PHARMACOKINETICS OF NAFTOPIDIL, A NOVEL ANTIHYPERTENSIVE DRUG, IN PATIENTS WITH HEPATIC-DYSFUNCTION

The pharmacokinetics of naftopidil, a novel alpha-1 adrenoceptor-block ing antihypertensive, were investigated in ten patients (9M/1F) with h epatic dysfunction after oral administration (50 mg, tablet) and after an intravenous infusion of 5.0 mg over 2 minutes. Results were compar ed to a control group of 12 healthy subjects (6M/6F) of a previous inv estigation, which was carried out according to the identical study pro tocol. The pharmacokinetic parameters obtained for the i.v. administra tion were comparable in both groups (half Life 3.6 +/- 3.4 hours in li ver-impaired subjects versus 3.3 +/- 2.1 hours in controls; clearance 11.9 +/- 4.7 ml/minute/kg versus 11.0 +/- 1.6 ml/minute/kg). Following oral administration the plasma levels and half-life times of naftopid il were significantly increased in Liver impairment (t(1/2) 16.6 +/- 1 9.3 hours versus 5.4 +/- 3.2 hours in controls; P = 0.012). Mean value s for the absolute bioavailability in patients with hepatic dysfunctio n were significantly higher (mean 75%, median 53%, range 13.4-211.0%) compared to healthy subjects (mean 17%, median 16%, range 6.7-29.6%, P = 0.001). Reduction of functional hepatic blood flow in chronic liver disease or, as evidenced in one case as a consequence of shunt surger y, is the probable cause of the observed alteration in naftopidil kine tics. This phenomenon occurred only following the oral 50 mg dose wher eas the intravenous 5 mg dose obviously still could be normally handle d. Naftopidil demethylation and hydroxylation were both less and non-u niformly affected. The pharmacokinetic findings suggest that in patien ts with severe hepatic impairment or evidence for marked changes in he patic blood how the dose of naftopidil may require adjustment to the l ower end of the therapeutic range and/or may be limited to once daily. However, before definite conclusions can be drawn, further steady-sta te studies are required. Despite the pharmacokinetic discrepancies no difference in drug tolerability was seen between patients and healthy subjects.