ABCMdb

PMID: 20237075

Janneh O, Bray PG, Jones E, Wyen C, Chiba P, Back DJ, Khoo SH
Concentration-dependent effects and intracellular accumulation of HIV protease inhibitors in cultured CD4 T cells and primary human lymphocytes.
J Antimicrob Chemother. 2010 May;65(5):906-16. Epub 2010 Mar 17., [PubMed]

Sentences

No. Mutations Sentence Comment

21 ABCB1 p.Gly1249Ala For example, despite some of the HPIs, e.g. lopinavir, being a substrate for ABCB1 and ABCC,12,19 an earlier retrospective study of HIV-infected patients under antiretroviral therapy found no influence of the ABCB1 C3435T polymorphism on the plasma and peripheral blood mononuclear cell (PBMC) levels of lopinavir (or the non-nucleoside reverse transcriptase inhibitor, efavirenz)20,21 even though polymorphisms at the ABCB1 C3435T and G2677T/ A, MRP1 (ABCC1) C218T and G2168A and MRP2 (ABCC2) G1249A have been associated with alterations in ABCB1, ABCC1 and ABCC2 activity.22 - 26 However, some studies found no association between the concentrations of saquinavir (alone or when boosted with ritonavir), atazanavir or lopinavir and polymorphisms in ABCB1 C3435T and G2677T/A.27,28 Furthermore, recent studies on three common exonic ABCB1 polymorphisms, C1236T, G2677T/A and C3435T, showed that these are poor predictors of the concentrations of lopinavir and ritonavir in saliva, semen and plasma.29 However, there is evidence of some association between G4544A polymorphism in ABCC2 and higher accumulation of lopinavir in PBMCs of HIV-treated patients.21 Similar studies on 74 HIV-infected patients showed significantly higher plasma levels of atazanavir in patients with genotype CC than those with CT or TT for polymorphism at the ABCB1 C3435T.30 Studies in cultured cells showed that the permeability of amprenavir, indinavir, lopinavir and ritonavir was greater in ABCB1 (G1199A) cells than in ABCB1 wt cells, suggesting that ABCB1 G1199A polymorphism may impact on the systemic bioavailability of HPIs.12 Clearly if inter-individual differences in the bioavailability of HPIs is caused by genetic variants of ABCB1, ABCC1 and ABCC2, this may have a profound effect on the pharmacokinetics and pharmacodynamics of substrate drugs. Login to comment 120 ABCB1 p.Gly1249Ala This is because being efficient inhibitors, substrates and inducers of some drug efflux proteins and drug metabolizing enzymes,9,46,47,51-53,60-65 there is a complex interaction between HPIs and drug efflux/influx transporters and enzymes, especially if the patients are on other medications.66-69 Indeed alterations in ABCB1 and ABCC2 activity have been associated with single nucleotide polymorphisms in ABCB1 (C3435T and G2677T/A), ABCC1 and ABCC2 (G1249A).22-26 While some studies showed no association between the exposure of HPIs and polymorphisms in ABCB1 C3435T, C1236T and G2677T/A,27 -29 some in vitro and in vivo studies found some association between G4544A and G1199A polymorphisms in ABCC2 and ABCB1, respectively and higher accumulation of some HPIs,12,21,30 suggesting that these polymorphisms may impact on the systemic bioavailability of various HPIs that are substrates of ABCB1 and ABCC2. Login to comment