Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2, CYP2D6, and CYP3A by H -receptor antagonists

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.

Interactions between Over-the-Counter and Illicit Drugs Utilizing Cytochrome P450 Metabolism: Potential for Exacerbation of Pharmacological Response

“…66 Studies that include CMT used different methodology such as Western blotting with serum containing anti-CYP2D6 67 and use different factors to determine the kinetic parameters for CMT. 29,68 Early studies examining the effects of CMT on CYP2D6 as well as other P450 isozymes describe the binding actions of CMT to CYP2D6 and that this interaction can reduce the metabolism of a benzodiazepine by up to 45%.…”

“…29 Literature describing the actions of DEX on CYP2D6 are the most prevalent and use DEX as a probe to determine enzyme activity or phenotyping. 29,41,68 Also DEX has been used to categorize the metabolizer-typing of the patient. 45 Studies on DEX-mediated CYP2D6 inhibition report IC 50 values for DEX of 1.89 μM to 2.0 μM dependent on drug concentration.…”

“…2,13,14 Comparing the actions of CMT and DEX at CYP2D6, CMT exhibits 20-fold lower potency at inhibiting compared to DEX (200 µM vs. 10 µM). 15 Inhibitors of CYP activity lead to increased drug adverse effects associated with the increase in the drug concentration.…”

Interações farmacológicas entre medicações clínicas e psiquiátricas

“…O resultado evidencia pouco ou nenhum efeito da ranitidina, ao contrário da cimetidina, resultado similar a outros estudos mais recentes (Martinez, 1999). Porém, existem estudos conflitantes.…”

Validated Method for the Simultaneous Determination of Gemifloxacin and H2‐receptor Antagonists in Bulk, Pharmaceutical Formulations and Human Serum by RP‐HPLC; In‐vitro Applications

“…1) i.e. Cimetidine (CIME) which produces its action by inhibiting the hepatic cytochrome P450 and its isoforms, 26 Famotidine (FAMO) is indicated for the treatment of duodenal ulcer, gastric ulcer, gastro esophageal reflux disease, Zollinger-Ellison syndrome, 27 as well as secretion stimulated by food and pentagastrin. 28 Ranitidine hydrochloride (RANI) has a furan ring structure and inhibits gastric acid secretion induced by various stim-uli.…”