Colchicine biotransformation by human liver microsomes. Identification of CYP3A4 as the major isoform responsible for colchicine demethylation.

Article Details

Citation

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
DrugEnzymeKindOrganismPharmacological ActionActions
ColchicineCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inhibitor
Details
Drug Reactions
Reaction
Details
Details
Details
Drug Interactions
DrugsInteraction
Colchicine
Clozapine
The metabolism of Colchicine can be decreased when combined with Clozapine.
Colchicine
Viloxazine
The metabolism of Colchicine can be decreased when combined with Viloxazine.
Colchicine
Aldesleukin
The metabolism of Colchicine can be decreased when combined with Aldesleukin.
Colchicine
Octreotide
The metabolism of Colchicine can be decreased when combined with Octreotide.
Colchicine
Fluvoxamine
The metabolism of Colchicine can be decreased when combined with Fluvoxamine.