The metabolism of gliclazide in man

Abstract

1. Gliclazide, 1-(3-azabicyclo[3, 3,0]oct-3-yl)-3-(4-methylphenylsulphonyl)urea, was orally administered to five healthy male volunteers at a dose of 40 mg.

2. Urine contained seven metabolites classified into two types according to the site of biotransformation. Two major metabolites, 1-(3-azabicyclo[3,3,0]oct-3-yl)-3-(4-carboxyphenylsulphonyl)urea and 1-(3-azabicyclo[3, 3,0]oct-3-yl)-3-(4-hydroxymethyl-phenylsulphonyl)urea, of the first type were oxidized at the methyl group of the tolyl group. Five metabolites of the second type including two glucuronides were hydroxylated at a specific site in the azabicyclo-octyl ring (6β, 7β and 7α). The molecular conformation of this type of metabolites could explain the existence of conjugates of the β-hydroxy groups in the azabicyclo-octyl ring and the absence of those of the α-hydroxy group.

3. Only the unchanged drug was detected in plasma. The peak concentration at four hours after dosing was 2.6±0.2 µg/ml, and the elimination half-life in plasma was 8.1 ± 1.1 hours which was apparently determined by the rate of metabolism.

4. Identified metabolites excreted in urine accounted for 45% of the dose in 24 h and 61% in 96 h, indicating that this was the major excretory route.