Metabolism of artelinic acid to dihydroqinghaosu by human liver cytochrome P4503A
| Autor: | J M Grace, D J Skanchy, A J Aguilar |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Male
Antifungal Agents Miconazole Vasodilator Agents Health Toxicology and Mutagenesis medicine.medical_treatment Pharmacology Paeonia Toxicology Biochemistry Troleandomycin chemistry.chemical_compound Cytochrome P-450 Enzyme System Sulfaphenazole Cytochrome P-450 CYP3A Drug Interactions Enzyme Inhibitors General Medicine Middle Aged Quinidine Artemisinins Recombinant Proteins Isoenzymes Drug Combinations Ketoconazole Cytochrome P-450 CYP2D6 Liver Inactivation Metabolic Microsomes Liver Female Aryl Hydrocarbon Hydroxylases Artelinic acid Sesquiterpenes medicine.drug Adult Biology Antimalarials Inhibitory Concentration 50 Glycyrrhiza medicine Humans IC50 Active metabolite Aged CYP3A4 Bufuralol Oxidoreductases N-Demethylating Metabolism Verapamil chemistry Microsome Drugs Chinese Herbal |
| Zdroj: | Xenobiotica. 29:703-717 |
| ISSN: | 1366-5928 0049-8254 |
| DOI: | 10.1080/004982599238335 |
| Popis: | 1. Artelinic acid (AL), a water-soluble artemisinin analogue for treatment of multidrug resistant malaria, is metabolized to the active metabolite dihydroqinghaosu (DQHS) solely by CYP3A4/5. Although AL is not metabolized by CYP2C9, it does inhibit diclofenac 4-hydroxylase activity with an IC50 = 115 microM. Interestingly, AL activates CYP2D6-mediated bufuralol metabolism in human liver microsomes but not recombinant CYP2D6-Val by approximately 30% at AL concentrations up to 100 microM. 2. In human liver microsomes, AL is metabolized to DQHS with a Km = 157 +/- 44 microM and Vmax = 0.77 +/- 0.56 nmol DQHS/min/mg protein. Human recombinant CYP3A4 catalysed the conversion of AL to DQHS with a Km = 102 +/- 23 microM and a Vmax = 1.96 +/- 0.38 nmol DQHS/min/nmol P450. The kinetic parameters (Km and Vmax) for DQHS formation from CYP3A5 were 189 +/- 19 microM and 3.60 +/- 0.42 nmol DQHS/min/nmol P450 respectively. 3. Inhibition studies suggest that azole antifungals and calcium channel blockers may present clinically significant drug drug interactions. In human liver microsomes, ketoconazole and miconazole were potent competitive inhibitors of DQHS formation with a Ki = 0.028 and 0.124 microM respectively. Verapamil is a non-competitive inhibitor of DQHS formation in human liver microsomes with a Ki = 15 microM. |
| Databáze: | OpenAIRE |
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