Pharmacokinetic variations of tetramethylpyrazine phosphate after oral administration in hepatic precancerous mice and its hepatoprotective effects.

CONTEXT: Pharmacokinetics of drug may be altered by abnormal physiological functions in illness, which will affect its pharmacodynamic efficacy in turn.

OBJECTIVE

To assess the preventive effects of tetramethylpyrazine (TMPZ) phosphate on hepatocarcinogenesis and its pharmacokinetic differentiations in model mice.

METHODS

Diethylnitrosamine (DEN) was adopted to induce hepatic precancerous model in mice through intraperitoneal injection, and prevention efficacy of TMPZ at a dose of 162 mg/kg was examined by liver histological analysis and activities of serum marker enzymes. Pharmacokinetic variations of TMPZ between control and model mice were measured for single oral administration.

RESULTS

DEN initiation led to a remarkable increase of serum marker enzymes, and abnormality such as bile canaliculi hyperplasia and presence of tumor cells were observed in liver histopathological examination in model mice, while the control ones revealed normal architecture. Oral treatment of TMPZ resulted in a marked reduction in serum marker enzymes and improvement in liver histopathology compared with model ones. In pharmacokinetic study, values of AUC and Tmax of TMPZ became significantly greater with increase of doses in both control and model mice, which elucidated the absorption was enhanced and delayed; meanwhile, its elimination was not affected markedly. When the mice were treated at same dose, the adsorption of TMPZ in model mice was greatly improved than that in control ones, while Tmax and MRT had no significant difference.

CONCLUSION

TMPZ was partly effective to protect liver from carcinogenesis initiated by DEN, and hepatic insufficiency could change its pharmacokinetics.