Marked effect of liver and kidney function on the pharmacokinetics of selegiline.

OBJECTIVES: The pharmacokinetics of selegiline was investigated in an open study with 4 parallel groups of 10 subjects in each. Patients with liver disease, those receiving a drug that induced hepatic enzyme activity, and those with impaired kidney function were compared with control subjects. METHODS: A single oral 20-mg dose of selegiline was administered after an overnight fast, and blood samples were collected over a period of 48 hours. Concentrations of serum selegiline and its main metabolites were determined and pharmacokinetic parameters calculated. RESULTS: The pharmacokinetic parameters of selegiline differed considerably between the patient groups and the control subjects. The area under the concentration-time curve of serum selegiline was, on average, 18-fold higher (P < .05) in patients with impaired liver function, 23-fold lower (P < .001) in patients with drug-induced liver function, and 6-fold higher (P < .05) in patients with impaired kidney function as compared with the control subjects. There was a large interindividual variation in every group. The changes in selegiline metabolite kinetics supported the changes in the kinetics of the parent compound. CONCLUSION: The elimination rate of selegiline was substantially increased in patients with drug-induced liver function and decreased in patients with impaired liver or kidney function when compared with control subjects. These results suggest that selegiline dosage adjustments may be required in patients with altered liver and kidney function.

Diabetes and elimination of antipyrine in man: an analysis of 298 patients classified by type of diabetes, age, sex, duration of disease and liver involvement.

UNLABELLED: Effects of diabetes on hepatic drug metabolism in man has not yet been adequately clarified. Two hundred ninety-eight diabetic patients, classified by type of the disease, age, gender, duration of therapy and liver involvement, were investigated. The antipyrine plasma clearance rate and cytochrome P450 content determinations in liver biopsies of subjects with diagnostic liver biopsy were used as indices of hepatic drug metabolising capacity. Drug metabolism was reduced as a function of age. Antipyrine elimination rate was dependent on the type of diabetes (type 1 versus type 2) and gender. Untreated type 1 patients eliminated antipyrine rapidly and insulin treatment normalised antipyrine elimination (clearance rates 89.5 +/- 20.3 versus 58.8 +/- 17.2 ml/min.; P<0.001). Males aged 16-59 years, but not over 60, who responded insufficiently to insulin therapy, had a rapid antipyrine elimination, which could be normalised by readjustment of insulin administration. Women with insufficient glucose control on insulin therapy had antipyrine elimination rate comparable to controls. Among type 2 diabetic patients, women metabolised antipyrine normally, but men over 40 years of age showed a reduced antipyrine metabolism. IN CONCLUSION: Drug metabolism in diabetes is affected by the type of disease, therapy and its effectiveness, and age and gender of the patients. These factors should be taken into account when evaluating overall drug metabolism in diabetic patients. This is especially important when investigating pharmacokinetics of new drugs for diabetic patients at different phases of the disease.