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

Content Provider	Semantic Scholar
Author	Eagling, V. A. Back, D. J. Barry, Michael G.
Copyright Year	1997
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.
Starting Page	3325
Ending Page	3335
Page Count	11
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://pubmedcentralcanada.ca/pmcc/articles/PMC2042821/pdf/bcp_0644.pdf
PubMed reference number	9278209v1
Volume Number	44
Issue Number	2
Journal	British journal of clinical pharmacology
Language	English
Access Restriction	Open
Subject Keyword	Chlorzoxazone Cytochrome P-450 CYP1A2 Cytochrome P-450 CYP2E1 Cytochrome P450 Drug Interactions Endopeptidases HIV Infections High pressure liquid chromatography procedure Hydroxylation Indinavir Inhibition Inhibitory Concentration 50 Liver diseases Metabolic Process, Cellular Microsomes Phenacetin Protein Isoforms Ritonavir Saquinavir Testosterone Tolbutamide enzyme activity
Content Type	Text
Resource Type	Article