Bosisio E, Kienle M G, Galli G, Ciconali M, Negri A, Sessa A, Morosati S, Sirtori C R
Diabetes. 1981 Aug;30(8):644-9. doi: 10.2337/diab.30.8.644.
The kinetics of phenformin and its metabolite, p-hydroxyphenethylbiguanide, was studied in eight diabetic patients with varying degrees of renal impairment. Plasma and urinary phenformin and p-hydroxyphenethylbiguanide levels were determined by the multiple selected ion monitoring technique. Phenformin half-lives were unrelated to the degree of renal impairment, whereas reduced renal clearances of insulin and creatinine were significantly correlated with a prolonged half-life of the metabolite. The excretion of p-hydroxyphenethylbiguanide was quite variable (between 4.9% and 27% of total urinary drug loss), probably due to a genetic polymorphism of hepatic mechanisms for hydroxylation. A reduced formation of the metabolite was concomitant with marked increases in the amount of circulating phenformin. A positive reciprocal correlation was detected between areas under the plasma curve of phenformin and both the renal clearance of the unchanged drug and the percentage of metabolite formation. A reduced hydroxylation of phenformin seems, therefore, to be responsible for the high plasma levels of the drug previously described in toxic patients.
在八名患有不同程度肾功能损害的糖尿病患者中研究了苯乙双胍及其代谢产物对羟基苯乙双胍的动力学。采用多选择离子监测技术测定血浆和尿液中苯乙双胍及对羟基苯乙双胍的水平。苯乙双胍的半衰期与肾功能损害程度无关，而胰岛素和肌酐肾清除率降低与代谢产物半衰期延长显著相关。对羟基苯乙双胍的排泄变化很大（占尿药总损失的4.9%至27%），这可能是由于肝脏羟基化机制的基因多态性所致。代谢产物生成减少的同时，循环中的苯乙双胍量显著增加。在苯乙双胍的血浆曲线下面积与未变化药物的肾清除率以及代谢产物生成百分比之间检测到正相关。因此，苯乙双胍羟基化减少似乎是之前所述中毒患者药物血浆水平升高的原因。
