Disposition of minaprine in animals and in human extensive and limited debrisoquine hydroxylators.
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 Cmax values of total radioactivity in plasma were 4.6 and 3.7 mg 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 Cmax 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 1/2 beta 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.
Davi
H
H
Sanofi Recherche, Service de Métabolisme et Pharmacocinétique, Montpellier, France.
Bonnet
J M
JM
Berger
Y
Y
D000328:Adult; D000818:Animals; D000928:Antidepressive Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D003647:Debrisoquin / Q000378:metabolism*; D004285:Dogs; D005243:Feces; D006801:Humans; D006900:Hydroxylation; D008252:Macaca fascicularis; D008297:Male; D015394:Molecular Structure; D011724:Pyridazines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced; D013045:Species Specificity
D000928:Antidepressive Agents; D011724:Pyridazines; C006149:minaprine; D003647:Debrisoquin