ArticleEuropean journal of clinical pharmacology2007
Inhibition of CYP3A4 and CYP3A5 catalyzed metabolism of alprazolam and quinine by ketoconazole as racemate and four different enantiomers.
Article in European journal of clinical pharmacology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 36 citations in OpenAlex.
- Erlotinib treatment induces cytochrome P450 3A activity in non-small cell lung cancer patients.British journal of clinical pharmacology · 2019Trial
- Changes in Alprazolam Metabolism by CYP3A43 Mutants.Biomedicines · 2022Article
- The role of cytochromes P450 in the metabolism of selected antidepressants and anxiolytics under psychological stress.Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia · 2022Review
- New insights into quetiapine metabolism using molecular networking.Scientific reports · 2020Article
- Metabolism of JQ1, an inhibitor of bromodomain and extra terminal bromodomain proteins, in human and mouse liver microsomes†.Biology of reproduction · 2020Article
- Pharmacokinetic Interaction Between Isavuconazole and a Fixed-Dose Combination of Lopinavir 400 mg/Ritonavir 100 mg in Healthy Subjects.Clinical pharmacology in drug development · 2017Article
- Gomisin A is a Novel Isoform-Specific Probe for the Selective Sensing of Human Cytochrome P450 3A4 in Liver Microsomes and Living Cells.The AAPS journal · 2016Article
- Dual effects of ketoconazole cis-enantiomers on CYP3A4 in human hepatocytes and HepG2 Cells.PloS one · 2014Article
- Article
- Metabolism of alprazolam (a marker of CYP3A4) in hemodialysis patients with persistent inflammation.European journal of clinical pharmacology · 2012Article
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4 authors at 1 institution in 1 country.
Funding
Abstract
objectiveThe antifungal drug ketoconazole (KTZ) is known as an inhibitor of, especially, the CYP3A subfamily, which catalyzes the metabolism of a large variety of drugs. Interactions between KTZ and CYP3A substrates have been reported both in vivo and in vitro. Most of them, however, involved the KTZ racemate. KTZ racemate and the separate enantiomers, 2R,4R; 2R,4S; 2S,4S, and 2S,4R, were evaluated for their selectivity in inhibiting alprazolam and quinine metabolism.
methodsThe inhibition of alprazolam and quinine metabolism was studied in an in vitro system of human liver microsomes (HLM), recombinant of CYP3A4 and CYP3A5. The concentrations of formed 3-hydroxyquinine and 4- and alpha-hydroxyalprazolam were measured by HPLC and LC-MS, respectively.
resultsQuinine 3-hydroxylation was catalyzed to a similar extent by CYP3A4 and CYP3A5. The formation rate of 4-hydroxyalprazolam was higher than that of alpha-hydroxyalprazolam for each HLM, CYP3A4 and CYP3A5. KTZ racemate and enantiomers showed differential inhibitory effects of quinine and alprazolam metabolism. Quinine metabolism catalyzed by HLM, CYP3A4 and CYP3A5 was potently inhibited by the trans-enantiomer KTZ 2S,4S, with IC(50) value of 0.16 microM for HLM, 0.04 microM for CYP3A4 and 0.11 microM for CYP3A5. The same enantiomer showed the lowest IC(50) values of 0.11 microM for HLM and 0.04 microM for CYP3A5 with respect to alprazoalm 4-hydroxylation and also the same pattern for alprazolamalpha-hydroxylation, 0.13 microM for HLM and 0.05 microM for CYP3A5. Alprazolam metabolism (both alpha- and 4- hydroxylations) catalyzed by CYP3A4 was inhibited potently by the cis-enantiomer KTZ 2S,4R, with IC(50) values of 0.03 microM.
conclusionsAlprazolam and quinine metabolism is catalyzed by both CYP3A4 and CYP3A5. The present study showed that different KTZ enantiomers inhibit CYP3A4 and CYP3A5 to different degrees, indicating that structural differences among the enantiomers would be related to their inhibitory potency on these two enzymes.
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