Involvement of sulfate conjugation and multidrug resistance-associated protein 2 (Mrp2) in sex-related differences in the pharmacokinetics of garenoxacin in rats

被引：6

作者：

Hayashi, Tamon ^{[1
]}

Abe, Fumie ^{[1
]}

Kato, Miki ^{[1
]}

Saito, Hiroko ^{[1
]}

Ueyama, Jun ^{[2
]}

Kondo, Yuya ^{[3
]}

Imai, Kuniyuki ^{[3
]}

Katoh, Miki ^{[3
]}

Nadai, Masayuki ^{[3
]}

Hasegawa, Takaaki ^{[1
]}

机构：

[1] Aichi Med Univ, Sch Med, Dept Pharm & Pharmacokinet, Nagakute, Aichi 4801195, Japan

[2] Nagoya Univ, Sch Hlth Sci, Dept Med Technol, Higashi Ku, Nagoya, Aichi 4618673, Japan

[3] Meijo Univ, Fac Pharm, Tenpaku Ku, Nagoya, Aichi 4688503, Japan

来源：

JOURNAL OF INFECTION AND CHEMOTHERAPY | 2011年 / 17卷 / 01期

关键词：

Garenoxacin; Bile; Metabolism; Sex; Conjugation; BLOOD-BRAIN-BARRIER; P-GLYCOPROTEIN; INTESTINAL SECRETION; BILIARY-EXCRETION; IN-VIVO; GREPAFLOXACIN; TRANSPORT; HYPERBILIRUBINEMIA; SPARFLOXACIN; EXPRESSION;

D O I：

10.1007/s10156-010-0095-z

中图分类号：

R51 [传染病];

学科分类号：

100401 ;

摘要：

In this study, the involvement of sulfate conjugation and drug efflux transporter multidrug resistance-associated protein 2 (Mrp2) in sex-related differences in the pharmacokinetics of a new quinolone antimicrobial agent, garenoxacin, was investigated in Sprague-Dawley (SD) rats and Eisai hyperbilirubinemic rats (EHBRs) lacking Mrp2. The disappearance of garenoxacin from plasma in female SD rats was significantly faster than that in male SD rats after a single intravenous injection of garenoxacin (5 mg/kg). The systemic clearance of garenoxacin in female rats was approximately threefold larger than that of male rats (2.43 +/- A 0.31 and 0.87 +/- A 0.06 l/h/kg, respectively), suggesting the existence of sex-related differences in the pharmacokinetics of garenoxacin. When rats received a constant-rate infusion of garenoxacin, the contribution of biliary and renal excretion of garenoxacin was small, and no significant difference in the biliary (CLBILE) clearance of garenoxacin was observed between male and female SD rats. The metabolic clearance [CLM (SULF)] of garenoxacin to garenoxacin sulfate conjugate (which is mainly excreted into the bile) in female SD rats was 8.5-fold larger than that in male SD rats (27.9 +/- A 2.94 and 3.28 +/- A 0.07 ml/h/kg, respectively). The CLBILE of garenoxacin was decreased in male and female EHBRs by approximately 50% compared with that in male and female SD rats. These results suggest that sulfate conjugation, but not Mrp2, is mainly involved in the sex-related differences in the pharmacokinetics of garenoxacin.

引用

页码：24 / 29

页数：6

共 22 条

[1] Secretion of sparfloxacin from the human intestinal Caco-2 cell line is altered by P-glycoprotein inhibitors [J].

Cormet-Boyaka, E ;

Huneau, JF ;

Mordrelle, A ;

Boyaka, PN ;

Carbon, C ;

Rubinstein, E ;

Tomé, T .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1998, 42 (10) :2607-2611

[2] In vitro and in vivo investigations on fluoroquinolones; effects of the P-glycoprotein efflux transporter on brain distribution of sparfloxacin [J].

de Lange, ECM ;

Marchand, S ;

van den Berg, DJ ;

van der Sandt, ICJ ;

de Boer, AG ;

Delon, A ;

Bouquet, S ;

Couet, W .

EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, 2000, 12 (02) :85-93

[3] HEPATOBILIARY SECRETION OF ORGANIC-COMPOUNDS - MOLECULAR MECHANISMS OF MEMBRANE-TRANSPORT [J].

ELFERINK, RPJO ;

MEIJER, DKF ;

KUIPERS, F ;

JANSEN, PLM ;

GROEN, AK ;

GROOTHUIS, GMM .

BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON BIOMEMBRANES, 1995, 1241 (02) :215-268

[4] Metabolism and disposition of novel des-fluoro quinolone garenoxacin in experimental animals and an interspecies scaling of pharmacokinetic parameters [J].

Hayakawa, H ;

Fukushima, Y ;

Kato, H ;

Fukumoto, H ;

Kadota, T ;

Yamamoto, H ;

Kuroiwa, H ;

Nishigaki, J ;

Tsuji, A .

DRUG METABOLISM AND DISPOSITION, 2003, 31 (11) :1409-1418

[5] THE ATP-DEPENDENT GLUTATHIONE S-CONJUGATE EXPORT PUMP [J].

ISHIKAWA, T .

TRENDS IN BIOCHEMICAL SCIENCES, 1992, 17 (11) :463-469

[6] Molecular cloning of canalicular multispecific organic anion transporter defective in EHBR [J].

Ito, K ;

Suzuki, H ;

Hirohashi, T ;

Kume, K ;

Shimizu, T ;

Sugiyama, Y .

AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 1997, 272 (01) :G16-G22

[7] Expression of rat Multidrug Resistance Protein 2 (Mrp2) in male and female rats during normal and pregnenolone-16α-carbonitrile (PCN)-induced postnatal ontogeny [J].

Johnson, DR ;

Guo, GL ;

Klaassen, CD .

TOXICOLOGY, 2002, 178 (03) :209-219

[8]

Kato H, 2007, JPN J CHEMOTHER, V55, P78

[9]

Murata M, 1999, J PHARMACOL EXP THER, V290, P51

[10] Active intestinal secretion of new quinolone antimicrobials and the partial contribution of P-glycoprotein [J].

Naruhashi, K ;

Tamai, I ;

Inoue, N ;

Muraoka, H ;

Sai, Y ;

Suzuki, N ;

Tsuji, A .

JOURNAL OF PHARMACY AND PHARMACOLOGY, 2001, 53 (05) :699-709

← 1 2 3 →