nitrophenols and Hypoglycemia

To assess the effect of tolcapone (an inhibitor of cytochrome P450 [CYP] 2C9 in vitro) on the pharmacokinetics and hypoglycemic effect of the CYP 2C9 substrate tolbutamide, 12 healthy male volunteers were randomized to receive a single dose of tolbutamide 500 mg plus either placebo or tolcapone 200 mg after an overnight fast and 30 minutes after the start of a 6.5-hour 5% glucose infusion (150 mL/h). The participants crossed over to receive the alternative regimen after a washout period of at least 7 days. Tolcapone had no effect on the pharmacokinetics of tolbutamide or its metabolites and did not influence the effect of tolbutamide on plasma glucose concentrations. No serious adverse events or abnormal laboratory results or vital signs were reported. In conclusion, clinically relevant drug-drug interactions between tolcapone and tolbutamide when given together in clinical practice appear unlikely.

Topics: Administration, Oral; Adult; Area Under Curve; Aryl Hydrocarbon Hydroxylases; Benzophenones; Blood Glucose; Cross-Over Studies; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Interactions; Enzyme Inhibitors; Glucose; Headache; Humans; Hypoglycemia; Hypoglycemic Agents; Infusions, Intravenous; Male; Nitrophenols; Single-Blind Method; Steroid 16-alpha-Hydroxylase; Steroid Hydroxylases; Tolbutamide; Tolcapone

Foetal rat brain aggregation cultures were exposed to a single episode of anoxia and hypoglycaemia for 30 min. Lactate dehydrogenase specific activity was estimated in the culture medium after ischaemia as a marker of lost cell integrity. Release of lactate dehydrogenase was most prominent during the first 24 hr period after the ischaemic damage, then it gradually declined. Immediately after ischaemic exposure, the cultures were treated with different concentrations of L-deprenyl or tolcapone. Significantly lower amounts of lactate dehydrogenase leaked into the culture medium during the first 24 hr after the ischaemic episode in cultures treated with deprenyl or tolcapone (1-100 nM). These results suggest that deprenyl and tolcapone may reduce cell damage after ischaemia, at doses causing enzyme inhibition.

Topics: Animals; Benzophenones; Brain Ischemia; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Cell Hypoxia; Cells, Cultured; Cytoprotection; Drug Combinations; Female; Hypoglycemia; In Situ Nick-End Labeling; L-Lactate Dehydrogenase; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Nitrophenols; Pregnancy; Prosencephalon; Rats; Rats, Sprague-Dawley; Selegiline; Tolcapone

Topics: Acetates; Acylation; Adipose Tissue; Alkylation; Animals; Arginine; Cattle; Glycine; Hypoglycemia; Insulin; Iodine; Isoleucine; Mice; Nitrophenols; Oxidation-Reduction; Seizures; Structure-Activity Relationship; Sulfonic Acids; Thiocyanates