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Abstract
1. The metabolism of gliclazide to hydroxygliclazide has been investigated in Sprague-Dawley rat liver microsomes.
2. The kinetics of hydroxygliclazide formation are consistent with Michaelis-Menten kinetics (mean (± SD, n = 3) apparent Km and Vmax = 256 ± 27 μM and 1.85 ± 0.10nmol/min/mg respectively).
3. Tolbutamide competitively inhibited hydroxygliclazide formation (Ki = 840 μM) and gliclazide competitively inhibited hydroxytolbutamide formation (Ki = 240 μM) with Ki similar to Km. Therefore gliclazide and tolbutamide may be metabolized by the same enzyme in the rat. In nine livers the formation of hydroxygliclazide correlated with the formation of hydroxytolbutamide (rs = 0.82, p < 0.01).
4. Diclofenac (Ki = 64 μM), phenytoin (Ki = 38 μM), mephenytoin ((Ki = 66 μM), glibenclamide (Ki = 14 μM) and glipizide (Ki = 189 μM) were fully competitive inhibitors of gliclazide hydroxylation. The rank order of Ki constants differed for gliclazide and tolbutamide suggesting that gliclazide and tolbutamide hydroxylases are not identical enzymes.
5. Quinine (Ki = 0.3 μM) and quinidine (Ki = 4.3 μM) were partially competitive inhibitors of hydroxygliclazide formation. Hydroxylation of gliclazide was related to the activity of CYP2D1 as assessed by dextrorphan production from dextromethorphan (rs = 0.83, p = 0.01).
6. In the rat gliclazide is metabolized to hydroxygliclazide by at least two cytochrome P450 isoforms, including tolbutamide hydroxylase and 2D1, which have similar affinities for gliclazide.