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KMID : 0606920110190020255
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Biomolecules & Therapeutics
2011 Volume.19 No. 2 p.255 ~ p.260
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Effects of Ticlopidine on the Pharmacokinetics of Diltiazem and Its Main Metabolite, Desacetyldiltiazem, in Rats
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Choi Jun-Shik
Yang Joon-Seung
Choi Dong-Hyun
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Abstract
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The purpose of this study was to investigate the effect of ticlopidine on the pharmacokinetics of diltiazem and its active metabolite, desacetyldiltiazem, in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined in rats after oral administration of diltiazem (15 mg · kg?1) with ticlopidine (3 or 9 mg · kg?1). The effects of ticlopidine on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activities were also evaluated. Ticlopidine inhibited CYP3A4 enzyme activity in a concentrationdependent manner with a 50% inhibition concentration (IC50) of 35 μM. In addition, ticlopidine did not signifi cantly enhance the cellular accumulation of rhodamine-123 in NCI/ADR-RES cells overexpressing P-gp. Compared with the control (given diltiazem alone), ticlopidine signifi cantly altered the pharmacokinetic parameters of diltiazem. The peak concentration (Cmax) and the area under the plasma concentration-time curve (AUC) of diltiazem were signifi cantly (9 mg · kg?1, p<0.05) increased in the presence of ticlopidine. The AUC of diltiazem was increased by 1.44-fold in rats in the presence of ticlopidine (9 mg · kg?1). Consequently, the absolute bioavailability (A.B.) of diltiazem in the presence of ticlopidine (9.3-11.5%) was signifi cantly higher (9 mg · kg?1, p<0.05) than that in the control group (8.0%). Although ticlopidine signifi cantly (p<0.05) increased the AUC of desacetyldiltiazem, the metabolite-parent AUC ratio (M.R.) in the presence of ticlopidine (9 mg · kg?1) was signifi cantly decreased compared to that in the control group, implying that ticlopidine could effectively inhibit the metabolism of diltiazem. In conclusion, the concomitant use of ticlopidine signifi cantly enhanced the oral bioavailability of diltiazem in rats by inhibiting CYP3A4-mediated metabolism in the intestine and/or liver rather than by inhibiting intestinal P-gp activity or renal elimination of diltiazem.
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KEYWORD
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Diltiazem, Desacetyldiltiazem, Ticlopidine, Pharmacokinetics, CYP3A4, Rat
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