The pharmacokinetics and biotransformation of 14C-lisuride hydrogen maleate in rhesus monkey and in man.

14C-labelled lisuride hydrogen maleate was administered intravenously (25 micrograms) and orally (200 micrograms) to three male and three female elderly volunteers. Following i.v. injection radioimmunologically determined plasma levels of unchanged lisuride showed a three-phasic decline with half-lives of 3 minutes, 16 minutes and 2.9 hours. The total clearance was 16 +/- 9 ml/min/kg. Bioavailability was estimated to be 14% of oral dose. Determination of 14C-radioactivity did not show any specific enrichment of lisuride metabolites in cellular components of blood. The drug was almost totally metabolized and its degradation products were eliminated equally via the kidney and liver. Total recovery was about 90% of dose. The elimination half-life was 10 hours. Small parts of the dose administered were renally excreted with a half-life of 23 hours. Lisuride is metabolized extensively. HPLC radiochromatograms of freely extractable metabolites from urine did not show marked differences between both routes of administration. More than 15 compounds were freely extractable, only one of them represented more than 5% of dose. Phase II reactions were quantitatively unimportant. From rhesus monkey urine 6 metabolites were isolated. Chemical structures were proposed for 5 of them. They were assigned to the pattern of freely extractable human urinary metabolites and covered about 50% of radiolabel corresponding to about 13% of dose. The main freely extractable urinary metabolite was thought to be the 2-keto-3-hydroxy-lisuride derivative. Structures of the other four metabolites and earlier observations on the stability of the N'-ethyl-3H label led to the interpretation of independent changes of lisuride by different enzymatic processes such as oxidative N-deethylation, hydroxylation of the benzene system, monooxygenation at C2 and C9, and oxidation of double bonds at C2/C3 and C9/C10.

The pharmacokinetics of lisuride hydrogen maleate in rat, rabbit and rhesus monkey.

The pharmacokinetics of lisuride hydrogen maleate (LHM) were investigated in rat, rabbit and rhesus monkey. Experiments were designed to meet not only the requirements of drug registration but also to serve other preclinical disciplines (toxicology, pharmacology). LHM is absorbed almost completely at a dose level of 100-250 micrograms/kg. During absorption and first liver passage (FPE) LHM is metabolized. The FPE was highest in the rhesus monkey and lowest in the rat. Calculated on bioavailability during chronic tolerance studies, in the highest dose group rats were burdened with 180-fold and rhesus monkeys with 70-fold the highest human dose (parkinsonism). Total clearance values indicated the presence of extrahepatic metabolism in all animal species. Terminal half-lives of unchanged drug in plasma were in the range of a few hours. Therefore, no accumulation of unchanged drug was expected to occur following daily repeated administration in the animal species investigated. Elimination of 14C-radioactivity proceeded mainly via the liver in rat and rabbit. The rhesus monkey excreted most of the dose administered in the urine. Enterohepatic circulation of 14C-material was demonstrated in the rat. In the rat but not in the other two species a small part of the dose (about 2%) accumulated in blood cells in the form of metabolites. Unchanged lisuride is able to cross membranes very rapidly, this was shown in distribution studies (whole-body autoradiography of rat, direct measurements in rat and rabbit). Transfer of lisuride into fetuses and brain is governed by its concentration in plasma. Drug level decrease in fetuses and brain was shown to somewhat slower than in plasma. Detailed evaluation of the distribution pattern in the brain of rat and rabbit showed a high affinity of lisuride for its preferential target tissue, the pituitary.

Investigations of pharmacokinetics of levonorgestrel to specific consideration of a possible first-pass effect in women.

PIP: This investigation, using levonorgestrel, estimated the extent of a first-pass effect and established a pharmacokinetic model to describe drug concentrations after intravenous and oral administration. 3 women received 30 mcg of levonorgestrel in succession by intravenous and oral routes; another 6 were given 150 mcg (as Microgynon) in similar fashion. Radiolabeled levonorgestrel was used for intravenous administration of 30 mcg and oral administration for 150 mcg. Radioimmunoassay was used to determine plasma drug level after all treatments. Urine and feces eliminations were also recorded. After intravenous and oral administration, drug concentration and total plasma radioactivity declined in 2 disposition phases, with half-lives in the range of 1.5 hours/day. After intravenous administration, an early phase with a half-life of about 10 minutes was observed. Levonorgestrel was rapidly absorbed, with a half-life of about 20 minutes. Orally administered doses were completely absorbed. Intraindividual comparison showed that intravenous and oral administration of levonorgestrel is not subject to any first-pass effect.^ieng