ArticleDrug metabolism and disposition: the biological fate of chemicals2012
Prediction of relative in vivo metabolite exposure from in vitro data using two model drugs: dextromethorphan and omeprazole.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 56 citations in OpenAlex.
- Does In Vitro Cytochrome P450 Downregulation Translate to In Vivo Drug-Drug Interactions? Preclinical and Clinical Studies With 13-cis-Retinoic Acid.Clinical and translational science · 2019Trial
- Role of metabolites in drug-drug interactions.Drug metabolism and pharmacokinetics · 2026Review
- Metabolite Identification Data in Drug Discovery, Part 1: Data Generation and Trend Analysis.Molecular pharmaceutics · 2025Article
- Article
- Effect of isotretinoin on CYP2D6 and CYP3A activity in patients with severe acne.British journal of clinical pharmacology · 2024Article
- Evaluation of Cytochrome P450-Mediated Cannabinoid-Drug Interactions in Healthy Adult Participants.Clinical pharmacology and therapeutics · 2023Article
- A clinical pharmacokinetic drug-drug interaction study between dextromethorphan and emvododstat, a potent anti-SARS-CoV-2 dihydroorotate dehydrogenase inhibitor.European journal of clinical pharmacology · 2023Article
- Infant Dextromethorphan and Dextrorphan Exposure via Breast Milk From Mothers Who Are CYP2D6 Extensive Metabolizers.Journal of clinical pharmacology · 2022Article
- Effects of elagolix on the pharmacokinetics of omeprazole and its metabolites in healthy premenopausal women.Clinical and translational science · 2022Article
- Physiologically-based pharmacokinetic modeling of dextromethorphan to investigate interindividual variability within CYP2D6 activity score groups.CPT: pharmacometrics & systems pharmacology · 2022Article
- Physiologically based pharmacokinetic (PBPK) modeling of the role of CYP2D6 polymorphism for metabolic phenotyping with dextromethorphan.Frontiers in pharmacology · 2022Article
- Prediction of Metabolite-to-Parent Drug Exposure: Derivation and Application of a Mechanistic Static Model.Clinical and translational science · 2020Article
- In vitro to in vivo extrapolation of the complex drug-drug interaction of bupropion and its metabolites with CYP2D6; simultaneous reversible inhibition and CYP2D6 downregulation.Biochemical pharmacology · 2017Article
- Pharmacokinetic comparison between the long-term anesthetized, short-term anesthetized and conscious rat models in nasal drug delivery.Pharmaceutical research · 2014Article
- Inhibition of CYP2C19 and CYP3A4 by omeprazole metabolites and their contribution to drug-drug interactions.Drug metabolism and disposition: the biological fate of chemicals · 2013Article
- A physiologically based pharmacokinetic model to predict disposition of CYP2D6 and CYP1A2 metabolized drugs in pregnant women.Drug metabolism and disposition: the biological fate of chemicals · 2013Article
- Hepatic Cyp2d and Cyp26a1 mRNAs and activities are increased during mouse pregnancy.Drug metabolism and disposition: the biological fate of chemicals · 2013Article
- In vitro analysis and quantitative prediction of efavirenz inhibition of eight cytochrome P450 (CYP) enzymes: major effects on CYPs 2B6, 2C8, 2C9 and 2C19.Drug metabolism and pharmacokinetics · 2013Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Metabolites can have pharmacological or toxicological effects, inhibit metabolic enzymes, and be used as probes of drug-drug interactions or specific cytochrome P450 (P450) phenotypes. Thus, better understanding and prediction methods are needed to characterize metabolite exposures in vivo. This study aimed to test whether in vitro data could be used to predict and rationalize in vivo metabolite exposures using two model drugs and P450 probes: dextromethorphan and omeprazole with their primary metabolites dextrorphan, 5-hydroxyomeprazole (5OH-omeprazole), and omeprazole sulfone. Relative metabolite exposures were predicted using metabolite formation and elimination clearances. For dextrorphan, the formation clearances of dextrorphan glucuronide and 3-hydroxymorphinan from dextrorphan in human liver microsomes were used to predict metabolite (dextrorphan) clearance. For 5OH-omeprazole and omeprazole sulfone, the depletion rates of the metabolites in human hepatocytes were used to predict metabolite clearance. Dextrorphan/dextromethorphan in vivo metabolite/parent area under the plasma concentration versus time curve ratio (AUC(m)/AUC(p)) was overpredicted by 2.1-fold, whereas 5OH-omeprazole/omeprazole and omeprazole sulfone/omeprazole were predicted within 0.75- and 1.1-fold, respectively. The effect of inhibition or induction of the metabolite's formation and elimination on the AUC(m)/AUC(p) ratio was simulated. The simulations showed that unless metabolite clearance pathways are characterized, interpretation of the metabolic ratios is exceedingly difficult. This study shows that relative in vivo metabolite exposure can be predicted from in vitro data and characterization of secondary metabolism of probe metabolites is critical for interpretation of phenotypic data.
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