BACKGROUND: Antiretroviral therapy including HIV protease inhibitors and nonnucleoside reverse transcriptase inhibitors can both inhibit and induce expression of cytochrome P450s, potentially leading to drug interactions. However, information is lacking on the impact of genetic polymorphism on this interaction. METHODS: This study examines the prevalence of 33 polymorphisms in NR1I2 (pregnane X receptor [PXR]), CYP3A4, and CYP2B6 in 1013 white and sub-Saharan African patients with HIV; explores the inductive ability of 16 antiretrovirals on CYP3A4 and CYP2B6 promoter activity through nuclear receptors PXR and constitutive androstane receptor (CAR); and evaluates the influence of naturally occurring PXR genetic variants on antiretroviral activation. RESULTS: Seventeen polymorphisms were present at different frequencies between the two ethnicities. Darunavir, fosamprenavir, lopinavir, nelfinavir, tipranavir, efavirenz, and abacavir increased CYP3A4 and/or CYP2B6 promoter activity, some through constitutive androstane receptor but mainly through PXR. Addition of low-dose ritonavir enhanced levels of CYP promoter activity for several protease inhibitors. Some PXR variants displayed lower fosamprenavir- and lopinavir-induced CYP3A4 promoter activity than the PXR reference sequence, whereas efavirenz and nelfinavir induction was unchanged. CONCLUSIONS: The presence of NR1I2 polymorphisms can alter the induction of CYP3A4 and CYP2B6 promoter activity, potentially adding to the unpredictable nature of antiretroviral drug interactions. These polymorphisms differ in prevalence between whites and sub-Saharan Africans.
BACKGROUND: Antiretroviral therapy including HIV protease inhibitors and nonnucleoside reverse transcriptase inhibitors can both inhibit and induce expression of cytochrome P450s, potentially leading to drug interactions. However, information is lacking on the impact of genetic polymorphism on this interaction. METHODS: This study examines the prevalence of 33 polymorphisms in NR1I2 (pregnane X receptor [PXR]), CYP3A4, and CYP2B6 in 1013 white and sub-Saharan African patients with HIV; explores the inductive ability of 16 antiretrovirals on CYP3A4 and CYP2B6 promoter activity through nuclear receptors PXR and constitutive androstane receptor (CAR); and evaluates the influence of naturally occurring PXR genetic variants on antiretroviral activation. RESULTS: Seventeen polymorphisms were present at different frequencies between the two ethnicities. Darunavir, fosamprenavir, lopinavir, nelfinavir, tipranavir, efavirenz, and abacavir increased CYP3A4 and/or CYP2B6 promoter activity, some through constitutive androstane receptor but mainly through PXR. Addition of low-dose ritonavir enhanced levels of CYP promoter activity for several protease inhibitors. Some PXR variants displayed lower fosamprenavir- and lopinavir-induced CYP3A4 promoter activity than the PXR reference sequence, whereas efavirenz and nelfinavir induction was unchanged. CONCLUSIONS: The presence of NR1I2 polymorphisms can alter the induction of CYP3A4 and CYP2B6 promoter activity, potentially adding to the unpredictable nature of antiretroviral drug interactions. These polymorphisms differ in prevalence between whites and sub-Saharan Africans.
Authors: V Michaud; E Ogburn; N Thong; A O Aregbe; T C Quigg; D A Flockhart; Z Desta Journal: Clin Pharmacol Ther Date: 2012-02-08 Impact factor: 6.875
Authors: E D Kharasch; D Whittington; D Ensign; C Hoffer; P S Bedynek; S Campbell; K Stubbert; A Crafford; A London; T Kim Journal: Clin Pharmacol Ther Date: 2012-03-07 Impact factor: 6.875
Authors: Tasmin Reuter; Rolf Warta; Dirk Theile; Andreas D Meid; Juan Pablo Rigalli; Carolin Mogler; Esther Herpel; Niels Grabe; Bernd Lahrmann; Peter K Plinkert; Christel Herold-Mende; Gerhard Dyckhoff; Walter Emil Haefeli; Johanna Weiss Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2015-07-04 Impact factor: 3.000
Authors: Ellen M McDonagh; Johnathan L Lau; Maria L Alvarellos; Russ B Altman; Teri E Klein Journal: Pharmacogenet Genomics Date: 2015-07 Impact factor: 2.089