Colchicine biotransformation by human liver microsomes. Identification of CYP3A4 as the major isoform responsible for colchicine demethylation.
Article Details
- CitationCopy to clipboard
Tateishi T, Soucek P, Caraco Y, Guengerich FP, Wood AJ
Colchicine biotransformation by human liver microsomes. Identification of CYP3A4 as the major isoform responsible for colchicine demethylation.
Biochem Pharmacol. 1997 Jan 10;53(1):111-6. doi: 10.1016/s0006-2952(96)00693-4.
- PubMed ID
- 8960070 [ View in PubMed]
- Abstract
Colchicine disposition involves both active biliary and renal excretion of parent drug, and at least in mammals a substantial fraction undergoes hepatic demethylation prior to excretion. We investigated the biotransformation of [3H]colchicine in a panel of microsomal preparations obtained from sixteen human liver samples. The production rate of the main metabolites of colchicine's 3-demethylcolchicine (3DMC) and 2-demethylcolchicine (2DMC), was linear in relation to incubation time, cytochrome (P450) content, and substrate concentration. Following the incubation of colchicine (5 nM) with microsomes in the presence of an NADPH-generating system for 60 min, 9.8% and 5.5% of the substrate were metabolized to 3DMC and 2DMC, respectively. The formation rate of colchicine metabolites exhibited a marked variation between the different microsomal preparations. The formation rates of both colchicine metabolites were correlated significantly with nifedipine oxidase activity, a marker of CYP3A4 activity (r = 0.96, P < 0.001), but not with the metabolic markers of CYP2A6, CYP2C19, CYP2C9, CYP2D6, and CYP2E1 activities. Chemical inhibition of CYP3A4 by preincubation with gestodene (40 microM) or troleandomycin (40 microM) reduced the formation of 3DMC and 2DMC by 70 and 80%, respectively, whereas quinidine, diethyldithiocarbamate, and sulfaphenazole had no inhibitory effect. Similarly, antibodies raised against CYP3A4 almost completely abolished colchicine demethylation and nifedipine oxidase activity, but preimmune IgG had no effect. In conclusion, colchicine was metabolized to 3DMC and 2DMC by human liver microsomes. The production of colchicine metabolites was mediated by CYP3A4, and its rate varied greatly between microsomal preparations obtained from different liver samples. The coadministration of colchicine with known inhibitors or substrates of CYP3A4 may inhibit colchicine metabolism, resulting in concentration-related toxicity.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Colchicine Cytochrome P450 3A4 Protein Humans UnknownSubstrateInhibitorDetails - Drug Reactions
Reaction Details Details Details - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareColchicineClozapine The metabolism of Colchicine can be decreased when combined with Clozapine. ColchicineViloxazine The metabolism of Colchicine can be decreased when combined with Viloxazine. ColchicineAldesleukin The metabolism of Colchicine can be decreased when combined with Aldesleukin. ColchicineOctreotide The metabolism of Colchicine can be decreased when combined with Octreotide. ColchicineFluvoxamine The metabolism of Colchicine can be decreased when combined with Fluvoxamine.