title: The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion-correlation of in vivo and in vitro studies.
abstract: Oseltamivir is an ester prodrug of the active metabolite [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), a potent and selective inhibitor of neuraminidase enzyme of influenza virus. Oseltamivir is rapidly hydrolyzed by hepatic carboxylesterases to Ro 64-0802, which is then exclusively excreted by glomerular filtration and active tubular secretion without further metabolism. In vivo and in vitro studies were conducted to evaluate the renal drug-drug interaction potential of oseltamivir. Crossover studies were conducted in healthy subjects in which oral oseltamivir was administered alone and coadministered with probenecid, cimetidine, or amoxicillin. Probenecid completely blocked the renal secretion of Ro 64-0802, increasing systemic exposure (area under the curve) by 2.5-fold, but no interaction was observed with cimetidine or amoxicillin. These in vivo data show that Ro 64-0802 is secreted via an organic anion pathway, but Ro 64-0802 does not inhibit amoxicillin renal secretion. In vitro effects of Ro 64-0802 on the human renal organic anionic transporter 1 (hOAT1) were investigated using novel Chinese hamster ovary cells stably transfected with hOAT1. Ro 64-0802 was found to be a low-efficiency substrate for hOAT1 and a very weak inhibitor of hOAT1-mediated transport of p-aminohippuric acid (PAH). Ro 64-0802 did not inhibit the hOAT1-mediated transport of amoxicillin. In contrast, probenecid effectively inhibited the transport of PAH, Ro 64-0802, and amoxicillin via hOAT1. These in vitro observations are consistent with the in vivo data, validating the usefulness of the in vitro system for evaluating such drug-drug interaction. The study results demonstrate that oseltamivir has a low drug-drug interaction potential at the renal tubular level due to inhibition of hOAT1.
authors.affiliation: Roche Pharmaceutical Global Development, 3401 Hillview Avenue, Palo Alto, CA 94304, USA. george.hill@roche.com
authors.forename: George
authors.initials: G
authors.lastname: Hill
authors.forename: Tomas
authors.initials: T
authors.lastname: Cihlar
authors.forename: Charles
authors.initials: C
authors.lastname: Oo
authors.forename: Edmund S
authors.initials: ES
authors.lastname: Ho
authors.forename: Ken
authors.initials: K
authors.lastname: Prior
authors.forename: Hugh
authors.initials: H
authors.lastname: Wiltshire
authors.forename: Jo
authors.initials: J
authors.lastname: Barrett
authors.forename: Baulian
authors.initials: B
authors.lastname: Liu
authors.forename: Penny
authors.initials: P
authors.lastname: Ward
mesh_terms: D000081:Acetamides / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use / Q000652:urine; D000293:Adolescent; D000328:Adult; D000658:Amoxicillin / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000652:urine; D001692:Biological Transport; D016466:CHO Cells; D002927:Cimetidine / Q000494:pharmacology; D006224:Cricetinae; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007251:Influenza, Human / Q000188:drug therapy / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D053139:Oseltamivir; D011339:Probenecid / Q000494:pharmacology; D011355:Prodrugs / Q000493:pharmacokinetics*; D010130:p-Aminohippuric Acid / Q000378:metabolism
chemical_list: D000081:Acetamides; D000998:Antiviral Agents; D027362:Organic Anion Transport Protein 1; D011355:Prodrugs; C403132:Ro 64-0802; D053139:Oseltamivir; D002927:Cimetidine; D000658:Amoxicillin; D009439:Neuraminidase; D011339:Probenecid; D010130:p-Aminohippuric Acid