Disposition of minaprine in animals and in human extensive and limited debrisoquine hydroxylators

Abstract

1. The disposition of ¹⁴C-minaprine was studied after oral administration of 5 and 20 mg/kg to rats, dogs and macaques, and of 200 mg to human volunteers with a genetic status of either limited or extensive hydroxylation of debrisoquine.

2. The drug was readily absorbed and a large proportion of the administered radioactivity was excreted within 48 h. The total excretion over 5 days ranged from 83% in monkeys to almost 100% in human with a status of extensive hydroxylators.

3. In the two limited hydroxylators C_max values of total radioactivity in plasma were 4.6 and 3.7mg equiv/l respectively. Those in the two extensive hydroxylators were 1.9 and 1.6 respectively. The highest value in the animal species was 8.1 in rats at a dose of 20 mg/kg. Plasma C_max values of minaprine were 4.0 and 1.4 mg/l in limited hydroxylators and 0.35 and 0.23 mg/l in extensive ones. The highest value in the animal species was 2.7 mg/l in dogs treated with 20 mg/kg.

4. In rats and dogs, the ratios of the plasma AUC values for 20 mg/5 mg doses were close to those of the ratios of the doses administered, whereas in the macaque a slower clearance of radioactivity occurred with the higher dose (t_1/2β 5.5 h at 5 mg/kg dose versus 25.7 h at 20 mg/kg dose).

5. Marked species differences were observed in the metabolic pathways. The dog and limited hydroxylators showed higher levels of minaprine and its N-oxide (M4) whereas p-hydroxy-minaprine (M3) prevailed in monkey, rat and extensive hydroxylators.

6. In dogs only, seizures appeared within 10–15 min after dosage with minaprine at 20 mg/kg, when the concentrations of minaprine in erythrocytes (6.9 mg/l) and of M4 in plasma (0.40 mg/l) and erythrocytes (0.25 mg/l), were high.

7. The measurements and clinical observations indicate that onset of an adverse behavioural response in humans is unlikely at the dose of 200 mg.