Influence of single- and multiple-dose omeprazole treatment on nifedipine pharmacokinetics and effects in healthy subjects

Soons, P. A.; Berg, Gerrit van den; Danhof, Meindert; Brummelen, P. Van; Jansen, J.B.M.J.; Lamers, C. B. H. W.; Breimer, D. D.

doi:10.1007/bf00266355

Cited by 58 publications

(53 citation statements)

References 30 publications

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“…Although 9 of 15, or 60%, of the clinical noninducers examined also activated PXR/CYP3A in DPX2 cells (Table 3), these same agents give induction of CYP3A4 mRNA in hepatocytes and other model systems . Among the noninducers, rosiglitazone promoted PXR activation in vitro only at concentrations exceeding 25 M, which far surpasses the C max of 1.4 M in vivo (Fahmi et al, 2008a), whereas omeprazole activated PXR at levels (Ͼ10 M) that exceeded the C max of 0.68 M (Soons et al, 1992). Despite eliciting substantial PXR activation (E max Ͼ9-fold), neither leflunomide nor omeprazole increased CYP3A-mediated luciferin-IPA metabolism in DPX2 cells (Fig.…”

Section: Dpx2 Cells For Predicting Ddi Due To Cyp3a Inductionmentioning

confidence: 91%

Utility of DPX2 Cells for Predicting CYP3A Induction-Mediated Drug-Drug Interactions and Associated Structure-Activity Relationships

et al. 2012

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ABSTRACT:The increase in cytochrome P450 (P450) enzyme activity noted upon exposure to therapeutics can elicit marked drug-drug interactions (DDIs) that may ultimately result in poor clinical outcome or adverse drug effects. As such, in vitro model systems that can rapidly and accurately determine whether potential therapeutics activate the human pregnane X receptor (PXR) and thus induce CYP3A P450 levels are highly sought after tools for drug discovery. To that end, we assessed whether DPX2 cells, a HepG2-derived cell line stably integrated with a PXR expression vector plus a luciferase reporter, could detect agents that not only cause PXR activation/CYP3A induction but also elicit clinical DDIs. All 20 clinical inducers and 9 of 15 clinical noninducers examined activated PXR in DPX2 cells (E max > 8-fold), although activation parameters obtained with the noninducers were not predictive of DDI. The relative induction score, calculated by combining PXR activation parameters (EC 50 and E max ) in DPX2 cells for seven inducers plus four noninducers with their efficacious total plasma concentrations, strongly correlated (R 2 ‫؍‬ 0.90) with the magnitude of induction of midazolam clearance. Thus, the DPX cell-based PXR activation system is not only capable of distinguishing potential inducers in a high-throughput manner but can also differentiate among compounds in predicting the magnitude of induction-mediated DDIs, providing a means for structure-activity relationship screening during discovery and development.

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Section: Dpx2 Cells For Predicting Ddi Due To Cyp3a Inductionmentioning

confidence: 91%

Utility of DPX2 Cells for Predicting CYP3A Induction-Mediated Drug-Drug Interactions and Associated Structure-Activity Relationships

et al. 2012

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“…These probe drugs are moderate or high clearance drugs (Greenblatt et al, 1998;Wong et al, 1998;Lin, 2006), and the clearance and bioavailability are dependent on CYP3A4 metabolism. Omeprazole and nifedipine have not been found to induce CYP3A in vivo (Soons et al, 1992;Bowles et al, 1993). The correlation of AUC/F 2 values from CYP3A4 mRNA induction and the in vivo induction (Fig.…”

mentioning

confidence: 99%

HepaRG Cells as an in Vitro Model for Evaluation of Cytochrome P450 Induction in Humans

2007

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“…tlj2) did not change. 20 In another study, a 14 d treatment with omeprazole (20 mg d-I ) caused an increase in AUC of carbamazepine in seven patients with duodenal ulcer.21 Similarly, a significant although small increase in digoxin AUCc-90 has been reported. The authors proposed a double mechanism to explain this interaction: an increase in absorption and a decrease in metabolism.…”

Section: Discussionmentioning

confidence: 93%

THE EFFECT OF CHANGES IN GASTRIC pH INDUCED BY OMEPRAZOLE ON THE ABSORPTION AND RESPIRATORY DEPRESSION OF METHADONE

Castro

Aguirre

Rodríguez-Sasiaín

et al. 1996

Biopharm. Drug Dispos.

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The effect of omeprazole (2 mg kg−1 i.v.) on respiratory depression induced in rats by acute oral methadone administration (5 mg kg−1) was examined and compared with control animals that only received methadone. Quantitative assessments of arterial pCO2, pO2, pH, and respiratory rate were employed as criteria for evaluation. Intragastric pH was measured in each rat immediately before and 2 h after methadone. Plasma concentration of methadone was measured for 3 h. The relationship between drug effect and the systemic bioavailability of methadone, measured as the area under the plasma concentration–time curve (AUC0–180 ), was also evaluated. The intensity of the methadone‐induced respiratory depression was significantly greater in the omeprazole group than in control rats. A significant variation (p<0·01) in all respiratory parameters was detected from 30 to 120 min after methadone. Omeprazole caused a significant increase in methadone levels (Cmax=156± 6·5 ng mL−1 against 51±5·8 ng mL−1 in control; p<0·05). AUC0–180 was higher (p<0·05) after omeprazole treatment (18·6±1·4 μg mL−1 min) than in control (6·8± 0·6 μg mL−1 min). Two hours after treatment with omeprazole, intragastric pH values were significantly elevated (4·7±0·1 against 2·2±0·04) and continued increasing, being 6·4±0·1 at the end of the experiment. Correlation was observed between intragastric pH and the area under the effect– (respiratory depression–) time curve (r=0·74; p<0·001). A relationship between plasma methadone levels at 120 min and gastric pH (r=0·92; p<0·001) was detected. A significant correlation between the area under the effect–time curve (0–120 min) and AUC0–180 has been also observed (r=0·90; p<0·01). These pharmacokinetic and pharmacodynamic changes could be gastric pH dependent because they were mimicked when gastric pH was experimentally modified by bicarbonate whereas opposite results were obtained with acidic pH 2 solution.

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Influence of single- and multiple-dose omeprazole treatment on nifedipine pharmacokinetics and effects in healthy subjects

Cited by 58 publications

References 30 publications

Utility of DPX2 Cells for Predicting CYP3A Induction-Mediated Drug-Drug Interactions and Associated Structure-Activity Relationships

Utility of DPX2 Cells for Predicting CYP3A Induction-Mediated Drug-Drug Interactions and Associated Structure-Activity Relationships

HepaRG Cells as an in Vitro Model for Evaluation of Cytochrome P450 Induction in Humans

THE EFFECT OF CHANGES IN GASTRIC pH INDUCED BY OMEPRAZOLE ON THE ABSORPTION AND RESPIRATORY DEPRESSION OF METHADONE

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