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Xenobiotica
the fate of foreign compounds in biological systems
Volume 43, 2013 - Issue 8
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Animal Pharmacokinetics and Metabolism

Effect of amlodipine on the pharmacokinetics of tacrolimus in rats

, , , , , , , , , , , & show all
Pages 699-704 | Received 25 Oct 2012, Accepted 05 Dec 2012, Published online: 11 Jan 2013
 

Abstract

1. The immunosuppressant tacrolimus (TAC) is a substrate of cytochrome P450 3A2 (CYP3A2) and P-glycoprotein (P-gp) in rats. Amlodipine (AML) is an inhibitor of CYP3A2 in rats. We investigated the effect of AML on the pharmacokinetics of TAC in rats.

2. When co-administered with TAC orally or intravenously, AML decreased the oral clearance and raised the blood concentration of TAC in rats, but the T1/2 of TAC was not significantly affected by AML. Upon oral administration of TAC, the effect of 15 mg/kg of AML on the AUC of TAC was lower than that seen with 5 or 10 mg/kg. However, upon intravenous TAC administration, the effect of 15 mg/kg of AML on the AUC of TAC was higher than that seen with 5 mg/kg.

3. AML is an inhibitor of P-gp and CYP3A2 in rats. If AML and TAC are co-administered orally, AML elicits greater inhibition in P-gp than CYP3A2 during first-pass metabolism. If AML is given orally and TAC given intravenously concurrently, AML mainly inhibits CYP3A2 activity and increases the blood concentration of TAC. There are significant pharmacokinetic interactions between TAC and AML. AML raises the blood concentration of TAC in rats probably by inhibiting P-gp and CYP3A2.

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