Specific and dose-dependent enzyme induction by omeprazole in human beings

Abstract

Omeprazole induces hepatic cytochrome P-4501A2. In a previous study this effect was shown to be significant in vivo in 6 poor metabolizers, including 1 intermediate metabolizer, but not in 12 extensive metabolizers of S-mephenytoin after 7 days of treatment with 40 mg/day omeprazole. In this study, the specificity of the inducing potential of omeprazole was investigated in these volunteers. Furthermore, in eight of the extensive metabolizers the dose-dependence of cytochrome P-450 1A2 induction was evaluated. Cytochrome P-450 1A2 activity was monitored by means of the 13C-[N3-methyl]caffeine breath test and by means of plasma caffeine clearance before omeprazole treatment with 120 mg/day, on the seventh day of dosage and after a 7-day washout. Omeprazole plasma concentration was measured. Results were compared with those after 40 mg. gamma-Glutamyltransferase activity in serum, as well as urinary excretion of D-glucaric acid and 6 beta-hydroxycortisol, were measured on the same study days in all study groups (n = 26). In the eight extensive metabolizers the breath test indicated a dose-dependent increase of cytochrome P-450 1A2 activity of 8.5% +/- 15.0% (40 mg, mean +/- SD, NS) and 27.2% +/- 16.5% (120 mg, p = 0.002). Caffeine clearance was increased by 31.6% +/- 20.7% (p < 0.001) with the higher dose. None of the study groups exhibited a significant increase of gamma-glutamyltransferase activity or urinary excretion of D-glucaric acid or 6 beta-hydroxycortisol. This was in contrast to the phenobarbital-type induction observed after treatment with antiepileptic drugs. Induction by omeprazole seems to be restricted to cytochrome P-450 1A enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of High‐Dose Esomeprazole on CYP1A2, CYP2C19, and CYP3A4 Activities in Humans: Evidence for Substantial and Long‐lasting Inhibition of CYP2C19

“…Moreover, no signs of CYP3A4 induction were observed in any of the study phases. However, similarly to some studies with omeprazole, 13,15,33 a slight induction of CYP1A2 by high-dose esomeprazole was observed in the present study. These effects on CYP3A4 and CYP1A2 activities can be clinically relevant in special situations, such as with anticancer agents or immunosuppressants with narrow therapeutic indices, or with drugs that are substrates for both CYP3A4 and 2C19.…”

“…Furthermore, clinical trials suggest that racemic omeprazole has a weak CYP1A2 inducing effect in poor metabolizers of CYP2C19 and when used at high doses. 13,14 However, clinical studies of the effects of esomeprazole on CYP3A4 or CYP1A2 activities are sparse and conclusive evidence is lacking. For example, although standard doses of esomeprazole increased the area under the plasma concentration-time curve (AUC) of the CYP3A4 substrate cisapride, it had no effect on the pharmacokinetics of clarithromycin or quinidine, and, in one study, in CYP2C19 poor metabolizers, it had no effect on CYP1A2 activity.…”

“…Based on small clinical studies, standard doses of racemic omeprazole slightly increase the concentrations of the CYP3A4 substrates carbamazepine and nifedipine 11,12 suggesting a net inhibitory effect on CYP3A4. Furthermore, clinical trials suggest that racemic omeprazole has a weak CYP1A2 inducing effect in poor metabolizers of CYP2C19 and when used at high doses 13,14 . However, clinical studies of the effects of esomeprazole on CYP3A4 or CYP1A2 activities are sparse and conclusive evidence is lacking.…”

CYP Induction-Mediated Drug Interactions: in Vitro Assessment and Clinical Implications

“…The individual who did not initially respond (20 mg/day) had a marked increase in both mRNA and enzyme activity after receiving 60 mg of omeprazole daily for 1 week, suggesting that enzyme induction is dose-dependent. Similarly, dosedependent induction of CYP1A2 by omeprazole has been demonstrated between 40-and 120-mg doses, as measured by 13 C-[N-3-methyl]-caffeine breath test (155). In another clinical study, CYP1A2 was induced in poor metabolizers (PMs) of CYP2C19, but not in extensive metabolizers (EMs) after 7 days treatment with omeprazole at 40 mg/day (156).…”

Arzneimittelinteraktionen

“…Diese In-vitro-Befunde wurden in klinischen Studien,mit Hilfe der Methylxanthine Theophyllin und Koffein nachgeprüft, die als geeignete Testsubstrate für das Enzym CYP1A2 gelten. Die Plasmaclearance von Koffein konnte dosisabhängig (Omeprazol 40-120 mg/Tag über 7 Tage) um bis zu 40% durch die Einnahme von Omeprazol beschleunigt werden[33,34]. Dieser Effekt konnte jedoch für niedrigere Dosen von Omeprazol (20 mg/Tag) nicht bestätigt werden[1,31].…”