Fentanyl Pharmacokinetics is not Dependent on Hepatic Uptake by Organic Anion‐Transporting Polypeptide 1B1 in Human Beings. (6th April 2013)

• Record Type: Journal Article
• Authors: Ziesenitz, Victoria C.; König, Sonja K.; Mahlke, Nina; Jantos, Ricarda; Skopp, Gisela; Weiss, Johanna; Haefeli, Walter E.; Mikus, Gerd
• Is Part Of: Basic & clinical pharmacology & toxicology. Volume 113:Number 1(2013)
• Page Start: 43
• Page End: 48
• Publication Date: 2013-04-06
• Subjects: Pharmacology -- Periodicals; Toxicology -- Periodicals; Pharmacology -- Periodicals; Toxicology -- Periodicals; Pharmacology, Clinical -- Periodicals; Computer network resources; Electronic journals; 615.1
• DOI: 10.1111/bcpt.12066
• Languages: English
• ISSNs: 1742-7835

Abstract

<abstract abstract-type="main" id="bcpt12066-abs-0001"> <title>Abstract</title> <p>A recent study investigating the pharmacokinetics of fentanyl in Sprague–Dawley rats suggested fentanyl to be a substrate of rat organic anion‐transporting polypeptide Oatp. In human beings, the most important OATP for the pharmacokinetics of many drugs is OATP1B1. Therefore, genetic variants of OATP1B1 <italic>(SLCO1B1)</italic> might modulate fentanyl pharmacokinetics and efficacy in human beings. Sixteen healthy male and female volunteers, homozygous for <italic>SLCO1B1*1a</italic> (genetic wild‐type) (n = 11) or <italic>*15</italic> (deficient haplotype carrying the single‐nucleotide polymorphisms rs2306283 and rs4149056 and exhibiting altered transport activity; n = 5), were included in this randomized crossover study. The participants received fentanyl (5 μg/kg) intravenously alone or with the OATP inhibitor rifampicin (600 mg single oral dose). The pharmacokinetics of fentanyl and norfentanyl were determined by liquid chromatography coupled to tandem mass spectrometry (LC‐MS/MS). In addition, fentanyl uptake <italic>in vitro</italic> was evaluated in OATP1B1 overexpressing HEK293 cells and compared to a mock‐transfected cell line. In the clinical trial, fentanyl clearance was 18.8 ± 8.2 mL/min. kg in <italic>SLCO1B1*1a</italic> and 19.5 ± 1.8 mL/min/kg in <italic>SLCO1B1*15</italic> carriers and not significantly different between the genotypes. During rifampicin, fentanyl clearance was 15.0 ± 4.4 mL/min/kg in <italic>SLCO1B1*1a</italic> and 16.7 ± 5.9 mL/min/kg in <italic>SLCO1B1*15</italic> carriers (<italic>p</italic> > 0.5). In addition, <italic>in vitro</italic> data also indicate that fentanyl is not transported by OATP1B1. In conclusion, our data indicate that OATP1B1 has no impact on fentanyl pharmacokinetics in human beings.</p> </abstract>