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Pharmacogenet Genomics. 2010 Dec;20(12):759-65. doi: 10.1097/FPC.0b013e3283402efb.

Maraviroc is a substrate for OATP1B1 in vitro and maraviroc plasma concentrations are influenced by SLCO1B1 521 T>C polymorphism.

Author information

1
Department of Infectious Diseases, University of Torino, Amedeo di Savoia Hospital, Torino, Italy. marco.siccardi@unito.it

Abstract

BACKGROUND:

Organic anion transporting polypeptides (OATPs) are emerging as major determinants of pharmacokinetics for numerous drugs, with the 1B1 isoform-mediating hepatic uptake. The 521 T>C polymorphism has been correlated earlier with higher plasma concentrations of several drugs and the aim of this study was to determine whether this polymorphism influences trough concentrations of maraviroc.

METHODS:

The uptake of maraviroc by OATP1B1 was assessed using a heterologous Xenopus laevis oocyte expression system and quantified using a novel liquid chromatography-mass spectrometry method. Regression analyses were conducted to identify factors associated with maraviroc Ctrough in 59 patients treated with maraviroc at 150, 300, or 600 mg twice daily.

RESULTS:

Maraviroc was identified as a substrate for OATP1B1 with a Km of 33.9 ╬╝mol/l. A dose of 600 mg of etravirine or efavirenz [odds ratio (OR) = 0.22, 95% confidence interval (95% CI): 0.06-0.76; P = 0.016] and SLCO1B1 521 heterozygosity were both associated with maraviroc Ctrough, above the suggested target concentration of 50 ng/ml (OR = 20.3, 95% CI: 2.2-182; P = 0.007).

CONCLUSION:

These findings show the importance of OATP1B1 for variability in maraviroc pharmacokinetics. Furthermore, the SLCO1B1 521 T>C polymorphism maybe useful in predicting higher plasma concentrations but these data should be confirmed before prospective clinical studies to define the clinical usefulness.

PMID:
21217360
DOI:
10.1097/FPC.0b013e3283402efb
[Indexed for MEDLINE]

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