42], it was considered expedient todetermine the pharmacokinetics of this drug,under the hot arid environment of the GreatThar desert of India, in order to determine anoptimal dosage regimen for camels.

2. MATERIALS AND METHODS

2.1. Animals

Experiments were conducted on six clinicallyhealthy male camels (Camelus dromedarius) ofthe Bikaneri breed, aged between 12 and 18 8months and weighing 125 to 156 kg, in themonths of May and June when stable temperature

during the day was 43 to 45 °C, at the NationalResearch Centre on Camels, Bikaner, India. Theanimals were maintained on khejri (Prosopiscineraria) and pala (Zizyphus nummularia).Water was provided ad libitum.

2.2. Drug administration

Sodium sulphadimidine (33.3 %) availableas an injectable preparatoin (Indian Drugs andPharmaceuticals Limited, Hyderabad, India) wasadministered in the left jugular vein of animals ata dose rate of 100 mg.kg body weight. For oraladministration, an aqueous solution of sul-phadimidine containing 100 mg of sodium sul-phadimidine per milliliter was prepared from apure crystalline sulphadimidine base by dis-solving it in warm, sterile, distilled water to whicha sufficient amount of 5 N sodium hydroxidewas added to permit its dissolution. The camelswere dosed via a stomach tube with sulphadimi-dine solution at a dose of 100 mg of sodium sul-

phadimidine per kg body weight. The stomachtube was flushed with isotonic saline solutionafter use.

2.3. Collection of samples

Blood samples (5-7 mL) were drawn fromthe right jugular vein into heparinized tubes justbefore (0 h) and at 0.17, 0.34, 0.67, 1, 2, 3, 4, 6,9, 12, 24, 36, 48, 60 and 72 h after intravenousadministration and at 0, 1, 2, 3, 4, 6, 9, 12, 24, 36,48, 60 and 72 h after oral administration of sul-phadimidine sodium. Plasma was separated bycentrifugation (at 1 500 g for 10 min) within20 min of sample collection and stored at -20 °Cuntil analysed.

2.4. Experimental design

Camels were randomly allotted to two groupsof three animals each. Administration of the drugto the animals was made according to a two-waycrossover design with a washout period of 21days between subsequent administrations.

2.5. Drug analysis

Drug analysis was carried out according tothe diazotizing and coupling method [11 I] within3 days of sample collection. The concentration oftotal sulphadimidine (SDM) was measured onthe same samples after acid hydrolysis with0.5 mL of 4N HCI in 10 mL of sample at 100 °Cfor I h. The concentration of 4N-acetylated SDMwas calculated as the difference between the con-centration of SDM before and after acid hydrol-ysis and was expressed as a percentage of thetotal. The minimum detection limit of the assaywas 1.0 pg.mL-1. The standard curve of sul-phadimidine in camel plasma was linear between2.5 and 80 pg.mL-1. The correlation coefficient(r) was greater than 0.98.

2.6. Pharmacokinetic analysis

Pharmacokinetic analysis of sulphadimidineconcentration-time data was performed, usinga computer program for non-linear regressionanalysis, MULTI [41 Data points were weighedaccording to the equation

where W! is the weight, Y¡ is the fitted value ofthe ith observation. After intravenous adminis-

tration, plasma concentration of sulphadimidinefrom individual camels was fitted to the generalpolyexponential equation

where Ct(P) represents plasma sulphadimidineconcentration at time t, Y is the coefficient ofthe ith exponential term and Ài is the exponent ofthe ith exponential term. Initial pharmacokineticvariable estimates were obtained using the linearregression method. The number of exponentsneeded for each data set was determined by

applying Akaike’s information criterion [40].The sulphadimidine plasma concentration ver-sus time points following intravenous adminis-tration were best fitted to a two-compartmentopen model

C/P)¡v = Y I e-À,t + Y 2 e-À21where Ct(P)1! is the plasma concentration at timet, Y! and Y, are zero-time intercepts, k, is thedistribution rate constant and k2 is the eliminationrate constant.

Plasma concentration versus time data afteroral administration were best fitted to a one-com-

partment open model with a first order adsorption,,t,

where Ct(P)oral is the plasma concentration attime t, after oral administration, Yz and Y) are

zero-time intercepts, ka is the absorption rateconstant and k is the elimination rate constant.

The two-compartment pharmacokinetic modelprovided simultaneous estimates of the extrapo-lated zero-time drug concentrations (Y! and Y!),initial concentration as sum of Y. and YZ (Co), ),hybrid rate constants (11,1 and k2), the apparentvolume of distribution [Vd!a!!a)! the total bodyclearance (CLB) and the area under the plasmaconcentration-time curve [AUC J. The firstorder rate constants for the drug elimination fromthe central compartment (Kel)’ and for the drugtransfer from the central compartment to theperipheral compartment and back (K!2 and K21)’ ),and the drug fraction in the central compartment(Fc) were calculated by standard procedures [5].The one-compartment model with a first orderabsorption provided hybrid rate constants (Kaand K), the elimination half-life (tI/2K)’ and thearea under the plasma concentration-time curve

[AUC(O-=¡]’ Peak plasma concentration (Cmax) )and peak time (TmaX) were reported as observedvalues.

Bioavailibility (F) was calculated by the for-mula:

2.7. Dosage regimen

The suitable dosage regimens were calculatedusing standard formulae [6, 8].

2.8. Statistical analysis

Data are presented as mean ± SEM. Forplasma half-lives, harmonic means were calcu-lated and their SEM values were calculated usinga jackknife technique [19]. Values of half-livesand areas under curves between the two experi-ments were compared using analysis of variance(ANOVA). The 0.05 level for probability wasused to judge significant differences [31 !.

3. RESULTS

The mean plasma concentrations of sul-phadimidine determined at different time

intervals following intravenous and oraladministration of 100 mg.kg-1 body weightare shown in figure 1. Pharmacokineticparameters were obtained from each animal

individually and are summarized in table I asmean ± SEM of six animals.

After intravenous administration, initialsulphadimidine concentration was 281.40± 4.91 1 pg,mL!’ measured at 0.17 h. Theconcentration declined rapidly to 100.60 ±2.80 ¡.tg.mL-l after 3 h, after which the drugconcentrations in plasma decreased slowly.At 72 h, mean drug concentration levelswere still above the detection limit (6.50 ±

0.97 pg.mL!’). The minimum therapeuticconcentration, 2 50 pg.mL-1 of drug wasmaintained up to 12 h.

Following oral administration the plasmaconcentration reached its peak value (C.a!,) )(63.23 ± 2.33 pg.mL!-1) at 24 h, and the min-imum therapeutic c concentration

(> 50 !ug.mL-!) of the drug was maintainedup to 24 h. The mean oral bioavailability ofthe drug was 99.7 %. The concentration of

4N-acetylated SDM varied from 2.8 to 3.7 %of the corresponding total sulphadimidineconcentration in the plasma after adminis-tration of the drug by either route. Taking 12 2and 24 h as convenient dosage intervals (!),with minimum therapeutic plasma concen-tration [Clil] at 50 pg.mL-1 and using thevalues o,7k2 and Vd!drea! of table I, thedosage regimens for sulphadimidine werecomputed and are presented in table II.

4. DISCUSSION

In the present investigation the pharma-cokinetics of sulphadimidine in camels isbest described by a two-compartment openmodel as recorded previously for crossbredcalves, cows, buffaloes, sheep, goats anddogs [12, 20-22, 27, 29, 30, 43]. This is incontrast to the one-compartment model [ 14]and three-compartment open model [42]used previously to describe the pharma-cokinetics of this drug in camels. The dif-ference in the choice of pharmacokineticmodels used to describe pharmacokinetics ofsulphadimidine in these studies appears to bedue to the difference in the frequency ofblood sampling in the initial phase of theexperiment and the sensitivity of analyticalmethods employed for the estimation ofplasma drug concentration.

The value ofVd(arca)’ 0.862 ± 0.02 L.kg-Iobtained in the present investigation com-pares well with an earlier reported value of0.73 ± 0.108 L.kg-1 in camels 142]. Thisvalue is, however, much higher than theyreported for sulphadimidine in cows (0.44 ±0.02 L.kg-I [24!); sheep (0.474 ±

0.0 12 L.kg-I [43 0.60:t 0.10 L.kg-1 [30];0.410 ± 0.07 L.kg-1 [12]); goats (0.316 ±0.007 L.kg-I [ 14]) and pigs (0.547 ±0.61 1 L.kg-! [ 13]) indicating that sul-phadimidine is more extensively distributedin fluids and tissues of camels than in cows,

sheep, goats and pigs. On the contrary, muchhigher values of V d area for sulphadimidinehad been reported tor lactating buffaloes,1.23 ± 0.07 L.kg-I [29]. The higher values ofK 12 versus K21 further indicated that the rateof transfer of sulphadimidine from the cen-tral to the peripheral compartment was fasterthan its transfer in the opposite direction.Moreover, only 31 % of the drug was avail-able for elimination in the central compart-ment (Fc; 0.31 ± 0.01) following its intra-venous administration to camels.

The elimination half-life of sulphadimi-dine in camels as established in the presentstudy ( 16.96 ± 0.98 h) or reported previ-ously, 13.2 ± 4. h [42], 8.7 to 16.5 h [ 171compares well with the half-life of this drugdescribed in monogastric animals, namelypigs, 16.0 h [341, 15.17 to 18.74 h [13] anddogs, 16.2 ± 5.7 h [27]. Much shorter half-

lives of sulphadimidine have, however, beenreported for other ruminant species such ascows, 11.3 h [24], young buffaloes, 9.4 h[3], sheep, 4.72 ± 0.26 h [ 14] and goats,4.00 ± 0.24 h [22], 2.77 ± 0.22 h [ 14]. Largevariations in the half-life of sulphadimidinein camels may, in part, be attributed to dif-ferences in the age, sex, breed of camelsand the environmental conditions in whichthese studies were conducted. The presentinvestigation was conducted in young malecamels (12-18 months of age) of theBikaneri breed as opposed to earlier stud-ies where old males of 3-5 years of age [ 14]and old females of 4-5 years of age [42] ofdifferent breeds were used. Furthermore,the present investigation was conducted dur-ing summer when the environmental tem-perature was very high and daytime tem-perature ranged between 43 and 45 °C. It iswell known in other species that sul-phadimidine clearance is urine flow depen-dent [25, 42]. Renal function is greatlyreduced in camels during the summer [38].In the heat of the summer, the glomerularfiltration rate, plasma flow rate and urineflow rate in camels is reduced by 75 % (from0.81 mL.min !.kg ! to 0.23 mL.min-l.kg-1), ),72 % (from 5.5 mL.min-l.kg-’ to

1.5 mL.min-l.kg-1) and over 50 % (from3.3 mL.mip to 0.7 mL.min-1), respectively[39]. The increased levels of aldosteroneand antidiuretic hormone (ADH) in the sum-mer account for the increased retention ofsalt and water in the body of the camel [28]. ] .Furthermore, the glomerular filtration rate(GFR) in the camel is 0.6 mL.kg-1.min-1[37], which is much smaller than reportedfor cattle, sheep and goats [5, 9, 26]. Thenephron in camels is twice as long as thatin cows or goats [1]. As a result, most ofthe water filtered through the glomerulus is sreabsorbed in the kidney via long loops ofHenle leading to significantly reduced urineflow; the urine flow in normal circumstancesbeing only 3.3 mL.kg-l.day-l [38] as com-pared to 10-40 mL.kg !.day ! in sheep andgoats and 17-45 mL.kg !.day-I in cattle[33]. This may lead to extensive reabsorp-

tion of sulphadimidine from renal tubularfluid into the systemic circulation. Apartfrom urine, sulphonamides are also excretedin large amounts into ruminal juice via sali-vary secretion [3]. Since the nature of camelsaliva is highly alkaline, pH 8.06-8.32 [10] ]and that large volume of parotid saliva(30 L.day-1) is continuously secreted [15], aconsiderably large amount of sulphadimi-dine (pKa 7.3) is likely to be excreted intoruminal fluid via this route. Ruminal epithe-lium is bi-directionally permeable to sev-eral drugs including sulphonamides [4]. Thetransport of drugs across the ruminal epithe-lium is affected by a concentration gradi-ent, plasma protein binding, anatomical dif-ferences [18] and lipid solubility [23]. Oncethe non-ionized fraction of sulphadimidinehad diffused into the rumen, it may be

trapped at a pH lower than that of plasma[5]. This drug may be reabsorbed, however,later as it is passed down the gastrointestinaltract. The inherent water recirculation mech-anism in camels [38] may increase recy-cling of sulphadimidine in the system thusaffecting its rate and mode of excretion fromthe body. Species variations with regard torate and the pattern of metabolism areknown to influence the pharmacokineticbehaviour of sulphonamides in animals [23,36]. The dependence of the half-lives of thedrug on the rate of metabolism was also sup-ported in the present study by the presenceof relatively small amounts of 4N-acetylSDM (2.8-3.7 %) in camels versus thatrecorded for cows ( 15 %), sheep (6-11 %),goats (8 %) and pigs (25 %) [36 The activ-ities of some drug metabolizing enzymessuch as mixed-function mono-oxygenasesand conjugating enzymes are lower incamels than in sheep and goats [2].

Following P.O. administration, the peakplasma concentration of drug (CmaX) wasmuch lower in camels (table ! than reportedfor sheep administered sulphadimidine atthe same dose level, 160 ± 43 ¡.tg.mL-l [12].The time to reach peak concentration (T ) )in camels (24 h) was, however, much longerthan reported for sheep (5.7 ± 1.8 h). But

when the same sheep were given calfspano,a sustained-release preparation of sul-phadimidine, orally at a dose of 39 mg.kg !,the T max was achieved after a much longertime (14.8 ± 12.9 h). The mean bioavail-abilities of the oral sulphadimidine solutionand calfspano preparation in sheep wererecorded to be 58.3 and 52.5 %, respectively[ 12] as compared to 99.70 ± 4.10 %recorded for camels in this study. The longabsorption half-life, ti/2Ka; 11.73 ± 0.34 h,coupled with high oral bioavailability of99.70 ± 4.1 % (88.20-116 %) indicated thatsulphadimidine is slowly but completelyabsorbed after oral administration in camels.Based on the bioavailability and resultingplasma concentrations, it was concluded thatthe oral route is an efficient means of sul-

phadimidine administration in camels.Since the activities of the drug metabo-

lizing enzymes and water turnover rate incamels is low it may affect the pharma-cokinetics of other drugs as well, especiallythose drugs which are excreted primarilythrough the kidney, with a danger of intox-ication. To prevent, sulphadimidine accu-mulation in the body, a dosage interval of24 h is advisable. To achieve and maintainthe therapeutically satisfactory plasma sul-phadimidine levels of > 50 [tg.mL-1 [32],the optimum dosage regimens for camelsfollowing either intravenous or oral admin-istration would be 1 10 0 mg.kg! ’ as the prim-ing dose and 69 mg.kg-I as the maintenance

dose, to be repeated at 24 h intervals.Though the method of drug analysis usedin the present investigation is less sensitivethan the HPLC method used by some otherinvestigators [14, 42], the calculated dosageregimen of SDM for camels remainedunchanged as they are based on rather highMIC values (> 50 pg.mL-!). ).

ACKNOWLEDGEMENT

The senior author is extremely thankful to DrN.D. Khanna, Project Director, NationalResearch Centre on Camel (NRCC), Jodbeer,Bikaner for providing necessary research )’aci)i-

ties to carry out this investigation at his farm.The help given by Indian Drugs and Pharma-ceuticals Ltd. (IDPL), Hyderabad, India, in theform of a free gift of pure sulphadimidine pow-der is also fully acknowledged.

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