ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 1994, p. 1129-1133 Vol. 38, No. 50066-4804/94/$04.00+0Copyright (© 1994, American Society for Microbiology

Effect of an Antacid Containing Magnesium and Aluminum onAbsorption, Metabolism, and Mechanism of Renal

Elimination of Pefloxacin in HumanstULRICH JAEHDE,"2 FRITZ SORGEL,l.3* ULRICH STEPHAN,3 AND WALTER SCHUNACK2

Institute for Biomedical and Pharmaceutical Research, 90562 Niimberg-Heroldsberg,' Department of Pediatrics,University of Essen, Essen, and Institute of Pharnacy, Free University of Berlin, Berlin,2 Germany

Received 19 March 1993/Returned for modification 10 July 1993/Accepted 9 March 1994

The effects of an antacid containing magnesium and aluminum hydroxide on the pharmacokinetics ofpefloxacin in 10 healthy volunteers were investigated. In a randomized crossover design, each subject receivedan oral dose of 400 mg of pefloxacin either with or without multiple doses of the antacid. The concentrationsof pefloxacin and its metabolites in plasma and urine were determined by high-performance liquidchromatography assays. We found that coadministration of magnesium and aluminum hydroxide caused adecrease of levels of pefloxacin in plasma and urine. The area under the plasma concentration-time curvedecreased significantly (P < 0.001), suggesting impaired absorption of pefloxacin from the gastrointestinaltract. The relative bioavailability of pefloxacin after the antacid treatment was 44.4% ± 23.8%, compared withthat after a single administration. The underlying mechanism of this drug interaction is the formation ofchelate complexes and probably also physical adsorption to the aluminum hydroxide gel. The metabolism ofpefloxacin was not altered by the antacid treatment. Renal clearance was found to depend on urinary pH.Terminal half-life was significantly shorter after the antacid treatment, probably because of an increase innonrenal clearance. In conclusion, pefloxacin should be given at least 2 h before the antacid to ensure sufficienttherapeutic efficacy of the quinolone.

Under clinical conditions, antacids may be administeredtogether with the new quinolone antibacterial agents. Antacidsare known to alter both absorption of drugs from the gastro-intestinal tract and renal elimination (12). A decrease in therate and extent of absorption of orally administered drugs by aconcomitant antacid treatment may reduce drug activity con-siderably. Alteration of urinary pH may lead to changes inrenal excretion of acidic and basic drugs.

In this investigation, the influence of an antacid containingmagnesium and aluminum hydroxide on the pharmacokineticsand bioavailability of pefloxacin was evaluated. Pefloxacin is anewer quinolone carboxylic acid derivative with a broad spec-trum of activity (3). A decrease in the bioavailability of severalquinolones after concomitant intake of magnesium-aluminumhydroxide has recently been described elsewhere (5, 9, 13, 18,19) and reviewed (4, 24). However, the extent of this interac-tion among individual quinolones, was quite different, whichmakes a prediction of the extent of the effect of the antacid onnew derivatives difficult. Therefore, antacid-quinolone interac-tion studies are required for each newly developed quinolone.Pefloxacin differs from other quinolones in its extensive me-tabolism and in its considerable reabsorption in the kidneytubules (14). For that reason, an interaction with antacids atthe hepatic and renal sites was also assessed in this study.

* Corresponding author. Mailing address: Institute for Biomedicaland Pharmaceutical Research, Schleifweg 3, 90562 Nurnberg-Herolds-berg, Germany. Phone: 49-9 11-5 18 29-0 (office); 49-9 11-5 18 85 37(home). Fax: 49-9 11-5 18 28-20.

t This work is dedicated to Marika Geldmacher von Mallinckrodt,Professor Emeritus and formerly head of the Division of ForensicToxicology of the University of Erlangen-Nurnberg, Germany, on theoccasion of her 70th birthday.

MATERIALS AND METHODS

Volunteers. Five female and five male subjects aged from 19to 30 years (mean age, 24.9 years), with a mean weight of 71.4± 9.0 kg, participated in this study after informed consent hadbeen obtained. All subjects were determined to be in goodhealth prior to the study on the basis of physical examinations,medical histories, and laboratory tests. Hematological andbiochemical tests were repeated after the study. No othermedication and no ingestion of alcohol were permitted.

Study design. After an overnight fasting period of 8 h, thesubjects received an oral dose of 400 mg of pefloxacin oncewith and once without coadministration with a suspension ofmagnesium and aluminum hydroxide (Maalox 70; ArzneiMuller-Rorer GmbH, Bielefeld, Germany). The study was

performed in a randomized crossover fashion separated by awashout period of at least 1 week. Each dose of the antacidcontained 600 mg of magnesium hydroxide and 900 mg ofaluminum hydroxide gel. The antacid treatment started the daybefore pefloxacin administration. One bag of antacid suspen-sion was given every 2 h, starting at 8 a.m. The last dose was

given at 10 p.m. On the day of pefloxacin administration,subjects received five additional bags 2.5 and 1 h before and 1,3, and 5 h following oral administration of the quinolone. Thesubjects remained in the fasting state for 6 h after drug intake.Sample collection. Blood was taken from an indwelling

intravenous cannula immediately before and 0.25, 0.5, 0.75, 1,1.5, 2, 2.5, 3, 3.5,4, 5, 6, 8, 10, 12, 24, 30, 36, and 48 h after drugadministration. The samples were heparinized, centrifuged,and frozen immediately at - 30°C. Urine was collected beforedosing and from 0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 30, 30 to36, and 36 to 48 h after intake of pefloxacin. Urine sampleswere frozen at - 30°C as soon as each volume and pH valuehad been determined.Drug analysis. Plasma samples were analyzed for unchanged

pefloxacin and urine samples were analyzed for pefloxacin and

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its main metabolites, pefloxacin N-oxide and norfloxacin,by reversed-phase high-performance liquid chromatography(HPLC) assays (15).For determination of the level of pefloxacin in plasma, the

mobile phase consisted of 50% methanol and 50% 0.1 Mphosphate buffer adjusted to pH 4.9. A Nucleosil C18 5-,umreversed-phase column heated to 40°C (Bischoff GmbH, Le-onberg, Germany) was used as the stationary phase. Plasmasamples were deproteinized by the addition of acetonitrile(1:2), and the supernatant was injected into the mobile phaseat a flow rate of 1.2 ml/min.For determination of the levels of pefloxacin and its metab-

olites in urine, the mobile phase consisted of 24.1% methanol,2.6% acetonitrile, and 73.3% 0.1 M phosphate buffer adjustedto pH 5.75. A C18 ,uBondapak reversed-phase column (WatersAssociation, Eschborn, Germany) was used for this assay.Urine samples were diluted with bidistilled water and wereinjected into the mobile phase at a flow rate of 1.0 ml/min.The fluorescence of the mobile phase was monitored by a

Perkin Elmer 650-10 LC Fluorescence Spectrometer (Perkin-Elmer, Uberlingen, Germany) to detect pefloxacin, pefloxacinN-oxide, and norfloxacin. The excitation wavelength was 275nm, and the emission wavelength was 415 nm.The calibration graphs were linear between 0.078 and 10

,ug/mI for pefloxacin in plasma, 0.78 and 100 ,ug/ml forpefloxacin in urine and between 3.13 and 200 ,ug/ml for themetabolites in urine, with coefficients of correlation of greaterthan 0.999. The lower limit of quantitation in plasma or urinewas the lowest level of the calibration curve.The within-day precision (coefficient of variation) was found

to be 3.2% for 2.5 ,ug of pefloxacin per ml in plasma, 6.9% for0.63 jig of pefloxacin per ml in plasma, 3.1% for 100 jig ofpefloxacin per ml in urine, and 5.1% for 12.5 jig of pefloxacinper ml in urine. The between-day precision was 2.7% for 3.8 ,ugof pefloxacin per ml in plasma, 3.4% for 1.5 ,ug of pefloxacinper ml in plasma, 3.8% for 40.2 jig of pefloxacin per ml inurine, and 7.3% for 8.3 jig of pefloxacin per ml in urine.

Pharmacokinetic calculations. The area under the plasmaconcentration-time curve (AUC) was estimated by the trape-zoidal rule and extrapolated to infinity. The extrapolation wasperformed by dividing the last measurable plasma concentra-tion by the terminal elimination rate constant (3). I wasestimated by modeling the plasma concentration to an expo-nential function with a negative exponent by an extendedleast-squares optimization procedure (23a). Terminal half-life(t012) was calculated according to the formula tl2 = in 2/r3. Themaximum concentration in plasma (Cmax) and the time to peakconcentration in plasma (Tmax) were taken directly from theplasma level curve. The relative bioavailability of pefloxacinafter coadministration with Maalox 70 was calculated bydividing the AUC after combined administration by the AUCafter single administration.

Recovery from urine was calculated as a percentage of thedose. Renal clearance (CLR) was determined by dividing thecumulative renal excretion of pefloxacin until the last measur-able concentration in plasma by the corresponding plasmaAUC. In addition, CLRs from individual urine collections werealso calculated by dividing the amounts of pefloxacin in theurine samples by the respective AUCs during the collectioninterval. Only the 4- and 6-h collection periods were used, sincefor longer collection periods in vitro changes of the pH of urinewhich would have lead to a bias of the results were to beexpected. The metabolic ratio (MR) of pefloxacin was calcu-lated by dividing the amount excreted in urine as metabolite bythe amount excreted as unchanged pefloxacin.

Statistical analysis. Student's paired t test was performed to

5,

4

.g 3~

2-

00 10 20 30 40 50

Time (h)

FIG. 1. Mean concentrations of pefloxacin in plasma with (0) andwithout (0) coadministration of magnesium-aluminum hydroxide (n= 10).

describe significant differences in pharmacokinetic parametersand urinary pH after single and combined administrations withMaalox 70. The significance level was set to P < 0.05.The relationship between urine pH and CLR of pefloxacin

(calculated for each urine collection interval for each volun-teer) was investigated by linear regression (procedure GLM[22a]). To increase the power of the statistical analysis, thedata were grouped according to the ranges of urine pHs: 5.0 to5.6, 5.61 to 5.8, 5.81 to 6.0, 6.01 to 6.4, 6.41 to 6.8, 6.81 to 7.2,and 7.21 to 7.8. Each group contained between 13 and 17observations. An analysis of covariance (procedure GLM[22a]) was performed with the group as the class variable andthe urine pH as the continuous variable. Finally, the differentpH groups were compared by Duncan's multiple range test(procedure GLM [22a]).

RESULTSMean concentrations of pefloxacin in plasma after single and

combined administrations with the antacid are plotted in Fig.1. Coadministration with magnesium and aluminum hydroxidereduced the levels of pefloxacin in plasma considerably at anytime of the observation period. The mean pharmacokineticparameters as well as the results of the statistical analysis aresummarized in Table 1. Cmaxs were significantly decreased andTmaxs were prolonged following the antacid treatment, but thedifferences in TmaxS were not significant and were considerablyaffected by an extremely high Tm. value of 6 h for one subject.t1,2S were significantly shorter when pefloxacin was giventogether with the antacid.The AUC of pefloxacin decreased significantly after com-

bined administration. Calculation of the relative bioavailabilityof pefloxacin following concomitant antacid treatment yieldeda mean value of 44.4% ± 23.8% compared with that ofpefloxacin alone. The individual relative bioavailability valuesranged from 21.3 to 99.3% (Table 2). In one subject (no. 10),we did not observe a decrease in AUC following combinedtreatment of pefloxacin and the antacid. The extent of theinteraction was also apparent from urine data. Renal excretionvalues of pefloxacin and its metabolites as percentages of theadministered dose are presented in Table 3. The antaciddiminished the cumulative renal excretion (0 to 48 h) ofpefloxacin, pefloxacin N-oxide, and norfloxacin to 46.8% +18.5%, 46.4% ± 18.6%, and 45.5% ± 17.2%, respectively,

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TABLE 1. Mean pharmacokinetic parameters of pefloxacin withand without coadministration of magnesium-aluminum hydroxide

Result ofPefioxacun Pefloxacin statistical analysis

Parametercwithot with antacida (paired t testP value)

Cm. (p.g/ml) 5.1 ± 1.0 2.0 ± 0.9 <0.001Tm. (h) 1.05 ± 0.67 1.95 ± 1.64 NSAUC (jug * h/ml) 56.5 ± 13.9 25.8 ± 17.5 <0.001t12 (h) 10.6 ± 3.0 9.6 ± 3.0 <0.05CLR (mlmin) 11.9 ± 2.4 13.4 ± 3.6 NSbMR of pefloxacin 2.10 ± 0.64 2.13 ± 0.78 NS

N-oxideMR of 1.69 ± 0.50 1.62 ± 0.53 NS

norfloxacina Values are means ± standard deviations.b NS, not significant.

compared with a single administration of pefloxacin. Thisresult confirms the relative bioavailability of 44.4% that wasobtained from plasma data.The metabolism of pefloxacin was evaluated by calculation

of the MR. We found no effect of magnesium and aluminumon MRs, suggesting no alteration in the conversion of pefloxa-cin to pefloxacin N-oxide and norfloxacin.The CLR calculated from cumulative renal excretion divided

by the corresponding AUC of pefloxacin was slightly increasedafter the antacid treatment, but the difference was not statis-tically significant. During the first 12 h after pefloxacin admin-istration, the urinary pH in all subjects was elevated. Meanurinary pH values were 6.11 ± 0.54 without and 7.18 ± 0.32with the antacid. The difference was statistically significant (P< 0.001). To evaluate whether the tendency for a higher CLRafter coadministration of the antacid is caused by an elevationof urinary pH, we calculated CLRs for the individual urinesamples and compared the mean CLRs for seven different pHranges. In Fig. 2, mean CLRs are plotted versus mean urinarypHs for each group. CLR exhibits a minimum at neutral pHand increases with acidification and alkalinization of the urine.The findings presented intuitively in Fig. 2 were confirmed

by statistical analysis. A linear regression analysis pooling allobservations of all urine collection intervals in all patientsdemonstrated that there is no simple linear relationship (r2 =0.005314 [P = 0.4429]). An analysis of covariance whichcorrelated urine pH with CLR of pefloxacin within the defined

TABLE 3. Mean renal excretion of pefloxacin and its metabolitespefloxacin N-oxide and norfloxacin with and without

coadministration of magnesium-aluminum hydroxide (n = 10)

Renal excretion (% of dose)' Results of

Compound Pefioxacin Pefioxacin statistical analysisCompoundPefloxacin Pefloxacin (paired t testwithout antacid with antacid P result)

Pefloxacin (unchanged) 9.4 ± 2.2 4.4 ± 2.0 <0.001Pefloxacin N-oxide 17.9 ± 2.7 8.2 ± 3.1 <0.001Norfloxacin 15.9 ± 3.0 7.0 ± 2.5 <0.001

a Values are means ± standard deviations.

groups of pH ranges reached only borderline significance (P =0.0578). However, when the groups of pH ranges were com-pared with Duncan's multiple range test at a significance level(P) of 0.05, it was clearly shown that the group with the lowestpH range (5.0 to 5.6) was no different from the group with thehighest pH range (7.21 to 7.8); however, both groups weresignificantly (P < 0.05) different from the two groups whichform the trough in Fig. 2, i.e., which range from 6.41 to 6.8 andfrom 6.81 to 7.2. Thus, the inverse-bell shape of the curve inFig. 2 was confirmed statistically.

DISCUSSIONThe results of this study show that the bioavailability of

pefloxacin is reduced to about 45% after coadministration ofmagnesium and aluminum hydroxide, suggesting that theabsorption process of pefloxacin is impaired by the antacid.For that reason, it is possible that the effective concentration ofpefloxacin at the site of action is not reached, particularly ininfections with less susceptible bacteria. Even though thisinteraction exhibits a wide interindividual variation, it has aclearly different extent than those previously reported for otherquinolones. Ciprofloxacin (9.5%), ofloxacin (30.8%), andtemafloxacin (39.8%) were more affected and fleroxacin(69.8%) was less affected by magnesium and aluminum hydrox-ide than pefloxacin (9, 13, 24, 27). Since our experimentaldesign was almost identical to that used in these studies, thiscomparison of data may be valid. An intraindividual compar-ison of the interaction of quinolones with a single dose of 1 gof aluminum hydroxide also resulted in large differencesamong individual compounds; the relative bioavailabilities fornorfloxacin, enoxacin, and ofloxacin were 2.7, 15.4, and 52.1%,respectively (23).

TABLE 2. Individual relative bioavailability of pefloxacin followinga concomitant treatment with magnesium-aluminum hydroxide

AUC (,ug * h/ml) RelativeSubject Pefloxacin Pefloxacin with bioavailability

without antacid antacid (%)

1 66.49 14.13 21.252 81.61 22.91 28.073 44.18 25.09 56.794 58.27 31.12 53.415 44.21 14.21 32.146 43.71 10.61 24.277 37.97 10.03 26.428 60.91 27.94 45.879 57.67 32.65 56.6210 70.10 69.60 99.29

Mean ± SD 56.51 ± 13.94 25.83 ± 17.50 44.41 ± 23.76

-

5 6 7Urinary pH

FIG. 2. Effect of urinary pH on CLR of pefloxacin (means ±standard errors).

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One mechanism of this gastrointestinal interaction may bethe formation of chelate complexes. The most likely site in thequinolone molecule for chelate formation has been proposedto be between the 3-carboxyl and the 4-oxo group (16, 21). Thephysicochemical properties of drug complexes may be quitedifferent from those of the drug itself, leading to an alterationand in most cases to a reduction in the rate and extent ofabsorption (8). There is much evidence that free aluminumions contribute to the interaction indicated by a comparison ofthe effects of the same amounts of aluminum hydroxide andaluminum chloride on the absorption of ofloxacin in rats (26).Whereas the relative bioavailability of ofloxacin was 80%following coadministration of aluminum hydroxide, it wasreduced to 31.2% when the drug was given with aluminumchloride, which releases more free aluminum ions than alumi-num hydroxide. The determination of complex stability con-stants indicated that aluminum ions form stable chelate com-plexes with quinolones, whereas the magnesium-quinolonecomplex is less stable (26). Moreover, the importance ofaluminum ions for this interaction has been shown in healthyvolunteers by coadministration of sucralfate, which contains 16aluminum ions per molecule. The bioavailabilities of severalquinolones were found to be considerably reduced whensucralfate was given concomitantly (7, 20).The physicochemical properties of the complex between

aluminum ions and nalidixic acid, which has the same struc-tural features in the 3 and 4 position of the nucleus, have beencharacterized by Nakano et al. (16). The nalidixic acid-to-aluminum ion ratio of the complex was found to be 3 to 1,which means a threefold increase in molecular size. Further-more, the complex was found to exhibit a higher solubility inwater and a lower lipophilicity and reduced permeabilitythrough a cellulose membrane than nalidixic acid itself (16).On the basis of these results, it is suggested that the

formation of aluminum-quinolone complexes is responsible forthe absorption inhibition. Since the stability constants of thosecomplexes are rather similar among individual quinolones(26), the differences in the extents of interaction remainunexplained.The second possible mechanism is the physical adsorption of

the quinolones to the aluminum hydroxide gel. We are notaware of any study of gel binding of quinolones. It is imagin-able that hydrophilic molecules have a higher affinity to thehydrophilic aluminum hydroxide gel than lipophilic com-pounds. The octanol-water partition coefficients of quinolonesindicate considerable differences in their lipophilicity (13a). Itis evident that the more-lipophilic gyrase inhibitors fleroxacin,ofloxacin, and pefloxacin are less affected by antacids than thehydrophilic derivatives ciprofloxacin, enoxacin, and norfloxa-cin. For these reasons, it is very likely that physical adsorptionas well as complexation contribute to the gastrointestinalinteraction between quinolones and antacids.

Physical adsorption may also be responsible for the shorterterminal t112 of pefloxacin after the antacid treatment. Re-cently, we reported that coadministration of charcoal signifi-cantly increases nonrenal elimination of intravenously admin-istered quinolones (14a, 25). This suggests that quinolonesundergo secretion from blood to the gastrointestinal lumenand subsequent reabsorption. In our study, pefloxacin is ex-posed to a comparable situation. The presence of an adsorp-tive agent in the gastrointestinal tract impairs reabsorption,increasing nonrenal clearance and decreasing terminal tl2.Similar findings were recently reported by Grasela et al. (10)and Nix et al. (17).With regard to the physicochemical interaction mechanisms

described above, it is surprising that absorption in one subject

is not affected by magnesium-aluminum hydroxide. At present,we have no explanation for this nonresponse. It is imaginablethat this subject emptied the antacid from the gastrointestinaltract much faster than other subjects.

In other studies, the time interval between the intake of thequinolone and the antacid and the order of intake were shownto be of great significance for the extent of the quinolone-antacid interaction. Whereas when given 5 to 10 min after themagnesium-aluminum hydroxide treatment, the relative bio-availability of ciprofloxacin was 15.2%, it was found to increasewhen the time interval between the treatments was prolonged,reaching values of 23.2% 2 h and 70% 4 h later (18). However,when the order of intake was changed and ciprofloxacin wasgiven 2 h before the antacid, no absorption impairment wasobserved (18). Similar results were reported for ofloxacin (5).

Recently, the effect of other divalent cations on the absorp-tion of quinolones has been investigated as well. In an intra-individual comparison, Nix et al. (19) found that calciumcarbonate affected the bioavailability of norfloxacin (37.5%);however, the extent of the interaction was less than that aftermagnesium-aluminum hydroxide treatment (9.0%). However,calcium had no effect on the pharmacokinetics of ofloxacin (5)or of ciprofloxacin when given together with a high-fat break-fast (6). Moreover, the absorption has been shown to beimpaired by ferrous sulfate, ferrous fumarate, and multivita-mins with zinc (2, 22). These findings suggest that quinolonescan potentially interact with all di- and trivalent cations.

After an intravenous treatment with aluminum over 3 weeks,specific alterations in the microsomal function of rats wereobserved (1). However, with our 2-day treatment of magne-sium and aluminum hydroxide, we did not observe any alter-ation in the metabolic pattern of pefloxacin. The reduced renalexcretion of the metabolites can be attributed to the lowerbioavailability of the parent compound, since the MRs werenot affected.The CLR of pefloxacin was found to depend on the urinary

pH, reflecting the betaine structure of the pefloxacin molecule.The relatively low CLR of pefloxacin suggests an extensivereabsorption of pefloxacin in the kidney tubules. At neutralpH, the zwitterionic pefloxacin molecule exhibits a maximumof lipophilicity (11, 24), which favors reabsorption and mini-mizes CLR. Under acidic and alkaline pH conditions, pefloxa-cin is positively or negatively charged, leading to a reduction ofreabsorption and an increase of CLR. In view of the nonlinearpH dependence of CLR of pefloxacin, one may conclude thatan elevation of pH can lead either to a decrease or to anincrease of CLR, depending on the absolute pH value reachedafter the antacid treatment. In a recent study with temafloxa-cin, a quinolone with a higher contribution of tubular secretionto CLR, we found no effect of urinary pH. However, CLR wasshown to increase with decreasing plasma concentrations andincreasing urinary flow rates (9).

In conclusion, pefloxacin and antacids containing magne-sium-aluminum hydroxide should not be administered con-comitantly. In severely ill patients who need both treatments,the interaction at the gastrointestinal site can be avoided if theantacid is given at least 2 h after the quinolone, when aconsiderable part of the administered dose is already absorbed.The urinary pH dependence of the CLR of pefloxacin is of noclinical significance with regard to the low contribution of renalexcretion to the overall elimination of pefloxacin. However,the pH dependence of the CLR of pefloxacin gives an insightinto the mechanism of its renal excretion that has not beenpreviously described.

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ACKNOWLEDGMENTS

This investigation was supported in part by a grant from Rhone-Poulenc Rorer, Antony, France.We thank Karin Backer and Christine Kraus for excellent technical

assistance. We express our gratitude to Martina Hofmann for excellentsecretarial help in the preparation of the manuscript.

REFERENCES1. Bidlack, W. R., R. C. Brown, M. S. Meskin, T. C. Lee, and G. L.

Klein. 1987. Effect of aluminum on the hepatic mixed functionoxidase and drug metabolism. Drug-Nutr. Interact. 5:33-42.

2. Brouwers, J. R. B. J., H. J. Van der Kam, J. Sijtsma, and J. H.Proost. 1990. Decreased ciprofloxacin absorption with concomi-tant administration of ferrous fumarate. Pharm. Weekblad Sci.12:182-183.

3. Clarke, A. M., S. J. V. Zemcov, and M. E. Cambell. 1985. In-vitroactivity of pefloxacin compared to enoxacin, norfloxacin, gentami-cin and new 3-lactams. J. Antimicrob. Chemother. 15:39-44.

4. Davies, B. I., and F. P. V. Maesen. 1989. Drug interactions withquinolones. Rev. Infect. Dis. 11(Suppl. 5):S1083-S1090.

5. Flor, S., D. R. P. Guay, J. A. Opsahl, K. Tack, and G. R. Matzke.1990. Effects of magnesium-aluminum hydroxide and calciumcarbonate antacids on bioavailability of ofloxacin. Antimicrob.Agents Chemother. 34:2436-2438.

6. Frost, R. W., J. D. Carlson, A. J. Dietz, A. Heyd, and J. T. Lettieri.1989. Ciprofloxacin pharmacokinetics after a standard or high-fat/high-calcium breakfast. J. Clin. Pharmacol. 29:953-955.

7. Garrelts, J. C., P. J. Godley, J. D. Peterie, E. H. Gerlach, and C. C.Yakshe. 1990. Sucralfate significantly reduces ciprofloxacin con-centrations in serum. Antimicrob. Agents Chemother. 34:931-933.

8. Gibaldi, M. 1984. Biopharmaceutics and clinical pharmacokinet-ics, 3rd ed., p. 59-60. Lea & Febiger, Philadelphia.

9. Granneman, G. R., U. Stephan, B. Birner, F. Sorgel, and D.Mukherjee. 1992. Effect of antacid medication on the pharmaco-kinetics of temafloxacin. Clin. Pharmacokinet. 22(Suppl. 1):83-89.

10. Grasela, T. H., J. J. Schentag, A. J. Sedman, J. H. Wilton, D. J.Thomas, R. W. Schultz, M. E. Lebsack, and A. W. Kinkel. 1989.Inhibition of enoxacin absorption by antacids or ranitidine. Anti-microb. Agents Chemother. 33:615-617.

11. Gruber, G., U. Jaehde, F. Sorgel, R. Hei B, and W. Schunack. 1988.Relationships between the chemical structure and the HPLCcapacity factor of gyrase inhibitors and their metabolites indifferent methanol-water eluents. Fresenius Z. Anal. Chem. 330:388-389.

12. Gugler, R., and H. Allgayer. 1990. Effects of antacids on theclinical pharmacokinetics of drugs. An update. Clin. Pharmacoki-net. 18:210-219.

13. HoSfken, G., H. Lode, R. Wiley, T. D. Glatzel, D. Sievers, T.Olschewski, K. Borner, and P. Koeppe. 1988. Pharmacokineticsand bioavailability of ciprofloxacin and ofloxacin: effect of foodand antacid intake. Rev. Infect. Dis. 10:S138-S139.

13a.Jaehde, U. 1989. Ph.D. thesis. Free University of Berlin, Berlin,Germany.

14. Jaehde, U., J. Zurcher, F. Sorgel, K. G. Naber, G. Sigl, P. Muth,and W. Schunack. 1989. Comparative bioavailability and pharma-cokinetics of ciprofloxacin and pefloxacin in healthy volunteers.

Rev. Infect. Dis. 11(Suppl. 5):S1024.14a.Kinzig, M., et al. 1991. 17th Internatl. Cong. Chemother., abstr.

no. 388.15. Manoharan, M., U. Jaehde, H. U. Koch, U. Malter, K. G. Naber,

and F. Sorgel. 1988. High-performance liquid chromatographicassays for gyrase inhibitors in plasma, urine, several body fluids,and tissues. Rev. Infect. Dis. 10:S98-S100.

16. Nakano, M., M. Yamamoto, and T. Arita. 1978. Interactions ofaluminum, magnesium, and calcium ions with nalidixic acid.Chem. Pharm. Bull. 26:1505-1510.

17. Nix, D. E., M. E. Lebsack, M. Chapelsky, A. J. Sedman, J. Busch,and A. Norman. 1993. Effect of oral antacids on disposition ofintravenous enoxacin. Antimicrob. Agents Chemother. 37:775-777.

18. Nix, D. E., W. A. Watson, M. E. Lener, R. W. Frost, G. Krol, H.Goldstein, J. Lettieri, and J. J. Schentag. 1989. Effects of alumi-num and magnesium antacids and ranitidine on the absorption ofciprofloxacin. Clin. Pharmacol. Ther. 46:700-705.

19. Nix, D. E., J. H. Wilton, B. Ronald, L. Distlerath, V. C. Williams,and A. Norman. 1990. Inhibition of norfloxacin absorption byantacids. Antimicrob. Agents Chemother. 34:432-435.

20. Parpia, S. H., D. E. Nix, L. G. Hejmanowski, H. R. Goldstein, J. H.Wilton, and J. J. Schentag. 1989. Sucralfate reduces the gastroin-testinal absorption of norfloxacin. Antimicrob. Agents Chemother.33:99-102.

21. Polk, R. E. 1989. Drug-drug interactions with ciprofloxacin andother fluoroquinolones. Am. J. Med. 87(Suppl. 5A):76S-81S.

22. Polk, R. E., D. P. Healy, J. Sahai, L. Drwal, and E. Racht. 1989.Effect of ferrous sulfate and multivitamins with zinc on absorptionof ciprofloxacin in normal volunteers. Antimicrob. Agents Che-mother. 33:1841-1844.

22a.SAS Institute. SAS/STAT, version 6.08. SAS Institute, Inc., Cary,N.C.

23. Shiba, K., A. Saito, T. Miyahara, H. Tachizawa, and T. Fujimoto.1987. Effect of aluminum hydroxide, an antacid, on the pharma-cokinetics of new quinolones in humans, p. 168-169. In B.Berkarda, and H. P. Kummerle (ed.), Progress in antimicrobialand anticancer chemotherapy. Ecomed Verlag, Landsberg, Ger-many.

23a.SIMED. 1993. SIPHAR/WIN 1.12. Pharmacokinetic modelingsoftware package. SIMED, Creteil, France.

24. Sorgel, F., and M. Kinzig. 1993. Pharmacokinetics of gyraseinhibitors. Part 1. Basic chemistry and gastrointestinal disposition.Am. J. Med. 94(Suppl. 3A):44-55.

25. Sorgel, F., K. G. Naber, U. Jaehde, A. Reiter, R. Seelmann, and G.SigI. 1989. Brief report: gastrointestinal secretion of ciprofloxacin.Evaluation of the charcoal model for investigations in healthyvolunteers. Am. J. Med. 87(Suppl. 5A):62S-65S.

26. Tachizawa, H., R. Kurata, and 0. Okazaki. 1987. Studies on themechanism of pharmacokinetic interaction of aluminum hydrox-ide, an antacid, with new quinolones in rats, p. 1850-1852. In B.Berkarda and H. P. Kummerle (ed.), Progress in antimicrobial andanticancer chemotherapy. Ecomed Verlag, Landsberg, Germany.

27. Wachter, T., H. Lode, B. Haupel, K. Borner, and P. Koeppe. 1987.Comparative pharmacokinetics and interaction of fleroxacin, ci-profloxacin, and ofloxacin. Abstr. 27th Intersci. Conf. Antimicrob.Agents Chemother. abstr. 1260.

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