Hydralazine-Phenobarbital Interactions in Rats. II. Disposition of Hydralazine and Its Acid-labile Conjugates, and Liver Drug-metabolizing Enzyme Activities in Normotensive and spontaneously Hypertensive Rats

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The effects of intraperitoneal treatment with hydralazine hydrochloride 5 mg/kg and phenobarbital 2.5 mg/kg daily for 7 d on the elimination of hydralazine (HP) and its acid-labile conjugates (ALC), on liver enzyme activities, and on hepatic and renal functions in both normotensive and spontaneously hypertensive rats (SHR) were studied. The rate constant (0.445±0.078 h^<-1>) for the elimination of HP from plasma in normotensive rats was significantly higher after the repeated treatment than that (0.205±0.085 h^<-1>) found in a single dosing study, while the rate constant after repeated treatment in SHR was only slightly higher (k=0.371±0.058 and 0.273±0.059 h^<-1> for repeated and single administrations, respectively). The elimination of ALC from plasma was also enhanced by the repeated administration in both types of rats. Comparative i.v. injection of the combined drugs showed that the plasma HP concentration-time curve was biphasic and the terminal elimination rate constant of HP was almost the same as that for a single i.p. injection. The repeated dosing of the combined drugs significantly enhanced the drug-metabolizing enzyme activities in microsomes as compared with those of the control, but did not change the N-acetyltransferase activity of the liver. In normotensive rats, the repeated treatment of the combined drugs led to a significant increase in hepatic and renal clearance, whereas in SHR the same treatment had little effect. These results suggest that the difference in the plasma elimination of HP between normotensive rats and SHR was mainly due to the different extents of enhancement of hepatic and renal clearance following the repeated treatment.
社団法人日本薬学会の論文
1983-01-25

Hydralazine-Phenobarbital Interactions in Rats. II. Disposition of Hydralazine and Its Acid-labile Conjugates, and Liver Drug-metabolizing Enzyme Activities in Normotensive and spontaneously Hypertensive Rats

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