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Session 113
Poster Abstracts Pharmacology of Protease Inhibitors Wednesday, 1:30 - 3:30 pm Hall A |
Background: Protease inhibitors (PI) are
substrates of CYP3A4 and of transporters such as P-glycoprotein (P-gp). Previous studies demonstrated discordant results
concerning associations between CYP3A4 activity, genetic variations of MDR1, P-gp expression on peripheral blood mononuclear cells (PBMC)
and of plasma and intracellular concentrations of different PI. The aim of this
study was to comprehensively evaluate the relevance of MDR1 polymorphisms and
of CYP3A4 activity on lopinavir (LPV) and ritonavir (RTV) drug concentrations in vivo.
Methods: In a prospective study 30 treatment-naïve HIV-infected
patients were phenotyped for hepatic and intestinal cytochrome P (CYP) 3A4 activity as published earlier before
and after start of an antiretroviral regimen (ART) containing LPV and RTV.
Multi-drug resistance (MDR) 1 genotypes (C1236T, G2677T/A, and C3435T) were
determined by direct sequencing. We performed 12-hour plasma pharmacokinetics
of LPV and RTV at steady state using LC-MS/MS methods. In 10 patients 12-hour
monitoring of intracellular drug concentrations was performed, and expression
of P-gp, MRP1, and BCRP on peripheral mononuclear
blood cells was investigated.
Results: CYP3A4 activity measured before and under ART did not correlate with
plasma pharmacokinetics (AUC0-12h, Cthrough)
of LPV and RTV. Assessing the effect of MDR1 genotypes C1236T, G2677T/A, and
C3435T on plasma concentrations we found a trend toward lower plasma- Cthrough of RTV with TT genotpye
of G2677T/A (GG vs TT, p = 0.071). LPV plasma concentrations were not associated with MDR1
genotype at all. Plasma-LPV exposure (AUC0-12h) was significantly
correlated with intracellular concentrations (p = 0.01), but for RTV no relationship between plasma and intracellular
exposure could be demonstrated (p = 0.596).
Intracellular accumulation of both LPV and RTV was not associated with
lymphocyte surface expression of P-gp, MRP1, and
BCRP.
Conclusions: In this study factors potentially influencing
plasma drug concentrations were examined. Neither CYP3A4 activity nor genetic
variations of MDR1 showed a correlation with LPV and RTV plasma concentrations.
Furthermore, intracellular concentrations of LPV and RTV were not related to
expression of different efflux transporters on lymphocytes. Further studies are
required to shed more light on the complex relationship between different
genetic variables and plasma concentrations of PI.
Keywords: P-gp; CYP3A4; Protease Inhibitors
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