Potent mechanism-based inhibition of human CYP3A in vitro by amprenavir and ritonavir: comparison with ketoconazole.
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.
von Moltke
L L
LL
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA. Lisa.vonmoltke@tufts.edu
Durol
A L
AL
Duan
S X
SX
Greenblatt
D J
DJ
D001189:Aryl Hydrocarbon Hydroxylases; D002219:Carbamates; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005663:Furans; D006801:Humans; D006900:Hydroxylation; D007654:Ketoconazole / Q000494:pharmacology*; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors*; D019438:Ritonavir / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D014229:Triazolam / Q000378:metabolism
D002219:Carbamates; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005663:Furans; D013449:Sulfonamides; D014229:Triazolam; C095108:amprenavir; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D019438:Ritonavir; D007654:Ketoconazole