L L von Moltke1, A L Durol, S X Duan, D J Greenblatt. 1. Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA. Lisa.vonmoltke@tufts.edu
Abstract
OBJECTIVE: Biotransformation of triazolam to its alpha-hydroxy and 4-hydroxy metabolites by human liver microsomes in vitro was used as an index of human cytochrome P450 3A (CYP3A) activity. RESULTS: The reaction was strongly inhibited by co-incubation with the viral protease inhibitors ritonavir (IC50 = 0.14 microM) and amprenavir (IC50 = 2.5 2.9 microM), and by the azole derivative ketoconazole (IC50 = 0.07 microM). Pre-incubation of microsomes with ritonavir or amprenavir increased inhibitory potency (IC50 reduced to 0.07 microM and 1.4 microM, respectively). This was not the case with ketoconazole. CONCLUSIONS: Thus, ritonavir and amprenavir are highly potent mechanism-based inhibitors of human CYP3A isoforms.
OBJECTIVE: Biotransformation of triazolam to its alpha-hydroxy and 4-hydroxy metabolites by human liver microsomes in vitro was used as an index of humancytochrome P450 3A (CYP3A) activity. RESULTS: The reaction was strongly inhibited by co-incubation with the viral protease inhibitors ritonavir (IC50 = 0.14 microM) and amprenavir (IC50 = 2.5 2.9 microM), and by the azole derivative ketoconazole (IC50 = 0.07 microM). Pre-incubation of microsomes with ritonavir or amprenavir increased inhibitory potency (IC50 reduced to 0.07 microM and 1.4 microM, respectively). This was not the case with ketoconazole. CONCLUSIONS: Thus, ritonavir and amprenavir are highly potent mechanism-based inhibitors of humanCYP3A isoforms.
Authors: David J Greenblatt; Diane E Peters; Lauren E Oleson; Jerold S Harmatz; Malcolm W MacNab; Noah Berkowitz; Miguel A Zinny; Michael H Court Journal: Br J Clin Pharmacol Date: 2009-12 Impact factor: 4.335