plasma protein binding
impaired hepatic elimination
Springer Online Journal Archives 1860-2000
Chemistry and Pharmacology
Summary Tiapamil 70 mg was administered i.v. to 8 healthy male volunteers and 8 patients (7 males, 1 female) with biopsy proven hepatic cirrhosis. Two of the patients also received 600 mg p.o. Serial plasma and urine samples were collected and the parent drug in plasma and urine and desmethyl-tiapamil in urine were assayed by a specific HPLC method. The plasma and urine data for the parent drug after i.v. and p.o. dosing were simultaneously fitted to linear p.o. and i.v. two compartment models with exit from and input into the central compartment. Absorption was assumed to be a first order process. In the volunteers the mean pharmacokinetic parameters were: 101 l for the steady-state volume of distribution, 750 ml·min−1 for nonrenal clearance, 195 ml·min−1 for renal clearance and 1.7 h for the half-life of the terminal disposition phase. The urinary recoveries of the parent drug and desmethyltiapamil averaged 21.4 and 0.8% of the dose, respectively. In the patients the steady-state volume of distribution, the amount of unchanged drug in urine and the half-life of the terminal disposition phase were significantly increased (171 l, 29.0% of the dose, 3.5 h, respectively). Decreased plasma protein binding in the patients accounted for the larger steady-state volume of distribution. The nonrenal clearance of 519 ml·min−1, tended to be smaller in the patients than in the volunteers. Together with the increased urinary recovery of tiapamil in the patients this indicates a moderately impaired elimination capacity in the cirrhotics. The renal clearance was similar in the patients (213 ml·min−1) and the volunteers. The absolute oral bioavailability of tiapamil was 55 and 49% in 2 patients. No effects of tiapamil on heart rate or supine blood pressure were detected, either in volunteers or in patients. Negative dromotropic effects were found in 2 volunteers and 2 patients after i.v. dosing.
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