In Vitro Hepatic Oxidative Biotransformation of Trimethoprim.
Article Details
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Goldman JL, Leeder JS, Van Haandel L, Pearce RE
In Vitro Hepatic Oxidative Biotransformation of Trimethoprim.
Drug Metab Dispos. 2015 Sep;43(9):1372-80. doi: 10.1124/dmd.115.065193. Epub 2015 Jul 2.
- PubMed ID
- 26138612 [ View in PubMed]
- Abstract
Trimethoprim (TMP) has been widely used since the 1960s, both alone and in combination with sulfamethoxazole. Unfortunately, information regarding the role that cytochrome P450 enzymes (P450s) play in the formation of TMP primary metabolites is scarce. Hence, we undertook in vitro studies to identify and more fully characterize the P450s that catalyze formation of six TMP primary metabolites: TMP 1-N-oxide (1-NO-TMP) and 3-N-oxide (3-NO-TMP), 3'- and 4'-desmethyl-TMP, a benzylic alcohol (Calpha-OH-TMP), and an N-acetyl cysteine (NAC) adduct of TMP (Calpha-NAC-TMP). Formation kinetics for each TMP metabolite in human liver microsomes (HLMs) were consistent with single-enzyme Michaelis-Menten kinetics, and Km values were markedly above (>/=10-fold) the therapeutic concentrations of TMP (50 microM). The combined results from correlation studies between rates of metabolite formation and marker P450 activities in a panel of HLMs along with inhibition studies utilizing selective P450 inhibitors incubated with pooled HLMs suggested that 1-NO-TMP, Calpha-NAC-TMP, and Calpha-OH-TMP were predominantly formed by CYP3A4. In contrast, 3-NO-TMP was formed predominantly by CYP1A2 in HLMs and inhibited by alpha-naphthoflavone. 4'-Desmethyl-TMP, which is believed to be a reactive TMP metabolite precursor, was formed by several P450s, including CYP3A4, correlated with multiple P450 activities, but was inhibited primarily by ketoconazole (up to 50%), suggesting that CYP3A4 makes a major contribution to TMP 4'-demethylation. TMP 3'-demethylation was catalyzed by multiple P450s, including CYP2C9, correlated with CYP2C9 activity, and was inhibited by sulfaphenazole (up to 40%). Overall, CYP2C9 and CYP3A4 appear to be the most significant contributors to TMP primary metabolism.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Trimethoprim Cytochrome P450 1A2 Protein Humans UnknownSubstrateDetails Trimethoprim Cytochrome P450 2C9 Protein Humans UnknownSubstrateDetails Trimethoprim Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails - Drug Reactions
Reaction Details Details Details Details Details Details
