Pharmacokinetics of cefodizime following single doses of 0.5, 1.0, 2.0, and 3.0 grams administered intravenously to healthy volunteers.

Cefodizime is a new expanded-spectrum cephalosporin for parenteral use which possesses a broad antibacterial spectrum and potent antibacterial activity and is stable against most beta-lactamases. The aim of this study was to assess the pharmacokinetics of cefodizime, administered intravenously, over the dose range of 0.5 to 3.0 g in healthy volunteers. Concentrations of cefodizime in the serum and urine were determined by high-performance liquid chromatography. The area under the concentration-time curve from 0 h to infinity and the amount of drug excreted in urine from 0 to 34 h increased in a linear, dose-dependent manner with increasing doses of antibiotic from 0.5 to 3.0 g. Mean concentrations of cefodizime in plasma at the end of infusion increased from 97 to 440 mg liter-1 over the dose range 0.5 to 3.0 g and displayed a slight deviation from linearity at doses in excess of 2.0 g. Total plasma clearance (3.11 liters h-1), volume of distribution at steady state (10.5 liters), terminal elimination half-life (3.3 h), and renal clearance (1.91 liters h-1) remained constant over the doses administered. Cefodizime was well tolerated in this study.

Pharmacokinetics of cefpodoxime in young and elderly volunteers after single doses.

Three pharmacokinetic studies involving single oral doses of cefpodoxime proxetil in healthy volunteers are reported. The first study was to determine the absolute bioavailability of cefpodoxime, the second was to study the relationship between the oral dose of cefpodoxime proxetil and pharmacokinetic parameters of cefpodoxime, and the third was to compare the pharmacokinetics of cefpodoxime in healthy young and elderly volunteers. Half the dose of cefpodoxime orally administered as cefpodoxime proxetil in tablet form reaches the systemic circulation, while 80% of the cefpodoxime absorbed is excreted unchanged in urine. The volume of distribution is large (32.3 l). The pharmacokinetics of cefpodoxime were linear in young and elderly subjects after 100 and 200 mg oral doses, which are those used therapeutically. The Cmax was about 1.4 mg/l (after 100 mg) and 2.6 mg/l (after 200 mg). Deviation from linearity appeared at 400 mg and the effect was confirmed at 800 mg. The differences between young and elderly subjects were negligible, with the exception of the half-life which increased by only 14%, from 2.67 to 3 h. Dosage adjustment is therefore not necessary in the elderly.

[Cancer of the prostate: biologic bases for the use of an antiandrogen in its treatment]. / Cancer de la prostate: bases biologiques pour l'emploi d'un antiandrogène dans le traitement.

Although orchiectomy, estrogens and LHRH agonists suppress testicular androgens, they are without effect on adrenal androgens which are converted into dihydrotestosterone in the prostate. It is therefore necessary to develop substances able to block the action of all androgens, whatever their source, on target organs. The non-steroid, Anandron (RU 23908), when administered orally, gives rise to a high and sustained plasma level of intact compound that inhibits testosterone binding to its receptor. This inhibition, however, occurs not only in the prostate but also in the pituitary. The negative feedback action of androgens is thus inhibited by Anandron resulting in an increased secretion of testosterone and explaining the necessity of combining Anandron with castration (whether surgical or medical by an LHRH agonist). Anandron opposes, on the one hand, the action of adrenal androgens and, on the one other, of the testosterone surge that occurs during the early days of treatment with the LHRH analog. The efficacy of the combined treatment has been demonstrated experimentally. Clinical trials are presently underway.

Pharmacokinetics and metabolism of moxestrol in animals--rat, dog and monkey.

The pharmacokinetics and metabolism of moxestrol have been compared in the rat, dog and monkey (rhesus and baboon) and, in some instances, confronted with data simultaneously obtained for ethynl estradiol and previously obtained in humans. The apparent initial volume of distribution (AIVD) of total radioactivity after i.v. administration was of the order of body volume in all species under study; the AIVD of intact moxestrol was even higher. This is in agreement with moxestrol's low binding to specific and non-specific plasma proteins. The half-life of total radioactivity elimination was 14-18 h in the rat and rhesus monkey, but longer (43 and 78 h, i.v. and oral respectively) in the baboon. In the dog, the elimination phase could not be distinguished from the distribution phase and had a half-life of 2 h. The half-life of unchanged moxestrol elimination was shorter and very similar in the rhesus, baboon and human (6.6, 7.5 and 8.2 h respectively) and only 1.4 h in the dog. Regardless of the route of administration or the species under study, the clearance and elimination rate of unchanged moxestrol were higher than of total radioactivity implying that metabolites and/or conjugation products were eliminated more slowly than intact product from plasma. Orally administered moxestrol was rapidly absorbed in all species. Since clearance of total radioactivity and of moxestrol was faster after i.v. than oral administration, but the radioactivity levels excreted in the urine were identical for the two routes, a significant first-pass-effect probably occurred in the liver. Radioactivity distribution in tissues was examined in the rat. Total radioactivity was higher 24 h after administration of labelled moxestrol than of labelled ethynyl estradiol in endocrine tissues; it was equivalent or less in the other tissues. For all tissues, the elimination rate of moxestrol was greater than, or equal to, that of ethynyl estradiol. In dog urine, the only product identified was moxestrol; in rhesus or baboon monkey urine, the principal metabolites were catechol estrogens, which were also present in appreciable amount in rat bile (as methyl ethers) but were minor metabolites in human urine. Hydroxylation in position 16 occurred in rats and humans only, in position 15 alpha in humans and, to a much lesser extent, in rats and monkeys. Thus, the metabolic profile of moxestrol in rats most closely resembles that in humans.

Pharmacokinetics and metabolism of moxestrol in humans.

Moxestrol, the 11 beta-methoxy derivative of ethynyl estradiol and a highly potent estrogen, is rapidly distributed in the body (AIVD = 148.6 +/- 19.71, MCR = 79.9 +/- 10.5 1/h) after i.v. administration because it is not bound by SBP and has low affinity for albumin. Its oral bioavailability is about 33% after administration of 30 or 100 micrograms to healthy volunteers and slightly lower than that of ethynyl estradiol (50%) due to a "first-pass effect". Moxestrol is rapidly metabolized by the liver as shown by the much increased bioavailability (60.5%) in patients with impaired liver function. The radioimmunoassay for moxestrol measures plasma moxestrol levels ranging from 100 pg/ml (maximum) to 10 pg/ml (24 h value) after treatment with a 100 micrograms commercial formulation (Surestryl). Moxestrol metabolism was studied on urine which contained 28% of administered radioactivity after i.v. or oral administration. Hydroxylation was the main transformation pathway as for ethynyl estradiol. Moxestrol yielded metabolites hydroxylated (or methoxylated) at C-2, C-15 and C-16, but not at C-6, and also gave rise to D-homo derivatives. The main difference between moxestrol and ethynyl estradiol lies in the relative importance of these pathways. The presence of the ethynyl group of ethynyl estradiol impedes attack at C-16 and hydroxylation at C-2 to form catechol estrogens becomes a major pathway, whereas the 11 beta-methoxy group of moxestrol impedes hydroxylation at C-2 and ring D hydroxylated products of moxestrol are formed. The low amount of catechol estrogens obtained with moxestrol compared to ethynyl estradiol could have important physiological implications in the human.

Reference compounds for the study of moxestrol metabolism.

Reference compounds for the subsequent identification of the metabolites of the potent estrogen, moxestrol (R 2858) , in various species were isolated from the bile of phenobarbital pretreated rats or obtained via enzymatic hydroxylation by microorganisms. A few of them were prepared by chemical synthesis. The structures of all these compounds were determined by physical and chemical methods.