In order to determine whether the metabolism of the antiarrhythmic drug N-propylajmaline is under the same genetic control as sparteine metabolism, the pharmacokinetics of this antiarrhythmic drug were studied in a groups of six extensive and four poor metabolizers of sparteine. Pronounced differences in terminal half-life, total plasma clearance, metabolic clearance and urinary excretion of N-propylajmaline were observed between extensive and poor metabolizers. A close relationship between the total clearance and metabolic clearance of N-propylajmaline and sparteine could be demonstrated. Clinically available N-propylajmaline is a 55% to 45% mixture of the i- and n-diastereomers. The extensive metabolizers exhibited stereoselective metabolism; the i-diastereomer was preferentially metabolized. Poor metabolizers were characterized by a loss of this stereoselective metabolism. Five subjects were treated for 7 days with a daily N-propylajmaline dosage of either 60 mg or 20 mg. Since a close relationship between the clearance of N-propylajmaline and the metabolic ratio of sparteine had been observed after single dosing the metabolic ratio of sparteine was used to predict N-propylajmaline steady-state plasma concentrations during multiple dosing. Only in two extensive metabolizers with a metabolic ratio less than 0.4 predicted and observed, steady-state plasma concentrations were in good agreement. In the other three subjects observed steady-state plasma concentrations were appreciably higher than predicted. In these three subjects metabolic N-propylajmaline clearance decreased indicating saturation N-propylajmaline metabolism during multiple dosing. The data indicate that N-propylajmaline metabolism is subject to a genetic polymorphism controlled by the sparteine/debrisoquine gene locus.

10 and 20 mg of N-Propyl-ajmalin-hydrogentartrate (N-PAB, Neo-Gilurytmal) were administered i.v. and orally respectively to healthy volunteers. In the study 14C-labelled N-PAB was used. The pharmacokinetics and the metabolic behaviour was examined. A fast and complete absorption of the compound could be observed. The bioavailability was 78%. The terminal plasma elimination half-life (beta-phase) was in the range of 4 to 6 hours. A total of 33% of the administered radioactivity was excreted via the kidney. 35 to 48% of the radioactivity found in urine was unchanged N-PAB. The excretion-kinetics of the three main metabolites as well as of the parent compound were determined. The possible presence of non-metabolizers is suggested.

Eleven male subjects aged 24 to 58 yr received cisplatin, 90 to 120 mg/m2 iv, in combination with other cytostatic drugs such as doxorubicin HCl and bleomycin. To prevent emesis, two high-dose metoclopramide regimens were started 2 hr before cytostatic therapy. Regimen A (n = 7) consisted of a loading dose infusion of 1 mg/kg/hr over 2 hr, followed by a maintenance infusion of 0.5 mg/kg/hr over 24 hr (total dose was 14 mg/kg in each cytostatic cycle). Regimen B (n = 6) consisted of half the metoclopramide dose. The following kinetics were derived from the metoclopramide steady-state plasma levels and the t1/2 of the elimination phase 26 to 38 hr after dosing (median value and range are listed): Steady-state plasma concentration in group A and group B was 750 (480 to 1520) and 360 (300 to 480) ng/ml plasma. Drug clearance in group A and group B was 0.67 (0.3 to 1.0) and 0.70 (0.5 to 0.8) l/hr/kg. Volumes of drug distribution in group A and group B were 4.4 (1.9 to 6.5) and 4.3 (3.2 to 5.9) l/kg. Values for the t1/2 in the elimination phase in group A and group B were 4.7 (3.0 to 5.4) and 4.3 (3.7 to 5.1) hr. It appears that metoclopramide kinetics at high doses were dose linear, i.e., without evidence of cumulation. There were few side effects; vomiting was effectively suppressed by both regimens.

The metabolism of 7-bromo-1-methyl-2-methoxymethyl-5-(2'-chlorophenyl)-2, 3-dihydro-1H-1,4-benzodiazepine (metaclazepam, Talis) in animals and men is described. Based upon mass spectrometry fifteen metabolites could be identified. Qualitative and quantitative differences in the biotransformation products of metaclazepam in comparison with the well known metabolites of other drugs in the 1,4-benzodiazepine class could be demonstrated. Metabolites with a benzodiazepine-2-one structure representing the most characteristic feature of other 1,4-benzodiazepines and their metabolites, were found in trace amounts only. The major metabolic pathways of metaclazepam led via stepwise demethylation of the O-methyl and/or the N-methyl group to O-demethyl-metaclazepam (M 2), N-demethyl-metaclazepam (M 7) and bis-demethyl-metaclazepam (M 6). Further aromatic hydroxylation yielded the metabolite M 1. Two metabolites with amino-benzophenone structure (M 5, M 8) which are in general known to result from other 1,4-benzodiazepines could be detected. Additionally a 3-oxo-benzodiazepine (M 4) was found. Minor biotransformation pathways led to a chlorophenyl-bromo-benzodiazepine (M 9) by loss of the side chain from bis-demethyl-metaclazepam and N-demethyl-metaclazepam. By further oxidation and degradation the 2-oxo-benzodiazepine M 10 and the dihydro-quinazoline M 12 were formed. The respective N-methylated metabolites M 13 and M 16 were possibly generated by the same pathway. Still open is the formation of M 15, a 1-methyl-3-hydroxy-4-(2'-chlorophenyl)-6-bromo-1,2-dihydroquinoline and M 11, a 2-methyl-4-(2'-chlorophenyl)-6-bromo-quinazoline. The substitution of bromine by a hydroxyl group during the formation of M 14 can be explained by a NIH-shift mechanism. Quantitative investigations show that the methoxymethyl side chain in the benzodiazepine ring system of metaclazepam acts as an effective barrier with respect to the metabolic attack at position two. We assume that this barrier only can be overcome by complete side chain degradation. This multi-step reaction can hardly compete with more favourable and faster conjugation and elimination processes.

The biliary excretion and apparent oral clearance of metoclopramide (MCL) were determined after oral administration of 1 mg MCL/kg body weight to 10 patients suffering from extrahepatic cholestasis with nasobiliary tube for drainage of the common bile duct. A bilioduodenal endoprosthesis was subsequently fitted in 6 of these patients, i.e. the enterohepatic circulation was restored, and the apparent oral clearance was re-determined. Biliary excretion, comprising free MCL and the products of conjugation, accounted for less than 1% of the administered dose. In accordance with this, the median areas under the plasma concentration-time-curves AUC(0-15 h) in patients with intact and interrupted enterohepatic recirculation were of similar size. The pharmacokinetic values in patients with cholestasis (median apparent oral clearance 0.5 l.kg-1.h-1; median t1/2 4.5 h) were similar to those previously reported in patients with healthy liver function. We conclude that it is not necessary to adjust single doses of MCL in patients recovering from obstructive jaundice.