Physiological disposition of verapamil in man.

14C-D,L-verapamil was administered intravenously (10 mg) and orally (80 mg) to five volunteer patients. Plasma concentrations of verapamil, which were determined by mass fragmentography, declined bi-exponentially with half-lives of the chi-phase ranging from 18 to 35 min and of the beta-phase from 170 to 440 min. The apparent volume of distribution ranged from 270 to 460 litre and plasma clearance from 730 to 1980 ml/min. Following oral administration absorption was almost complete as judged from the area under the curve (AUC) of 14C-activity and cumulative urinary excretion of 14C. After intravenous infusion of verapamil about 80% of the radioactivity administered could be recovered in urine and faeces within 5 d. Despite its almost complete absorption after oral administration verapamil was shown to undergo extensive first pass metabolism as the bioavailability was only 10 to 22%. Rapid biotransformation had occurred as only a small percentage of AUC of 14C was seen to correspond to unchanged verapamil after both intravenous and oral administration.

[Pharmacokinetics of azlocillin, a new semisynthetic, wide-spectrum antibiotic (author's transl)]. / Zur Pharmakokinetik von Azlocillin, einem neuen halbsynthetischen Breitspektrumantibiotikum

Azlocillin, a new semisynthetic penicillin with a wide spectrum of antimicrobial activity and a member of the ureidopenicillin group, was administered to ten adults in a dosage of 2 g by intravenous bolus injection. The determination of antibiotic activity in serum and urine demonstrated an average concentration of 58.9 mug/ml after one hour, 28.1 mug/ml after two hours and 6.1 mug/ml after four hours. The total urinary excretion was 60% within six hours. The pharmacokinetic parameters were calculated for the one and two compartment models, respectively. Mathematical analysis according to an open two-compartment model resulted in better curve adjustment as judged from the sum of the deviant squares. The resulting parameters for volume of distribution and rate of elimination show only minor differences however. Similar results were seen on comparison with the respective data for ampicillin.

Mass spectrometric identification of DL-verapamil metabolites.

DL-verapamil [2,8-bis(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6-azaoctanitrile; Isoptin] is metabolized in man by N-dealkylation -- mainly by cleavage of the N6-C7 bond -- and by demethylation of the methoxy groups. After oral administration, besides unchanged verapamil, 12 metabolites could be isolated from urine and their structures were elucidated by (GC-) mass spectrometry.

The metabolism of DL-[14C]verapamil in man.

The metabolism of DL-verapamil in man was studied after oral administration of an aqueous solution of DL-[14C]verapamil. Between 67 and 71% of the 14C administered was excreted in the urine within 5 days. Verapamil was extensively metabolized; only 3--4% of the dose was excreted in the urine as unchanged drug. Cleavage of the C--N--C bond by N-'dealkylation, preferentially at the C-atom belonging to the shorter side chain, was the main metabolic step. Verapamil and its N-dealkylated metabolites were further metabolized by O-demethylation. Inasmuch as approximately 10 times more of the metabolites formed from the tertiary amine verapamil are secondary amines than are primary amines, it would seem that N-dealkylation of this tertiary amine proceeds at a much higher rate than the N-dealkylation of the secondary amine metabolites to primary amine metabolites.