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

This paper is available online at http://dmd.aspetjournals.org 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 drugdrug interaction. The study results demonstrate that oseltamivir has a low drug-drug interaction potential at the renal tubular level due to inhibition of hOAT1.Oseltamivir is an orally bioavailable prodrug of Ro 64-0802 1 (GS4071), a potent and selective inhibitor of influenza A and B neuraminidase (Bardsley-Elliot and Noble, 1999). After oral administration, the prodrug is extensively hydrolyzed to its active metabolite Ro 64-0802, which is then extensively excreted by glomerular filtration and renal tubular secretion without further metabolism (He et al., 1999a).Active renal secretion occurs via specific transport proteins located in the basolateral and apical membrane of the proximal tubule (Pritchard and Miller, 1993). Two general drug secretion pathways exist in proximal tubules, one for basic compounds (organic cation transport system) and another for acidic compounds (organic anion transport system). Thus far, two active pathways capable of transporting organic cations have been identified in kidney, OCT1 and OCT2 (Grundemann et al., 1994;Okuda et al., 1996). Similarly, several renal organic anion transporters have been recently cloned and characterized. Of these, organic anion transporter 1 (OAT1) is the main component mediating tubular secretion of organic acids (Sekine, 1...

Low Penetration of Oseltamivir and Its Carboxylate into Cerebrospinal Fluid in Healthy Japanese and Caucasian Volunteers

“…In the overall study population, oseltamivir was detectable in the CSF for a median duration of 5.5 h and in OC for a median duration of 12.0 h. In one subject, whose first six CSF samples were contaminated with blood, OC persisted in the CSF for 24.0 h. While oseltamivir is a P-gp substrate and is eliminated from the CNS by this transporter, it has been speculated that active efflux of OC from the brain at the BBB may occur via organic anion transporter 3 (OAT3) (25), which is a homologue of OAT1, the mediator of renal tubular secretion of OC (11). OAT3 is expressed at the BBB and actively eliminates organic anions from the brain (15,16).…”

Nonclinical Pharmacokinetics of Oseltamivir and Oseltamivir Carboxylate in the Central Nervous System

“…OC is a weak substrate for organic anion transporter 1 (OAT1) (8) and, as recently reported by Ose et al (23), a substrate of OAT3 and MRP4. All three transporters are expressed in the BBB (11,12,25) and could theoretically contribute to the active transport of OC out of the brain.…”

Species-Dependent Uptake of Glycylsarcosine but Not Oseltamivir in Pichia pastoris Expressing the Rat, Mouse, and Human Intestinal Peptide Transporter PEPT1

“…The pharmacokinetics of both oseltamivir and oseltamivir carboxylate are seemingly uncomplicated because of low protein binding (i.e., 42% for prodrug and 3% for active metabolite), a lack of cytochrome P450 interactions, and no other metabolic species being formed (He et al, 1999;Dutkowski et al, 2003). Renal clearance of both compounds exceeds their filtration clearance because of active tubular secretion via the organic anionic pathway (Hill et al, 2002). However, this mechanism has low potential for drug-drug interactions given the weak affinity of Ro 64-0802 for human OAT1 (K i of 45.1 mM).…”