Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir

Aims: To compare the inhibitory potential of the HIV Protease Inhibitors saquinavir, ritonavir and indinavir against CYP1A2, CYP2C9, CYP2E1 and CYP3A4 catalysed metabolic reactions in human liver microsomes in vitro.

Methods: Microsomes from six human livers were utilized in this study. The probe substrates were phenacetin (CYP1A2), tolbutamide (CYP2C9), chlorzoxazone (CYP2E1) and testosterone (CYP3A4). Metabolites were analysed by high performance liquid chromatography. IC50 (concentration of inhibitor giving 50% decrease in Enzyme activity) and, where appropriate, K(i) values were calculated.

Results: Ritonavir was a very potent inhibitor of CYP3A4 mediated testosterone 6beta-hydroxylation (mean K(i) = 0.019 +/- 0.004 microM, mean +/- s.d.; n = 6) and also inhibited tolbutamide hydroxylation (IC50 = 4.2 +/- 1.3 microM, mean +/- s.d.; n = 6). Inhibition of phenacetin O-deethylation and chlorzoxazone 6-hydroxylation was negligible. Indinavir was an order-of-magnitude less potent in inhibiting CYP3A4 (K(i) = 0.17 +/- 0.01 microM) and did not produce appreciable inhibition of the CYP1A2, CYP2C9 or CYP2E1 catalysed reactions. Saquinavir was the least potent CYP3A4 Inhibitor (K(i) = 2.99 +/- 0.87 microM) and produced some inhibition of CYP2C9 (approximately 50% at 50 microM).

Conclusions: The HIV Protease Inhibitors have differential effects on CYP isozymes. There is obvious potential for clinically significant drug interactions particularly with ritonavir. Pharmacokinetic drug interaction studies are crucial to gain an overall understanding of the beneficial and potentially harmful effects of this important group of drugs.