[Study on metabolism of tetramethylpyrazine in system of rat liver microsomes].
OBJECTIVE
The metabolic character of tetramethylpyrazine (TMPz) in rat liver microsomes was studied in vitro and in vivo to identify which isoforms of cytochrome P450 were responsible for TMPz metabolism in rats, offer the theoretical foundation for the fact that it is rational to use medicine in clinic.


METHODS
Set up UV- HPLC method of TMPz, determine concentration of TMPz and its formation in rat plasma and liver microsomes incubation solution, analyze the correlation between TMPz's metabolic eliminate rate and each inducer. Erythromycin( ERY) N-demethylase activity of each sample in rat liver microsomes was measured using N-demethylation reaction of ERY as probe. The correlation between the rate of TMPz metabolite formation and the demethylase activity was analysed. After the SD rats who had been treated with inducer, inhibitor, or untreated, received administration of TMPz in vein, the plasma concentration of TMPz were determined by HPLC. Pharmacokinetic parameters of TMPz were computed and compared.


RESULTS
The disppearing rate of TMPz in the incubation solutions of the rats liver microsomes, which treated with DEX, were markedly quicker than that of control group (P < 0. 01) , while no obvious difference between P-NF group or PB and control group was observed (P > 0. 05). The activity of ERY-N-demethylase in DEX-induced group was corespondingly enhanced, was much higer than that in control group. The correlation between the rate of TMPz metabolic product formation and the activity of N-demethylase was significant. After using Ket, the CYP3A inhibitor, the metabolism of TMPz could be significantly inhibited the metabolism of TMPz in rat liver microsomes. In vivo, CL( s) were larger than that of the control group,t,/2 were smaller than the control group in DEX group; By contrary, CL(s) was smaller than the control group,t1/2 was larger than the control group in Ket group.


CONCLUSIONS
Results suggest that CYP3A plays a major role in TMPz metabolism in rats, TMPz lie in the possibility of Interaction among the medicines between TMPz and CYP3A inducers or inhibitors when they are used in clinic.
Kuang
Xiao-dong
XD
Institute of Clinical Pharmacology, Jiangxi Medical College, Nanchang 330006, China.
Li
Xi-hua
XH
Xiong
Yu-qing
YQ
D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D003907:Dexamethasone / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D011719:Pyrazines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics
D065692:Cytochrome P-450 CYP3A Inhibitors; D011719:Pyrazines; D014665:Vasodilator Agents; D003907:Dexamethasone; D051544:Cytochrome P-450 CYP3A; D007654:Ketoconazole; C017953:tetramethylpyrazine