In vitro metabolism of dorzolamide, a novel potent carbonic anhydrase inhibitor, in rat liver microsomes.
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Hasegawa T, Hara K, Kenmochi T, Hata S
In vitro metabolism of dorzolamide, a novel potent carbonic anhydrase inhibitor, in rat liver microsomes.
Drug Metab Dispos. 1994 Nov-Dec;22(6):916-21.
- PubMed ID
- 7895610 [ View in PubMed]
- Abstract
The in vitro metabolism of dorzolamide, a potent carbonic anhydrase inhibitor, was investigated using liver microsomes from Sprague-Dawley rats. The liver microsomes metabolized dorzolamide to an N-deethylated form, whereas N-deethylation of dorzolamide was not detected in 10,000g supernatant from the small intestine, brain, heart, lung, kidney and spleen, or the cytosol fraction of liver. The dorzolamide N-deethylase activity was not detected without an NADPH-generating system and was inhibited by classical inhibitors for cytochrome P450, metyrapone and n-octylamine. Orphenadrine and diphenhydramine (specific inhibitors for CYP2B1/2), diethyldithiocarbamate, disulfiram and isoniazid (inhibitors for CYP2E1), troleandomycin (inhibitor for CYP3A), and testosterone inactivated dorzolamide N-deethylase activity. On the other hand, ajmalicine, a specific inhibitor for CYP2D1, did not inhibit the reaction. With phenobarbital-induced microsomes, 66%, 72%, 36%, and 53% of the 2 beta-, 6 beta-, 16 alpha-, and 16 beta-testosterone hydroxylase activities were inhibited by 5 mM dorzolamide, respectively, whereas the 2 alpha-hydroxylase activity was not inactivated. Antisera against rat CYP2B1, CYP2E1, and CYP3A2 suppressed dorzolamide N-deethylase activity by 52%, 43% and 46%, respectively, whereas only 18% and 15% of the activity were inhibited by anti-CYP1A1 and anti-CYP4A1 antibodies, respectively. Analysis of the N-deethylase reactions using Eadie-Scatchard plots showed high- and low-affinity components in rat liver microsomes. The high-affinity reaction was induced with phenobarbital and dexamethasone, but not with 3-methylcholanthrene. These results suggest that CYP2B, CYP2E1, and CYP3A subfamilies are involved in the dorzolamide N-deethylation in rat liver microsomes.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Dorzolamide Cytochrome P450 2B1 Protein Rat NoSubstrateDetails Dorzolamide Cytochrome P450 2E1 Protein Humans NoSubstrateDetails Dorzolamide Cytochrome P450 3A2 Protein Rat NoSubstrateDetails - Drug Reactions
Reaction Details
