Effects of Phenobarbital and Dosing Time on The Plasma Concentration and Pharmacological Activity of Tadalafil in Mice
Abstract
Tadalafil is a potent selective phosphodiesterase 5 inhibitor used to treat pulmonary arterial hypertension. As tadalafil is a substrate of CYP3A, coadministration with a CYP inducer or inhibitor may affect the pharmacokinetics and pharmacological activity of tadalafil. Additionally, CYP expression is regulated by biological clocks and its activity fluctuates diurnally. Moreover, tadalafil's dosing time may also affect its pharmacokinetics. Therefore, this study aimed to investigate the effects of phenobarbital and tadalafil dosing time on the plasma concentration and pharmacological activity of tadalafil. Adult male ICR mice were treated with phenobarbital for 5 days, followed by oral administration of tadalafil perorally. Phenobarbital pretreatment decreased plasma tadalafil and pulmonary cGMP levels in a dose-dependent manner. In mice without phenobarbital pretreatment, the plasma tadalafil concentration tended to be higher when administered in the morning than in the evening. In contrast, plasma tadalafil concentration was higher when administered in the evening than in the morning in mice pretreated with phenobarbital. Similarly, pulmonary cGMP levels were higher when tadalafil was administered in the evening than in the morning in mice pretreated with phenobarbital. Notably, these effects on metabolism and pharmacological activity were observed at clinically relevant doses. Conclusively, these results indicate that the coadministration of phenobarbital and tadalafil…
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