The metabolic fate of the anti-androgenic agent, oxendolone, in man.

After intramuscular administration of 16 beta-ethyl-17 beta-hydroxy-4-4-[4-14C]estren-3-one (14C-oxendolone; 300 mg) to 3 human subjects, excretion of 14C was very slow and incomplete despite a 20-day sample collection period. During this time, means of 37% and 21% of the administered 14C were recovered in urine and faeces, respectively, and if excretion continued at the same rate, approximately 90% of the administered 14C would have been excreted during 5-12 weeks. Peak plasma 14C concentrations were reached at 3-6 days after dosing, when they represented 0.2-1.1 micrograms equiv./ml, and declined very slowly thereafter with a half-life of 5.0-6.6 days. Concentrations of unconjugated drug-related steroids circulating in plasma never exceeded about 0.1 microgram/ml. Mass spectroscopic analysis of isolated urinary and faecal metabolites indicated that the principal routes of biotransformation of oxendolone in man are similar to those of the endogenous androgens-namely, reduction of the 4,5-double bond, further reduction of the saturated 3-ketone to the 3 alpha-hydroxysteroid, and oxidation of the 17 beta-alcohol to the corresponding ketone, followed by conjugation, mainly with glucuronic acid, and excretion in the urine and bile.

Post-marketing surveillance of lisinopril in general practice in the UK.

A total of 4676 patients and 1759 patients were treated with lisinopril and nifedipine respectively in a post-marketing surveillance study conducted in general practice in the UK. Patients were followed up for 12 months. Most of the lisinopril patients had hypertension, but a small number (180) had heart failure. Most of the nifedipine patients had uncomplicated hypertension, but some (22.57%) had other cardiovascular disease with or without hypertension. Lisinopril and nifedipine were equally effective in reducing blood pressure. During the study, 1.5% of hypertensive patients assigned to lisinopril died compared with 1.8% of patients assigned to nifedipine, and 15.1% of lisinopril patients compared with 19.7% of patients in the nifedipine group withdrew because of adverse events. Cough, malaise and fatigue, nausea and vomiting were more frequent causes of withdrawal from lisinopril than nifedipine. Conversely, headaches, pallor and flushing, oedema and palpitations caused more frequent withdrawals from nifedipine. Anaemia was more often encountered on nifedipine treatment than on lisinopril. In hypertensive patients, the frequency of first-dose hypotension was similar on both treatments. Serious events occurred in 0.8% and 0.5% of patients given lisinopril and nifedipine respectively. Lisinopril was well tolerated by heart failure patients: 16 patients (8.88%) died and an incidence of 4.44% of serious adverse events was reported, a pattern to be anticipated in such patients; dizziness, giddiness, dyspnoea, cough, nausea and vomiting were the most frequent causes of withdrawal; the incidence of first-dose hypotension was low (2.22%).(ABSTRACT TRUNCATED AT 250 WORDS)

The disposition and metabolism of meropenem in laboratory animals and man.

The disposition and metabolism of meropenem were studied in rats, dogs and cynomolgus monkeys following intravenous administration of [14C]-meropenem, and also in man following intravenous infusion of meropenem. Following intravenous administration to rats and dogs, radioactive material was very rapidly and widely distributed in the tissues, with highest levels detected in the kidney and other highly perfused organs. Concentrations in all tissues decreased rapidly with time. The plasma elimination half-life of meropenem was approximately 6 min in rats, 30 min in monkeys, 45 min in dogs and 1h in man. In all species 90-100% of the dose was excreted via the urine within 24 h. Analysis of the radioactive material in urine from animal studies showed that the major components were unchanged compound (36-43%) and a metabolite corresponding to a beta-lactam ring-opened form (34-51%). In man, approximately 65% of the dose was excreted in urine as unchanged meropenem and most of the remainder as the ring-opened metabolite. As part of the preclinical safety evaluation programme of meropenem, the distribution, metabolism and excretion of [14C]-meropenem were studied in the rat, dog and cynomolgus monkey after single intravenous administration at dose levels corresponding to the lower doses used in toxicity studies. In addition, the metabolism and pharmacokinetics of meropenem in human volunteers were studied.

Biotransformation of lofexidine in humans.

1. Concentrations of unchanged drug and patterns of radioactive components in urine have been determined by h.p.l.c. following single oral doses of [14C]lofexidine hydrochloride (0.32 mg) to six human subjects. 2. A mean of 12% of the administered dose was excreted in urine as unchanged lofexidine, but the wide range (5-20% dose) indicated significant intersubject variation in the extent of biotransformation. This drug would appear to be metabolized more extensively than the related anti-hypertensive agent, clonidine. 3. The principal metabolite of lofexidine was 2,6-dichlorophenol, which was apparently excreted in urine as two O-glucuronic acid conjugates. The same two metabolites were also the main 14C components circulating in plasma at peak 14C concn. Formation of the phenol from lofexidine probably involved direct O-dealkylation rather than stepwise degradation of the side-chain. 4. Patterns of 3H components in the urine of rats and dogs after oral administration of [3H]lofexidine hydrochloride (0.1 mg/kg) were generally similar to those in human urine.

Metabolism and pharmacokinetics of the dihydropyridine calcium antagonist, ryosidine, in man.

The metabolic fate of [14C]ryosidine (ryodipine) has been investigated after oral administration to human subjects (by capsule), and to rats and dogs (in solution). The excretion patterns of 14C were similar for all three species: about 50% dose was excreted in urine, mainly in 24 h, but a proportion was excreted slowly, particularly by humans. Absorption in man appeared to be less than in the animal species, probably as a result of the capsule dosage form used. Mean concentrations of total 14C in human plasma reached a peak value of 0.41 microgram equiv./ml at four hours and declined biphasically thereafter (mean terminal t1/2 = 28 h). Unchanged ryosidine was only detected in plasma from two to six hours (mean t1/2 = 80 min), and never accounted for more than 5% of the plasma 14C. The extent of binding of ryosidine to the plasma proteins (in vitro) was similar (greater than 90%) to that of total 14C (in vivo; mainly metabolites). Less than 0.5% of the dose to human subjects was excreted via the kidneys as unchanged ryosidine, whereas the bulk of the extractable faecal 14C was in the form of unchanged drug and presumably represented unabsorbed material. The principal routes of biotransformation of ryosidine in all three species involved oxidative aromatization of the 1,4-dihydropyridine ring, followed by ester hydrolysis, O-dealkylation, hydroxylation of an alpha-methyl group (and lactonization) and some glucuronidation, although quantitative interspecies differences were apparent.