[Metabolic kinetics of MN9202 in Beagle dog liver microsomes].
OBJECTIVE
To study the metabolic kinetics of MN9202 in Beagle dog liver microsome.


METHODS
Beagle dog liver microsomes were prepared by using ultracentrifuge method. After incubating 0.4 micromol x L(-1) MN9202 with 1 g x L(-1) microsomes for 30 min at 37 degrees C, the reaction was terminated by adding 0.5 mL alkalization. The RP-HPLC was used to determine the drug in the incubation mixture. The Michaelis-Menten parameters Km, and Vmax in Beagle dog liver microsomes were initially estimated by analyzing Lineweave-Brurk plot. Various selective CYP inhibitors were used to investigate their inhibitory effect on the metabolism of MN9202.


RESULTS
The Km, Vmax and CLint of MN9202 were (22.6 +/- 8.0) micromol x L(-1), (0.54 +/- 0.17) micromol x g(-1) x min(-1) and (0.0242 +/- 0.0009) L x g(-1) x min(-1), respectively. The metabolism of MN9202 was significantly inhibited by ketoconazole (Ket) and troleandomycin (Tro) in Beagle dog liver microsomes. Tranylcypromine (Tra) could inhibit the metabolism of drug as well. While other inhibitors showed little inhibitory effect on the metabolism of MN9202.


CONCLUSIONS
It was shown that CYP3A and CYP2C19 were involved in MN9202 metabolism. The inhibitors of human CYP3A and CYP2C19 may have potential interaction with MN9202, and this can reduce the metabolism rate and increase the toxicity of MN9202.
Yang
Zhi-fu
ZF
Department of Pharmacy, Xijing Hospital, Xian 710032, China.
Zhou
Si-yuan
SY
Mei
Qi-bing
QB
Yang
Tie-hong
TH
Liu
Zhen-guo
ZG
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000493:pharmacokinetics*; D065731:Cytochrome P-450 CYP2C19; D065692:Cytochrome P-450 CYP3A Inhibitors; D004095:Dihydropyridines / Q000378:metabolism / Q000493:pharmacokinetics*; D004285:Dogs; D007654:Ketoconazole / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D009578:Nitrobenzenes / Q000378:metabolism / Q000493:pharmacokinetics*; D014191:Tranylcypromine / Q000494:pharmacology; D014217:Troleandomycin / Q000494:pharmacology
D002121:Calcium Channel Blockers; D065692:Cytochrome P-450 CYP3A Inhibitors; D004095:Dihydropyridines; D009578:Nitrobenzenes; C429364:methylpentyl-1,4-dihydro-2,6-dimehtyl-4-(3-nitrophenyl)-3,5-pydridinedicarboxylate; D014191:Tranylcypromine; D014217:Troleandomycin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D007654:Ketoconazole