The effect of the monoamine oxidase inhibitor selegiline on tyramine metabolism and intravenous and oral tyramine pressor sensitivity was studied in healthy subjects. After oral doses of tyramine, which caused systolic blood pressure to increase by 30 mm Hg, we determined plasma concentrations of p-hydroxyphenylacetic acid (HPAA) and of conjugated and unconjugated tyramine. When 20 mg/day of selegiline was administered, the AUCspec of HPAA decreased from 86% to 64% and the AUCspec of conjugated tyramine increased from 13% to 35% of the sum of total tyramine and HPAA. Pressor sensitivity was enhanced more with oral administration of tyramine than with intravenous administration of tyramine. After the drug was discontinued, initial values were reached within 4 days (one subject) and 2 weeks (two subjects). Fifty-five percent of the selegiline dose was eliminated in urine as amphetamine and methamphetamine. The findings support the assumption that selegiline does not selectively inhibit monoamine oxidase-B (MAO-B) when administered in doses of 20 mg/day and higher.

The metabolic fate of brofaromine (CGP 11 305 A), a new, reversible, selective MAO-A inhibitor, has been assessed in poor (PM) and extensive (EM) metabolizers of debrisoquine. Compared to EM, PM had significantly longer t1/2 (136%) and larger AUC(0-infinity) (110%) of the parent compound brofaromine and a lower Cmax (69%) and AUC (0-72 h) (40%) of its O-desmethyl metabolite. The mean metabolite/substrate ratio (based on urine excretion) was about 6-times greater in EM than in PM. Treatment with quinidine converted all EM into phenocopies of PM. All pharmacokinetic parameters of brofaromine and O-desmethyl-brofaromine in EM treated with quinidine were similar to those of untreated PM, including the metabolite/substrate ratio. Quinidine treatment of PM did not alter the pharmacokinetics of brofaromine or of its metabolite, nor the metabolite/substrate ratio. The results indicate a role for the debrisoquine type of oxidation polymorphism in the O-demethylation and pharmacokinetics of brofaromine.

1 The systemic availability of oxprenolol after colonic and oral administration has been compared in a crossover study involving six healthy male volunteers. Drug administration into two regions of the colon (caecum and left flexure) was achieved by means of a colonoscopic technique. 2 There were no obvious differences in plasma concentrations after drug administration to the caecum and left flexure, although in one subject it was necessary to repeat colonic administration because of unexpectedly high plasma drug levels on the first occasion. The possible reasons for this abnormal response are discussed. 3 The mean systemic availability of oxprenolol was 82% after colonic compared with oral dosing, although marked differences were observed in individual plasma levels following drug administration by the two routes. 4 The results of this study support the concept of extending the duration of oxprenolol release from a rate-controlled dosage form to permit once-daily administration with this short elimination half-life drug.

No abstract

CGS 8216, a pyrazoloquinolinone, is a potent benzodiazepine antagonist. The results of a pharmacokinetic study in the rat were described by Lister et al. (1984). One group of animals (male hooded Lister rats, weighing approximately 400 g) was treated IP with a single dose of 10 mg/kg; the other group received five once-daily injections of the same dose. The plasma samples collected 30 min after a single injection had concentrations of 679+231 ng/ml of the drug. Thirty minutes after the last dose of the repeated treatment, a level of 2,520_+190ng/ml CGS8216 was found. The large differences in plasma concentrations could not be attributed to drug accumulation, because the concentrations measured 6h later were low (72+_11 and 96_+ 28 ng/ml, respectively). The authors suggest that caution must be exercised in studies in which CGS 8216 is repeatedly administered, since the plasma kinetics of CGS 8216 might be altered. The authors could not detect any CGS 8216 in the brain tissue of the rats.We would like to present the results of a similar trial we performed in rats, as well as some findings from the Offprint requests to." P.R. Bieck first pharmacokinetic study in man. Groups of five male Tif: RAIf (SPF) rats (Tierfarm Sisseln, Switzerland), weighing approximately 160 g were treated with 10 or 25 mg/kg CGS 8216 given IP in a solution of polyethylene glycol: water, 2:1 (2 ml/animal). The plasma concentrations of 15,700+_5,000 ng/ml CGS 8216 30rain after a single dose of 10 mg/kg were 20 times higher (Table 1, B) than those determined by Lister et al. (Table 1, A). After 25 mg/kg, 12 times higher concentrations of the drug compared to Lister's results were found (30,900_5,100 ng/ml). CGS 8216 is metabolised in the rat to the hydroxy metabolite CGS 1I 361. Its plasma concentrations were 1,060 ± 230 and 1,240+230 ng/ml after 10 and 25 mg/kg of the parent compound, respectively. In contrast to Lister et al., we found CGS 8216 in the brain of the animals decapitated 30rain after the dose. The concentrations were 130+_41 and 461 +_ 129 ng/g tissue for both doses, respectively. The corresponding brain/plasma ratios (w/v) were 0.08 and 0.15. The hydroxy metabolite could not be detected in any of the brain samples. In a human pharmacokinetic study, six healthy volunteers were treated with 9 mg/kg single dose given PO as capsules. The analyses of the plasma samples Table 1. Plasma and brain levels of CGS 8216 and its hydroxy metabolite in rat and man Dose Administration Time after Plasma (ng/ml) (mg/kg) treatment CGS 8216 CGS 11 361 Brain (ng/g tissue) CGS 8216 CGS 11 361 A 10 10