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

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Eagling VA, Back DJ, Barry MG

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

Br J Clin Pharmacol. 1997 Aug;44(2):190-4.

PubMed ID

9278209 [ View in PubMed

]

Abstract

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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Ritonavir	Cytochrome P450 1A2	Protein	Humans	Unknown	Inducer	Details

Drug Interactions

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drugs	Interaction
Integrate drug-drug interactions in your software
Diazepam Saquinavir	The serum concentration of Diazepam can be increased when it is combined with Saquinavir.
Flurazepam Saquinavir	The serum concentration of Flurazepam can be increased when it is combined with Saquinavir.
Quinidine Saquinavir	The metabolism of Quinidine can be increased when combined with Saquinavir.
Triazolam Saquinavir	The serum concentration of Triazolam can be increased when it is combined with Saquinavir.