Premium
Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2, CYP2D6, and CYP3A by H 2 ‐receptor antagonists
Author(s) -
Martínez Carmen,
Albet Carlos,
Agúndez José A.G.,
Herrero Eduardo,
Carrillo Juan A.,
Márquez Miguel,
Benítez Julio,
Ortiz José Alfonso
Publication year - 1999
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(99)70129-3
Subject(s) - cyp3a , cyp1a2 , cyp2d6 , pharmacology , in vivo , cytochrome p450 , in vitro , chemistry , biology , biochemistry , enzyme , genetics
The isozymes CYP1A2, CYP2D6, and CYP3A4/5 are involved in the majority of all cytochrome P450– mediated drug biotransformations. In this study we investigated the inhibition profiles of CYP1A2 (substrate: caffeine) CYP2D6 (substrate: dextromethorphan), and CYP3A4/5 (substrate: dextrorphan) by cimetidine, ranitidine, and the novel H 2 ‐receptor antagonist ebrotidine in human liver microsomes. The inhibitory effect of the drugs on the enzymes activities were as follows: CYP1A2: cimetidine >> ranitidine = ebrotidine; CYP2D6: cimetidine >>> ranitidine = ebrotidine; CYP3A4/5: ebrotidine > cimetidine >>> ranitidine. The inhibition of CYP3A4/5 enzyme activity by ebrotidine was competitive. To test whether the inhibitory effect of ebrotidine in CYP3A activity was also found in vivo, we analyzed the biodisposition of midazolam in 8 healthy volunteers. Midazolam biodisposition was significantly reduced when administered together with cimetidine ( P < .05), whereas no significant inhibition was observed with ebrotidine or ranitidine compared with placebo. Psychomotor performance analysis revealed no significant effect of the observed reduction on midazolam biodisposition. We concluded that patients who are receiving treatment with drugs metabolized through CYP3A may experience enhanced drug effects as a result of pharmacokinetic interaction when treated concomitantly with cimetidine. In contrast, the effect of ranitidine or ebrotidine on CYP3A activity in vivo seems to have little clinical significance. Clinical Pharmacology & Therapeutics (1999) 65 , 369–376; doi: