Pharmacokinetic interaction between metoprolol and SP-8203 in rats: competitive inhibition for the metabolism of metoprolol by SP-8203 via hepatic CYP2D subfamily

Abstract

1. The occurrence of cerebral ischemia is prevalent in patients with hypertension and the combination drug therapy is needed. Thus, the pharmacokinetic interaction between metoprolol (anti-hypertension drug) and SP-8203 (a new drug candidate for cerebral ischemia) with respect to the metabolism via CYP isozymes was evaluated.

2. Metoprolol and SP-8203 were administered intravenously or orally to rats. Concentrations (I) of each drug in the liver and intestine in in vivo studies, the disappearance and apparent K_i of each drug in in vitro microsomes and [I]/K_i ratios for each drug were determined. In addition, the disappearance of each drug via CYPs in rat and human microsomes were measured.

3. The AUC and CL_NR of intravenously administered metoprolol with SP-8203 were significantly greater and slower, respectively, than without SP-8203. However, pharmacokinetic parameters of oral metoprolol and intravenous/oral SP-8203 were not altered.

4. The hepatic metabolism of metoprolol via CYP2D was inhibited by SP-8203 in a competitive manner. However, the intestinal metabolism of metoprolol was not influenced by SP-8203. SP-8203 was not metabolized via CYP isozymes in rats and then co-administration of metoprolol did not affect the metabolism of SP-8203.

Keywords::

• Metoprolol
• SP-8203
• pharmacokinetics
• hepatic metabolism
• inhibition
• CYP2D