Pharmacokinetics and Drug Disposition
Clinical Pharmacology & Therapeutics (1999) 65, 369–376; doi:
Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2, CYP2D6, and CYP3A by H2-receptor antagonists*
Carmen Martínez MD, PhD1, Carlos Albet PharmD1, José A.G. Agúndez MD, PhD1, Eduardo Herrero PharmD1, Juan A. Carrillo MD, PhD1, Miguel Márquez MD, PhD1, Julio Benítez MD, PhD1 and José Alfonso Ortiz MD, PhD1
1Department of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain and Centro de Investigación Farmacéutica Grupo Ferrer, Barcelona, Spain
Correspondence: Julio Benítez, MD, PhD, Departamento de Farmacología, Facultad de Medicina, Universidad de Extremadura, Avda. de Elvas s/n, 06071, Badajoz, Spain. E-mail: jbenitez@unex.es
*Supported in part by grants from Ferrer Internacional and CICYT-SAF96-0006 from Comisión Interministerial de Ciencia y Tecnología (Madrid, Spain).
Received 20 July 1998; Accepted 24 November 1998.
Abstract
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 H2-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.
