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The pharmacokinetics of carumonam after a single 1,000-mg intravenous infusion (20 min) were evaluated in four groups of subjects who had various degrees of renal impairment: group 1, CLCR greater than 60 ml/min; group 2, CLCR = 30 to 60 ml/min; group 3, CLCR = 10 to 30 ml/min; and group 4, CLCR less than 10 ml/min). The elimination half-life of carumonam increased with decreasing creatinine clearance (CLCR) from 1.7 h in group 1 to 11.3 h in group 4. Peak carumonam concentration (103 micrograms/ml) and steady-state volume of distribution (12.8 liters) did not change with decreasing CLCR. Total body clearance (r = 0.98), renal clearance (r = 0.98), and nonrenal clearance (r = 0.67) of carumonam correlated with decreasing CLCR. Mean nonrenal clearance was 21 ml/min in group 1 and 12 ml/min in group 4. With regard to dosage, patients with a CLCR above 60 ml/min should receive their standard maintenance dose of carumonam without any changes; patients with a CLCR between 30 and 60 ml/min should receive the dose every 12 h; and individuals with a CLCR between 10 and 30 ml/min should be given the dose once a day. Patients with a CLCR of less than 10 ml/min should receive one-half of the dose once a day. Our recommended dosage regimens should produce within the CLCR borderlines of each group average plasma concentrations that are between one and two times that achieved in normal subjects with a t.i.d. dosage regimen.

Steroid profiles of women suffering from idiopathic hirsutism show in more than 50% of the cases of 10--100 fold increase in the excretion of dehydroepiandrosterone (DHEA) compared with normal values. The excretion of DHEA was reduced much more than that of other 17-ketosteroids if the adrenals (NNR) were suppressed by dexamethasone (DXM). Within one week they reached values at the compound noise level of the gas chromatograms. If the ovaries were stimulated with human chorionic gonadotropin during continued suppression of the NNR with DXM no increase of DHEA could be detected.

A highly sensitive and specific method for the determination of the aromatic retinoic acid Ro 13-7410 in plasma at the picogram per millilitre level is described. The method involves extraction of plasma using Extrelut-1 columns, purification of the extract with Bond Elut-NH2 cartridges, derivatization with pentafluorobenzyl bromide, and subsequent analysis by two-dimensional capillary gas chromatography using the zone-cutting technique, stable isotope dilution and selective negative ion monitoring chemical ionization mass spectrometry. A tetradeuterated analogue is used as internal standard. Quantification is possible down to 25 pg/ml using 1 ml of plasma. The coefficients of variation of the method as calculated from quality control samples are 8.5 and 4.2% at the 100 and 400 pg/ml levels. The method has been applied to the analysis of plasma of volunteers following an oral dose of 40 micrograms Ro 13-7410 and plasma of dogs following an intravenous and oral dose of 25 and 50 micrograms, respectively.

The neutral steroid fractions in the urine of eleven patients suffering from various forms of liver disease with cholestasis and of ten healthy individuals were studied by glass capillary gas chromatography-mass spectrometry. The steroid conjugates in urine were enzymatically solvolysed, the liberated steroids extracted and transformed into the trimethylsilylether for measurements. The excretion rates of androstane and pregnane metabolites of patients with liver disease were far lower than those of healthy persons. The main compounds in the urine of the former were the bile alcohols 27 - nor - 3 alpha, 7 alpha, 12 alpha, 24 xi, 25 xi - pentahydroxy - 5 beta - cholestane and 3 alpha, 7 alpha, 12 alpha, 25 xi, 26 - pentahydroxy - 5 beta - cholestane. Our data suggest a correlation between the excretion rates of these bile alcohols and the serum levels of bilirubin. While the excretion rate of the two bile alcohols in the urine of healthy individuals was approximately 0.24 mg/24 h (0.6 mumol/24 h) a patient with a serum bilirubin of 841 mumol/l excreted 4 mg/24 h (9 mumol/24 h). The accumulation of bile alcohols described in this study possibly indicates alternative pathways of cholic acid formation in liver disease.

Ro 17-2301 (AMA-1080) is a new N-sulfonated monocyclic beta-lactam that is highly active against gram-negative bacteria, especially against Enterobacteriaceae and Haemophilus, Neisseria, and Pseudomonas spp. (Kondo et al., Proc. Int. Congr. Chemother. 13th, Vienna, Austria, p. 56/1-56/5, 1983). The single-dose pharmacokinetics of this compound were studied in six healthy male volunteers who received intravenous infusions of 500, 1,000, and 2,000 mg. A good linear correlation (r2 = 0.99) was found between the dose infused and the resulting area under the plasma concentration-time curve. Maximal plasma concentrations of 36, 78, and 150 micrograms/ml appeared after doses of 500, 1,000, and 2,000 mg, respectively. The mean terminal elimination half-life was 1.8 h (range, 1.4 to 2.3 h), the apparent volume of distribution at steady state was 17 liters, and the total systemic clearance was 150 ml/min. Within 72 h 78 to 89% of the dose was recovered intact from urine. After administration of 14C-labeled Ro 17-2301, 96% of the radioactivity was found in the urine and 3% was found in the feces. The concomitant administration of probenecid did not affect the renal clearance or urinary excretion of this beta-lactam, an indication that the renal elimination of this substance is only by glomerular filtration. Ro 17-2301 was 18% bound to human plasma protein, and this binding was independent of concentration between 25 and 400 micrograms/ml. Based on these data, the pharmacokinetics of this monocyclic beta-lactam should be predictable in the foreseen dose ranges.

A sensitive and selective high-performance liquid chromatography method has been developed for the determination of the new monocyclic beta-lactam antibiotic carumonam in plasma and urine. The method for plasma involves protein precipitation with acetonitrile and removal of lipids with dichloromethane; urine is diluted with buffer. Separation and quantification are achieved using a mobile phase based on either ion-suppression or ion-pair chromatography on a reversed-phase column with UV detection. The limit of determination is 0.5 micrograms/ml plasma, using a 0.5-ml specimen, and 25 micrograms/ml urine, using a 50-microliter specimen. The inter-assay reproducibility is generally better than 4% when an internal standard is used. Since beta-lactam antibiotics may degrade on storage, close attention must be paid to the stability of these drugs in biological fluids; novel measures to prevent degradation on storage are described. The assay has been successfully applied to the analysis of several thousand samples from pharmacokinetic studies, including a study involving patients with impaired renal function.

Few data are available on placental transfer of anticonvulsants during early pregnancy. Nevertheless, it has been demonstrated that at this early stage of gestation, considerable amounts of phenytoin, primidone/phenobarbitone and carbamazepine as well as some of their metabolites are already present in fetal tissues. Potentially reactive metabolites of anticonvulsants can be formed by the fetal liver and accumulate in some organs. At term, most anticonvulsants are present in neonatal plasma in concentrations similar to those in maternal plasma. Valproic acid, on the other hand, can accumulate in fetal blood, for still unknown reasons. Elimination by the neonate is variable and is dependent on several factors, such as clinical state, pre- or perinatal enzyme induction, absorption of the drugs and their plasma protein binding. Neonatal acquisition of anticonvulsants via breast-feeding does not seem to be harmful for the neonate. In the case of phenobarbitone, however, the drug may accumulate in nursing neonates to levels approaching or even exceeding those of their mothers. Significant drug levels can also build up in neonates and infants nursed by carbamazepine- and ethosuximide-treated mothers. This review contains relevant pharmacokinetic data on anticonvulsant drugs widely used during pregnancy and the neonatal period. The differences between pregnant and non-pregnant adults as well as between neonates and older age groups are emphasized. Some pharmacokinetic data are correlated with clinical manifestations, such as seizure frequency, neonatal depression and withdrawal symptoms.