Karl Olof Borg

Pharmacokinetic studies on the selectiveβ1-receptor antagonist metoprolol in man

The pharmacokinetics of3H-metoprolol, a new selective β1-receptor antagonist, have been studied in healthy volunteers by following the plasma concentrations and the urinary excretion of the unchanged compound and its total radioactive metabolites after oral and intravenous administration. The compound was rapidly and completely absorbed after oral administration, and about 40% of the dose reached the systemic circulation. The estimated half-life of the absorption process was 10 min. Metoprolol was extensively distributed to extravascular tissues, with the half-life of the distribution phase close to 12 min. About 95% of the dose was excreted in the urine within 72 hr, mainly in metabolized form. The elimination halflife of the compound was close to 3 hr as was also the half-life of the total metabolites after oral administration. After intravenous administration, the elimination half-life of the metabolites was raised to 5 hr, indicating that the route of administra tion might influence the metabolic pathways of the parent compound.

CORRELATION BETWEEN DRUG, LIPID AND CARBOHYDRATE METABOLISM IN THE RAT AFTER CHRONIC BETA-ADRENORECEPTOR ANTAGONIST TREATMENT

Rats were treated for fourteen months with the two beta-receptor blockers propranolol * (non-selective) and metoprolol * (cardio selective). Activities of hepatic and cardiac enzymes, the level of blood-borne substrates representative for different metabolic steps and different parameters representative for drug metabolism were correlated to each other in all fifteen animals. The chosen enzymes represent aerobic and anaerobic breakdown of glucose, anabolism and catabolism of glycogen, the pentosphosphate shunt, β-oxidation of fatty acids, citric acid cycle and the electron transport chain. The following reactions within drug metabolism were studied: epoxide metabolism, O- and N-demethylation, aromatic and aliphatic hydroxylation, kinetic parameters (K S , K m , V max , ΔOD max ) in the metabolism of metoprolol and cyt-P-450 content. Several correlations were found within lipid and carbohydrate metabolism and the parameters within drug metabolism were also correlated to each other. There were very few correlations between drug metabolism and lipid-carbohydrate metabolism. However, glycogen phosphorylase activity in the heart was negatively correlated to several enzymes in drug metabolism, probably through a common hormonal influence. Glutathione-S-epoxide transferase was positively correlated to the liver activity of glycogen phosphorylase, hexokinase and malic enzyme. This result demonstrates the possible role of glycolysis and malic enzyme for the supply of NADPH in epoxide metabolism. To summarize, lipid – carbohydrate metabolism and drug metabolism seems to be functionally interrelated to a very limited extent.