Hepatic microsomal metabolism of the potential memory-enhancing agent, CL 275,838, to its desbenzyl derivative.
1. The oxidation of the potential memory-enhancer and antidepressant agent CL 275,838 by rat liver microsomes was investigated. CL 275,838 was rapidly and extensively biotransformed in vitro to its desbenzyl derivative (II), the main metabolite observed in vivo. No other known metabolites could be detected in the incubation mixture except for trace amounts of a hydrolysis product (IV). 2. The formation of the desbenzylated derivative II required the presence of an NADPH-generating system and was significantly inhibited by carbon monoxide, SKF 525-A and cimetidine, indicating the participation of P450 in the oxidation of CL 275,838. The reaction was markedly enhanced by phenobarbital and by pregnenolone-16 alpha-carbonitrile [particularly in the female]. beta-Naphthoflavone did not significantly affect desbenzylation. 3. Kinetic studies indicate that there are sex-dependent differences in CL 275,838 metabolism in vitro, as observed in vivo in rat. Maximal velocity for the oxidation of CL 275,838 in microsomes isolated from the male rat was 17 times greater than in the female rat. The apparent Km for metabolism of CL 275,838 was similar in microsomes derived from the male and female rat. 4. CL 275,838 does not appreciably affect its own oxidation and does not cause significant hepatic microsomal enzyme induction in the male or female rat, except for slight enhancement of some components of the P450 system at doses (300 mg/kg once daily for 7 days) well above the effective pharmacological range.
Ferrarese
A
A
Istituto di Richerche Farmacologiche Mario Negri, Milan, Italy.
de Palma
F
F
Celeste
S
S
Marini
P P
PP
Caccia
S
S
D000284:Administration, Oral; D000818:Animals; D001711:Biotransformation; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction; D005260:Female; D007700:Kinetics; D008297:Male; D008568:Memory / Q000187:drug effects*; D008862:Microsomes, Liver / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology; D010879:Piperazines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D011720:Pyrazoles / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D065607:Cytochrome P-450 Enzyme Inhibitors; D010879:Piperazines; D011720:Pyrazoles; D011743:Pyrimidines; C074871:CL 275838; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010634:Phenobarbital