Effects of Antacids, Ferrous Sulfate, and Ranitidine on Absorption of DR-3355 in Humans

Transcription

1 ANTIMICROBLAL AGENTS AND CHEMOTHERAPY, OCt. 1992, p /92/1227-5$2./ Copyright 1992, Amerian Soiety for Mirobiology Vol. 36, No. 1 Effets of Antaids, Ferrous Sulfate, and Ranitidine on Absorption of DR-3355 in Humans KOHYA SHIBA,' OSAMU SAKAI,' JINGORO SHIMADA,2 OSAMU OKAZAKI,3* HIROYUKI AOKI,3 AND HIDEO HAKUSUI3 Seond Department of Internal Mediine, The Jikei University Shool of Mediine, 1 and Division of Clinial Pharmaology, Institute ofmedial Siene, St. Marianna University Shool ofmediine,2 Tokyo, and Dnrg Metabolism and Analytial Chemistry Researh Center, Developmental Researh Laboratories, Daiihi Pharmaeutial Co., Ltd., , Kita-kasai Edogawa-ku, Tokyo 134, apan Reeived 8 July 1991/Aepted 17 July 1992 This study examined the effets of widely used antaids (aluminum hydroxide, magnesium oxide, and alium arbonate), ferrous sulfate, and ranitidine on the absorption of a fluorinated quinolone, (-)-(S)-9- fluoro-3-methyl-1-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7h-pyrido- [1,2,3-de [1,4]benzoxazine-6-arboxyli aid hemihydrate (DR-3355), in healthy male volunteers enrolled in three separate randomized rossover studies. Study 1 used 1-mg doses of DR-3355 and onurrent doses of aluminum hydroxide (1 g) or magnesium oxide (5 mg), while study 2 used DR-3355 (1 mg) and onurrent ferrous sulfate (16 mg) or alium arbonate (1 g). Study 3 used DR-3355 (1 mg) and onurrent ranitidine (15 mg). Eah study inluded ontrol doses of DR-3355 (1 mg) alone. When aluminum hydroxide, ferrous sulfate, and magnesium oxide were oadministered with DR-3355, the relative bioavailability of DR-3355 was dereased to 56, 81, and 78%Y, respetively, of that for DR-3355 (1 mg) alone. Urinary exretion of DR-3355 was also signifiantly dereased by oadministration of these drugs. Thus, the magnitude of the derease in the area under the onentration-time urve for DR-3355 varied among antaids, and the ranking of their inhibitory effets orrelated with previously reported rankings of stability onstants for helate formation. DR-3355 bioavailability was not influened by the onurrent administration of alium arbonate and ranitidine, indiating that hanges in gastri ph do not affet DR-3355 absorption. DR-3355, a fluorinated quinolone-arboxyli aid derivative, is an optially ative (S)-(-)-enantiomer of ofloxain (OFLX). This ompound exhibits marked bateriidal ativity by inhibiting DNA gyrase (6, 19). As DR-3355 is 8 to 128 times more potent than (R)-(+)-OFLX and approximately twie as potent as the raemate (±)-OFLX in inhibiting the multipliation of gram-positive and gram-negative bateria (4), the drug is believed to be largely responsible for the effiay of raemi OFLX in linial therapy. The pharmaokinetis of DR-3355 in experimental animals have been doumented (2a). Comparison of the areas under the onentration-time urves (AUCs) of DR-3355 and OFLX revealed a marked stereoseletivity in rats (17). The differenes were aused by the stereoseletive gluuronidation in favor of (S)-(-)-OFLX (DR-355) (15). However, the disposition of (S)-(-)- and (R)-(+)-OFLX in humans after an oral dose of raemi OFLX showed little differene (14). With regard to antibaterial ativity, therefore, a given dose of DR-3355 should produe the same linial results as a dose of OFLX twie as large. Maalox, an antaid ontaining aluminum and magnesium, is widely used for the treatment of various gastri symptoms and is frequently oadministered with new quinolone antibaterial agents. However, ombination therapy with Maalox impairs the bioavailability of new quinolone antibaterial agents (1, 3, 5, 1, 12, 2). Moreover, oadministration with other metal ion-ontaining drugs also dereases the absorption of some new quinolones, suh as iprofloxain (CPFX) and norfloxain (NFLX) given with alium arbon- * Corresponding author. 227 ate (12) and CPFX given with ferrous sulfate (18). This interation is mainly due to helate formation (16). This study ompared the effets of aluminum hydroxide and magnesium oxide on the absorption of DR-3355 in healthy male volunteers. We also evaluated the potential for interation between DR-3355 and the other metal ion-ontaining drugs, ferrous sulfate and alium arbonate. In addition, we studied the effet of ranitidine on absorption of the drug. MATERIALS AND METHODS Chemials. DR-3355, (-)-(S)-9-fluoro-3-methyl-1-(4-methyl -1 - piperazinyl) oxo - 2,3 - dihydro - 7H- pyrido - [1,2,3-de] [1,4]benzoxazine-6-arboxyli aid hemihydrate, was synthesized in our laboratory (Fig. 1). DL-8493, (+)-9-fluoro-3- methyl-1-(4-allyl-1-piperazinyl)-7-oxo-2,3-dihydro-7h-pyrido-[1,2,3-de][1,4]benzoxazine-6-arboxyli aid, was used as an internal standard for high-performane liquid hromatography (HPLC). All other reagents and hemials were of analytial reagent grade. Volunteers. A total of 18 healthy male volunteers ranging in age from 2 to 33 years (mean, 22.4 years) partiipated in the study. Their heights ranged from 165 to 178 m (mean, m), and their weights ranged from 53 to 72 kg (mean, 61.5 kg). Eah subjet was determined to be in good health before the start of the study on the basis of medial history, physial examination, eletroardiogram, and linial laboratory tests. All subjets abstained from affeine-ontaining foods and alohol during the study. Smoking was forbidden from 1 h before to 4 h after drug administration. Volunteers fasted from 12 h before to 4 h after administration. The Downloaded from on Deember 18, 218 by guest

2 VOL. 36, 1992 EFFECTS OF ANTACIDS ON DR-3355 ABSORPTION r( Ǹ * N H2 CH3 J JSCH3 FIG. 1. Chemial struture of DR subjets were instruted not to take any mediations from 1 week before the study until after the study was ompleted. Ethial onsiderations. The protool was approved by the Review Committee for Clinial Trials at Kitasato Institute Bio-Iatri Center. Subjets reeived written information regarding the aims and proedures of the study. Written onsent was obtained from eah subjet before partiipation. Protool. The study onsisted of three separate treatment phases. Six subjets in eah group were alloated to eah treatment, aording to the Latin square rossover design. Study 1 onsisted of 1 mg of DR-3355 (1-mg tablet, lot S-1719-PMG; Daiihi Pharmaeutial Co., Ltd., Tokyo, Japan) and simultaneous administration of aluminum hydroxide (1 g of fine granules, lot K9J1; Chugai Pharmaeutial Co., Ltd., Tokyo, Japan) or magnesium oxide (5 mg of fine granules, lot 153; Iwaki Pharmaeutial Co., Ltd., Tokyo, Japan). Study 2 involved 1 mg of DR-3355 and simultaneous administration of alium arbonate (5 mg, lot VE-9; Kosakai Pharmaeutial Co., Ltd., Tokyo, Japan) or ferrous sulfate (16-mg tablet, lot 4; Chiba Gaigi Japan Co., Ltd., Tokyo, Japan). Study 3 onsisted of 1 mg of DR-3355 and simultaneous administration of ranitidine (15-mg tablet, lot 9Z271; Glaxo Japan Co., Ltd., Tokyo, Japan). Eah study inluded 1 mg of DR-3355 alone. Drugs were ingested with 1 ml of water at 9 a.m. under fasting onditions, and a ontrolled meal was given 4 h after administration. A 7-day break period was provided between rossover studies in eah treatment phase. Sample olletion. Serial blood and urine samples were obtained after administration. Approximately 1 ml of blood was drawn immediately before and at.25,.5,.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 h after dosing. Immediately after olletion, eah sample was gently inverted a few times for omplete mixing with heparin. Eah sample was entrifuged within 1 h of olletion for 1 min at 1, x g to separate plasma. The separated plasma was transferred to another tube and stored at or below -2 C until analysis. Total urine olletions were made just prior to dosing and over the intervals of to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, and 12 to 24 h after dosing. To failitate olletion, all subjets took 2 ml of water at 3 h after drug administration. Drug assay. DR-3355 onentrations in plasma and urine were determined by HPLC as reported previously (13). Portions of plasma (.1 ml) and urine (.1 ml) were diluted with 5 mm potassium dihydrogen phosphate ontaining the internal standard. These samples were applied to a C8 artridge olumn (Bond Elut; Analytihem International, Harbor City, Calif.) and washed with 5 mm potassium dihydrogen phosphate followed by tetrahydrofuran-distilled water (2:8, vol/vol). Elution was performed with tetrahydrofuran-.5% orthophosphori aid (2:8, vol/vol), and the eluents were onentrated with a vauum. The resulting solutions were injeted onto the hromatograph. The hromatographi system onsisted of an HPLC pump (model CCPM; Tosoh, Tokyo, Japan), a fluoresene detetor (model F-115; Hitahi Ltd., Tokyo, Japan), and a sample -3 DR-3355 alone o* **A- With magnesium oxide (.5 g) lwith auminum hydroxide (1. g) FIG. 2. Plasma DR-3355 onentration-time profiles after a single 1-mg dose of DR-3355 alone and with onurrent doses of aluminum hydroxide (1. g) or magnesium oxide (.5 g) in healthy male volunteers. Values are means ± standard deviations. autoinjetor. Separation was ahieved with a TSK gel ODS- 8T (inside diameter, 15 by 4.6 mm; Tosoh) at a flow rate of 1 ml/min. The mobile phase onsisted of tetrahydrofuran-5 mm potassium dihydrogen phosphate (ph 2., adjusted with orthophosphori aid)-1 M ammonium aetate (7.5:92.5:1, vol/vol). Detetion was performed by spetrofluorimetry at an exitation wavelength of 296 nm and an emission wavelength of 54 nm. Peak area ratios of DR-3355 to an internal standard were linear over the onentration ranges of.1 to 1.2 Fg/ml in serum and 1 to 2,ug/ml in urine. The intra- and interday oeffiients of variation in serum (5 ng/ml) were 4 and 5%, respetively, and in urine (5 Lg/ml) were.3 and 4%, respetively. The determination limits of serum and urine were 1 ng/ml and 1,g/ml, respetively. Pharmaokineti analysis. Peak onentration in plasma (Cm.) and time to peak onentration were determined from data for onentration in plasma versus time. The elimination rate onstant was obtained by least-squares linear regression analysis. The terminal log-linear portion of the plasma onentration-time urve was defined by the last n (n. 3) datum points, where n was seleted to minimize the mean square error. Plasma elimination half-life (t1/2) was alulated by dividing.693 by the elimination rate onstant. The AUC for plasma from time zero to the last measured onentration was determined by the linear trapezoidal rule. The AUC from h to infinity was alulated by the trapezoidal rule and extrapolated to infinity by dividing the last observed onentration by the elimination rate onstant. Mean residene time (MRT) was omputed by dividing the area under the first moment of the drug onentration-time urve by the AUC. The relative bioavailability was alulated by dividing the AUC of eah treatment group by that of the ontrol group. Statistial analysis. Analysis of variane was applied to Cmax, the AUC, t1/2, MRT, and urinary exretion to determine any statistially signifiant (P <.5) differenes in pharmaokineti parameters among treatment groups. The initial analysis of variane model inluded terms for subjet, period, arryover, and drug treatment. Statistial signifiane was assessed at the 5% level. RESULTS As shown in Fig. 2, levels of DR-3355 in plasma were Downloaded from on Deember 18, 218 by guest

3 2272 SHIBA ET AL. ANTIMICROB. AGENTS CHEMOTHER. E Lo 1. - DR-3355 alone &--. With alium arbonate (1. g) - With ferrous sulfate (16 mg) S FIG. 3. Plasma DR-3355 onentration-time profiles after a single 1-mg dose of DR-3355 alone and with onurrent doses of alium arbonate (1. g) and ferrous sulfate (16 mg) in healthy male volunteers. Values are means ± standard deviations. dereased by onomitant administration of aluminum hydroxide or magnesium oxide. Ferrous sulfate also dereased levels of DR-3355 in plasma, but alium arbonate had minimal influene on the pharmaokinetis of DR-3355 (Fig. 3). Pharmaokineti parameters for DR-3355 after eah treatment are provided in Table 1. Parameters among the ontrol groups of the three separate studies were almost the same. In study 1, simultaneous administration of aluminum hydroxide resulted in signifiant redutions in the AUC and Cm. (44 and 65%, respetively) relative to those for DR (1 mg) alone. When magnesium oxide was oadministered with DR-3355, small but signifiant dereases in the AUC (78%) and Cm.. (62%) were observed, whereas time to peak onentration, t1,2, and MRT showed no hange. In study 2, values for relative bioavailability (97%), Cma (1.12 p,g/ml), t1,2 (6.27 h), and MRT (6.69 h) obtained when alium arbonate was onurrently given did not differ from those for DR-3355 alone. Treatment with ferrous sulfate produed signifiant redutions in the AUC and Cm. (19 and 45%, respetively). Thus, the effet of onurrent antaid and ferrous sulfate dosing on DR-3355 bioavailability was largest for aluminum hydroxide and was next largest for magnesium oxide and ferrous sulfate, in that order, while alium arbonate had no effet on pharmaokineti parameters. As shown in Fig. 4, ranitidine did not redue the absorption of DR-3355, nor did its pharmaokineti parameters differ from those of the ontrol group (Table 1). The effet of oadministration on umulative exretion of DR-3355 is presented in Table 1. The effet of treatment on urinary reovery of DR-3355 ourred in a proportion similar to that of hanges in the AUC and Cm.. Coadministration of aluminum hydroxide and ferrous sulfate resulted in signifiant redutions (28 and 19%, respetively) in the amount of DR-3355 exreted in the urine. Insignifiant dereases in urinary reovery for magnesium oxide and alium arbonate were observed. Urinary exretion for ranitidine treatment was slightly greater than that for the ontrol, but it was not signifiantly different. DISCUSSION The present study showed the bioavailability of DR-3355 to be dereased by onomitant antaid or ferrous sulfate administration. These interations an be explained primar- (E) - DR-3355 alone Tie ae With rantidine (15 mg) FIG. 4. Plasma DR-3355 onentration-time profiles after a single 1-mg dose of DR-3355 alone and with onurrent doses of ranitidine (15 mg) in healthy male volunteers. Values are means standard deviations. ily by the inhibition of absorption. However, bioavailability assessed by urinary reovery was not affeted to the same extent as that assessed by the AUC. This effet may be aused by inomplete urinary exretion within 24 h, espeially in study 1. Previous studies have demonstrated that absorption of orally administered new quinolone antibaterial agents suh as OFLX (1, 1, 2), CPFX (5, 11), enoxain (3, 2), and NFLX (12, 2) is dereased by onomitant administration of aluminum-ontaining antaids. Currently, it is generally aepted that the mehanism of interation between metal ion-ontaining drugs and quinolone antibiotis is helate formation (8, 16). Okazaki et al. reported that aluminum hloride dramatially enhaned the inhibition of gastrointestinal absorption of OFLX in rats over that by an equivalent amount of aluminum hydroxide (16). The mehanism of the interation is thought to be stable helate omplex formation between the 3-arboxyl- and 4-oxosubstituents of quinolones and the aluminum ion (8). In this study, treatment with aluminum hydroxide, ferrous sulfate, and magnesium oxide resulted in 44, 19, and 22% dereases, respetively, in DR-3355 bioavailability, and ranking orrelated with the stability onstant of the metal helation omplex formed between OFLX and the metal ions (16). Although the stability onstants of helate formation between quinolone antibaterial agents are almost idential (16), the magnitude of the derease in bioavailability varied, being 44% for DR-3355, 84.% for enoxain (2), 97.3% for NFLX (2), and 84.9% for CPFX (11) after onomitant administration of aluminum hydroxide (Alumigel; 1 g) or an aluminum- and magnesium-ontaining antaid (Maalox, 3 ml [1.8 g of magnesium hydroxide and 3.6 g of aluminum hydroxide]). Consequently, it is supposed that mehanisms other than helate formation ontribute to the interation between antaids and quinolone antibaterial agents. Our study showed ranitidine to have no effet on the bioavailability of DR Sine ranitidine has been reported to exhibit its effet on gastri aid seretion for several hours (2), it is doubtful whether the gastri ph atually inreased. For CPFX, a 2-h pretreatment with ranitidine has no effet on the bioavailability of CPFX (11). In this study, however, alium arbonate, whih shows Downloaded from on Deember 18, 218 by guest

4 VOL. 36, 1992 EFFECTS OF ANTACIDS ON DR-3355 ABSORPTION 2273 TABLE 1. Pharmaokinetis of DR-3355 alone and with onurrent doses of antaid, ferrous sulfate, and ranitidinea AUCO,MT h Study DR-3355 treatment Cm,, (GLg/ml) Tm. (h) t1/2 (h) (jgh MRT (h) (% of dose)b 1 Alone 1.82 ±.89.8 ± ± ± ± ± 13. With magnesium oxide *.8 ± ± ± 2.2* 6.72 ± ± 9.5 With aluminum hydroxide.64 ±.2** 1.5 ± ±.52* 5.62 ± 1.51*** 7.15 ± ± 1.3* Urinary reovery 2 Alone 1.45 ± ± ± ± ± ± 3.5 With alium arbonate ± ± ± ± 5.5 With ferrous sulfate.8 ±.27** 1.33 ± ± ± 1.5*** 7.12 ±.49** 66.1 ± 3.6* 3 Alone ± ± ± ± ± 9.4 With ranitidine ± ± ± ± ± 1.8 a Subjets reeived a single oral dose of DR-3355 (1 mg) alone or with onurrent doses of magnesium oxide (5 mg), aluminum hydroxide (1 g), alium arbonate (1 g), ferrous sulfate (16 mg), or ranitidine (15 mg) under fasting onditions. Eah value represents the mean ± the standard deviation for six subjets. Tmax, time to peak onentration; AUCO,, AUC from h to infinity. *, *, and ***, signifiantly different from ontrol value at P <.5,.1, and.5, respetively. b Cumulative urinary exretion at 24 h. markedly lower levels of helation with quinolone antibaterial agents than aluminum ion does, did not hange the absorption rate of the drug. This observation indiates that hanges in gastri ph may not affet the absorption of DR Sine physiohemial properties suh as water solubility and partition oeffiient vary among quinolones (7, 9, 21), it is possible that hanges in gastri ph redue absorption by dereasing the solubility of many quinolone antibaterial agents other than OFLX and DR In fat, ranitidine treatment signifiantly dereases enoxain absorption, while that of NFLX is dereased by alium arbonate (12). Numerous reports have demonstrated that Maalox (aluminum hydroxide plus magnesium hydroxide), used for treatment of gastrointestinal symptoms, affets the intestinal absorption of new quinolones, resulting in a signifiant redution in the bioavailability of these antibaterial agents (1, 5, 11). This mehanism is generally explained by helate formation with aluminum or magnesium ions (16), but it is not known whih metal ion exerts the greater influene on bioavailability of the drug. In this regard, the present study showed that aluminum hydroxide auses a greater derease in the AUC of DR-3355 than does magnesium oxide and is therefore the main fator in the interation between new quinolones and Maalox. DR-3355 is rapidly and ompletely absorbed from the intestine and is exreted into the urine mainly as the unhanged form. The disposition of DR-3355 in humans is really idential to that of OFLX (loa). The degrees of the effets of onurrent aluminum hydroxide ingestion on the bioavailability of DR-3355 and OFLX were therefore nearly idential (2). For the test drugs ontaining metal ions, the present study showed the bioavailability of DR-3355 after an oral 1-mg dose to be most influened by the simultaneous administration of aluminum hydroxide. However, the derease in relative bioavailability of DR-3355 was only 44%, and the ratio of this derease was markedly lower than that for other quinolones with the exeption of OFLX (2). Moreover, levels of DR-3355 in plasma after oadministration of aluminum hydroxide were maintained at.6,tg/ml, onsiderably exeeding the range of MICs for 9% of strains tested reported for many moderately suseptible pathogens (4). However, further linial studies are needed to establish speifi dosage regimens for oadministration of DR-3355 with metal ion-ontaining drugs. REFERENCES 1. Flor, S., D. R. P. Guay, J. A. Opsahl, K. Tak, and G. R. Matzke Effets of magnesium-aluminum hydroxide and alium arbonate antaids on bioavailability of ofloxain. Antimirob. Agents Chemother. 34: Frank, W. O., K. E. Peae, M. Watson, J. J. Seaman, P. L. Szego, A. Braverman, B. Mio, and B. Dikson The effet of single intravenous doses of imetidine or ranitidine on gastri seretion. Clin. Pharmaol. Ther. 4: Grasela, T. H., Jr., J. J. Shentag, A. J. Sedman, J. H. Wilton, D. J. Thomas, R. W. Shultz, M. E. Lebsak, and A. W. Kinkel Inhibition of enoxain absorption by antaids or ranitidine. Antimirob. Agents Chemother. 33: Hayakawa, I., S. Atarashi, S. Yokohama, M. Imamura, K.-I. Sakano, and M. Furukawa Synthesis and antibaterial ativities of optially ative ofloxain. Antimirob. Agents Chemother. 29: Hoffken, G., H. Lode, R. Wiley, T. D. Glatzel, D. Sievers, T. Olshewski, K. Borner, and T. Koeppe Pharmaokinetis and bioavailability of iprofloxain and ofloxain. Rev. Infet. Dis. 1(Suppl. 1):S138-S Hoshino, K., K. Sato, T. Une, and Y. Osada Inhibitory effets of quinolones on DNA gyrase of Esherihia oli and topoisomerase II of fetal alf thymus. Antimirob. Agents Chemother. 33: Ihihashi, H., Y. Kawahito, and Y. Nakanishi Physiohemial properties of (+)-7-(3-amino-1-pyrrolidinyl)-1-ethyl-6- fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-arboxyli aid hydrohloride (AT-2468). lyakuhin Kenkyu 19: Kakano, M., M. Yamamoto, and T. Arita Interation of aluminum, magnesium, and alium ions with nalidixi aid. Chem. Pharm. Bull. 26: Kokei, T., H. Sakai, and T. Maeda Chemial struture and physiohemial properties of (±)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-arboxyli aidp-toluenesulfonate hydrate (T-3262). lyakuhin Kenkyu 19: Matsumoto, K., H. Shishido, A. Takahashi, T. Harada, T. Sakamoto, S. Kaida, and K. Watanabe In vitro pharmaokineti and linial studies of DL-828, a new oxazine derivative. Chemotherapy (Tokyo) 32(Suppl. 1): a.Nakashima, M., T. Uematsu, M. Kanamaru,. Okazaki, S. Hashimoto, and H. Tahizawa Pharmaokinetis of DR- 3355, a new quinolone, in healthy volunteers, abstr. 951, p Program Abstr. 28th Intersi. Conf. Antimirob. Agents Chemother. Amerian Soiety for Mirobiology, Washington, D.C. 11. Nix, D. E., W. A. Watson, M. E. Lener, R. W. Frost, G. Krol, H. Goldstein, J. Lettieri, and J. J. Shentag Effets of aluminum and magnesium antaids and ranitidine on the absorp- Downloaded from on Deember 18, 218 by guest

5 2274 SHIBA ET AL. tion of iprofloxain. Clin. Pharmaol. Ther. 46: Nix, D. E., J. H. Wilton, B. Ronald, L. Distlerath, V. C. Williams, and A. Norman Inhibition of norfloxain absorption by antaids. Antimirob. Agents Chemother. 34: Okazaki, O., H. Aoki, and H. Hakusui High-performane liquid hromatographi determination of (S)-(-)-ofloxain and its metabolites in serum and urine using a solid-phase lean-up. J. Chromatogr. 563: Okazaki, O., C. Kojima, H. Hakusui, and M. Nakashima Enantioseletive disposition of ofloxain in humans. Antimirob. Agents Chemother. 35: Okazaki, O., T. Kurata, H. Hakusui, and H. Tahizawa Stereoseletive gluuronidation of ofloxain in rat liver mirosomes. Drug Metab. Dispos. 19: Okazaki, O., T. Kurata, and H. Tahizawa Studies on the mehanism of pharmaokineti interation of aluminum hydroxide, an antaid, with new quinolones in rats. Xenobio. Metab. Dispos. 3: Okazaki, O., T. Kurata, and H. Tahizawa Stereoseletive metaboli disposition of enantiomers of ofloxain in rats. ANTIMICROB. AGENTS CHEMOTHER. Xenobiotia 19: Polk, R. E., D. P. Healy, J. Sahai, L. Drwal, and E. Raht Effet of ferrous sulfate and multivitamins with zin on absorption of iprofloxain in normal volunteers. Antimirob. Agents Chemother. 33: Sato, K., Y. Inoue, T. Fujii, H. Aoyama, and S. Mitsuhashi Antibaterial ativity of ofloxain and its mode of ation. Infetioit 14: Shiba, K., A. Saito, T. Miyahara, H. Tahizawa, and T. Fujimoto Effet of aluminum hydroxide, an antaid, on the pharmaokinetis of new quinolones in humans. Xenobio. Metab. Dispos. 3: a.Tahizawa, H.,. Okazaki, T. Kurata, K. Mitsugi, and Y. Ezumi Metaboli disposition of DR-3355, a new quinolone antibaterial, abstr. 26, p Program Abstr. 27th Intersi. Conf. Antimirob. Agents Chemother. Amerian Soiety for Mirobiology, Washington, D.C. 21. Takahashi, Y., H. Tamura, I. Hirako, C. Shioyama, T. Funaba, and H. Hiller Physiohemial properties and stability of iprofloxain hydrohloride. Iyakuhin Kenkyu 17: Downloaded from on Deember 18, 218 by guest