I The pharmacokinetic behaviour of the psychotropic drug clobazam, a 1,5 benzodiazepine, and its metabolism were studied with the "4C-labelled compound in rats, dogs, monkeys and man. The absorption was practically complete in all three animal species. Clobazam was not excreted in the unchanged form by all species. The main metabolite in plasma of monkeys, dogs and man was N-demethylclobazam. The metabolites were partially in the conjugated form.2 The binding to serum proteins (concentration range 0.05-10 jg/ml serum) amounted to between 66% (in rats) and 85% (in man). The maximal levels of total radioactivity (original compound and metabolites) in blood were 0.24 + 0.043 ig Equ/ml (2-4 h) in doses and 0.67-0.82 jg Equ/ml (0.5-1 h) in rhesus monkeys. These levels were markedly higher than those in rats with values of 0.064 + 0.012 jig Equ/ml (-0.5 h). The elimination of radioactivity from blood occurred in two phases.3 After repeated daily administration of oral doses, the 24-h blood levels accumulated in rats to about three times the initial value. In dogs the 24-h serum concentrations remained practically unchanged. Long-term treatment with clobazam in monkeys neither caused enzyme induction nor other processes retarding metabolism and elimination. 4 Both after a single oral and intravenous dose, more than two-thirds of the radioactivity administered to rats was excreted with the faeces. Dogs, however, excreted about three-quarters of the radioactivity with the urine, irrespective of the route of administration. In monkeys, the excretion also occurred mainly in the urine. In all three species, renal excretion was similarly rapid to that from blood or plasma. 5 Apart from gastro-intestinal tract, liver and kidneys, the distribution in rats and dogs was remarkably even within the range of maximal blood levels. In the rat brain, the concentration amounted to only one-third of that in the blood. Special accumulations were not found. In dogs, the concentration in the brain was as high as that in the blood. 6 In rats, kinetics and metabolism were not significantly changed by pregnancy. 7 For metabolism studies in the four species (man, monkey, dog and rat) urine and faeces (and in some cases also serum) were examined after a single dose or repeated administration. The number and kind of metabolites detected in the individual species were partially different. In autoradiographic studies, exceptionally up to 14 radioactive spots were found for clobazam. 8 The structures of the metabolites were elucidated by independent methods, mainly mass spectrometry. In addition to the original substance, eight metabolites were identified for clobazam amounting to 70-90%/o of the total number of metabolites, depending on the species.The two most important chemical changes of clobazam during metabolism are dealkylation and hydroxylation. Dealkylation at nitrogen-(I), particularly pronounced in the species dog, does not differ between the 1,4-and 1,5-benzodiazepines. The difference in metabolism is only pronounced in oxidative deco...

I The pharmacokinetics of clobazam and its biotransformation product N-desmethylclobazam were investigated after single and multiple doses in normal subjects. 2 The relevant physicochemical properties of clobazam were measured and are presented. Different assay methods (radiochemical, fluorimetric and gas chromatographic) were applied and the results correlated. 3 After single doses the pharmacokinetic profile of clobazam includes time to peak levels 1-4 h after dosing, peak levels increasing linearly with the logarithm of dose, and terminal half-lives of about 18 hours. At least 87% of an oral dose is absorbed, as indicated by urinary recovery of labelled material. 4 In multiple-dose studies unchanged clobazam levelled off at minimum steady-state concentrations within one week of dosing. During 28 d of medication N-desmethylclobazam accumulated to near steady-state levels about eight times higher than those of the unchanged compound. 5No pharmacokinetic interactions were discovered between clobazam and the antidepressant nomifensine.

The direct introduction of crude oil samples diluted in organic solvents to be analyzed by inductively coupled plasma-atomic emission spectroscopy (ICP-OES) and inductively coupled plasma mass spectrometry (ICP-MS) is an attractive way to perform elemental analysis, particularly in high sample volume facilities, where turnaround time is critical. Here, it is presented results obtained by performing direct injection of a broad set of petroleum crude oils diluted in o-xylene and analyzed by ICP-OES/MS. By utilizing proper sample preparation and instrument tuning parameters, we set out to assess data accuracy, standard deviation, and recovery, particularly in the region of mg kg–1 to μg kg–1. A multielement Conostan standard (10 elements at 2 mg kg–1 in crude oil) as well as NIST 1634c CRM were selected for this purpose. In general, the data from both instruments were comparable regarding precision, relative standard deviation, and recoveries for metals evaluated at a concentration range of interest. The potential effect of crude oil viscosity on a sample introduction system was assessed using three crude oil samples representative of the total group, diluted in o-xylene diluent. In general, the viscosity values of the final solutions do not impact the quality of the results obtained. Furthermore, 18 petroleum crude oil samples with API values spanning from 9.5° up to 51° were analyzed. In general, there is good agreement between the two techniques as seen from ICP-OES/ICP-MS ratio values for the elements spanning in most cases from 0.80 to 1.20. Finally, V/(V + Ni) ratios were successfully determined for all samples and the ICP-OES/ICP-MS ratios calculated span from 0.96 up to 1.05, which provides insight into the high precision that was achieved by the direct dilution method for both instruments.

Trace elemental analysis using microwave-induced plasma (MP) generated by nitrogen gas was employed as an atomization and excitation source for emission spectrometric (microwave plasma atomic emission spectroscopy, MP-AES) analysis for crude oil samples. Nitrogen gas produced from air through a gas generator, and in combination with an external gas control module (EGCM) used to introduce air into the plasma, leads to a stable robust microwave-induced plasma, enough to perform the analysis of crude oil samples with different API values, sulfur (0.5−5 wt %) and nitrogen (500 −2500 mg/kg) by direct dilution in a o-xylene diluent. Excellent detection limits and spike recoveries at low and high concentration levels were determined for Ni, V, Fe, Ca, and Na in crude oil matrix. The recoveries obtained from the analysis of the three quality control (QC) test materials were within ±10% of the actual/certified values. Comparable results for Ni and V as well as the V/(V + Ni) ratio in crude oils between nitrogen plasma and conventional argon plasma such as inductively coupled plasma atomic emission spectroscopy (ICP-AES) and inductively coupled plasma mass spectrometry (ICP-MS) were achieved in terms of precision, relative standard deviation, and recoveries for the concentration range from 2 to 230 mg/kg.

The pharmacokinetics and pharmacodynamics of the angiotensin converting enzyme inhibitor HOE 498 were investigated in 10 healthy normotensive male subjects. Serum levels of the active metabolite M 1 (dicarboxylic acid) of HOE 498 were measured by HPLC up to 14 days after a single oral dose of 10 mg HOE 498. Peak serum concentration of M 1 between 5-50 ng/ml was observed 1.5-3.0 h after administration. The serum concentration-time curve of M 1 was polyphasic and exhibited a prolonged terminal phase with a half-life of approximately 110 h. Despite the long terminal half-life M 1 could not be detected in urine later than 72 h after administration. The activity of the angiotensin converting enzyme in plasma was completely suppressed for up to 12 h, and 72 h after dosing 50% inhibition of the enzyme was still observed.