1 The pharmacokinetic behaviour and the bioavailability of midazolam were investigated in six volunteers after intravenous (0.15 mg/kg) and oral administration (10, 20 and 40 mg). 2 Following rapid intravenous injection of midazolam, the plasma concentration of the substance decreased to approximately 10% within 2 h owing to a rapid rate of distribution. 3 A two compartment model adequately described the kinetics of midazolam in plasma. The following average values were found: elimination half-life, 2.3 h; total clearance, 323 ml/min, and apparent volume of distribution at steady-state (V,s), 50.21. 4 After oral administration, the drug is rapidly absorbed. Maximum plasma levels are reached within 30 min and the drug is rapidly eliminated from plasma with practically the same half-life as determined after i.v. administration. 5 The bioavailability after the ingestion of 10, 20 and 40 mg midazolam in the form of tablets ranged from 31 to 72%, due to the high liver extraction quota of midazolam.

Aims To investigate the rate of excretion and routes of metabolism of tolcapone, a novel inhibitor of catechol-O-methyltransferase (COMT). Methods Six healthy male volunteers were given 200 mg [14 C]-tolcapone (approximately 50 mCi) orally. To assess excretion balance and to identify metabolites, urine and faeces were collected before administration and until radioactivity fell below 75 d min −1 ml −1 (urine) and 100 d min −1 mg −1 (faeces). Blood samples were collected frequently before and after administration to determine plasma radioactivity, to identify tolcapone metabolites and to measure plasma tolcapone and its methylated derivative 3-O-methyltolcapone (3-OMT).Results The mean proportion of the dose excreted in urine was 57.3% and in faeces 40.5%. Excretion was almost complete (more than 95%) in all participants after 9 days. The major early metabolite present in plasma was the 3-O-b,d-glucuronide conjugate, which was detectable within 2 h after dosing. The major late metabolite in plasma was 3-OMT. The 3-O-b,d-glucuronide was also the most abundant metabolite in urine and faeces, accounting for 27% and 33%, respectively, of the total radioactivity excreted by these routes and for 26% of the original dose. Reduction of the nitro moiety yields an amine derivative, detected in both urine and faeces, with subsequent modifications, such as acetylation of the amine group and conjugation with glucuronic acid or sulphate, or both. Oxidative reactions due to cytochrome P450 enzymes are of small significance, as is 3-O-methylation by COMT. Conclusions Tolcapone is almost completely metabolized and excreted in urine and faeces (only 0.5% of tolcapone was excreted unchanged); glucuronidation is the most important route of metabolism. The relatively long duration of excretion is caused by the long half-life of 3-OMT.

The pharmacodynamics of carprofen and its pharmacokinetics in plasma and milk of healthy cows and cows with endotoxin-induced mastitis were studied after a single intravenous dose of 0.7 mg/kg body weight. Carprofen was administered to five clinically healthy cows and to the same cows 3 weeks later, 2 h after intramammary infusion of endotoxin. Mastitis developed in all endotoxin-infused quarters. The pharmacokinetic characteristics of carprofen in healthy cows were a small volume of distribution (0.09 l/kg), a relatively low systemic clearance (2.4 ml/h kg), and a long elimination half-life (30.7 h). In the mastitic cows, systemic clearance (1.4 ml/h kg) was significantly lower (P less than 0.01), and elimination half-life (43.0 h) was significantly longer (P less than 0.01) than in the normal animals. Concentrations of carprofen in milk from healthy quarters were below the limit of detection for the assay (0.022 micrograms/ml). In milk from mastitic quarters, concentrations of carprofen increased up to 0.164 micrograms/ml during the first 12 h after induction of mastitis, but were less than 0.022 micrograms/ml at 24 to 48 h. Compared with the untreated mastitic controls, carprofen treatment significantly reduced heart rate (P less than 0.01), rectal temperature (P less than 0.001), quarter swelling (P less than 0.01) and other parameters measured. Local and systemic adverse reactions to carprofen were not observed.

1 In a double-blind, cross-over study in six healthy volunteers, the effects of different oral doses of midazolam (10, 20 and 40 mg), or 0.15 mg kg-'midazolam administered intravenously and of placebo were investigated. Plasma concentrations of midazolam and of its active a-hydroxy metabolite were measured at the same time. 2 The effect was assessed using objective and subjective methods (reaction time, tracing test, subjects' self-assessment and investigator's subjective assessment). 3 The respective time courses of the plasma concentration and of the effect (reaction time, number of errors in the tracing test) were almost identical. Peak plasma levels and maximum effects were attained within 30 min. In general, the effect after intravenous injection of 0.15 mg kg-' and after an oral dose of 10 mg midazolam lasted for 2 h following administration and its duration was doubled (i.e. to 4 h) after the 20 mg oral dose. Between the logarithm of the plasma concentration and the effect, there is a sigmoidal relationship that is virtually time independent. 4 Particularly in the first few hours after oral administration the effect is intensified by the a-hydroxy metabolite of midazolam which is formed by first-pass metabolism. 5 At identical plasma concentrations of midazolam, the oral dose produced more marked effects than did the intravenous administration. 6 Correlation of the measured effects with the total (midazolam + a-hydroxy midazolam) plasma concentration reveals a closer sigmoidal relationship.

The pharmacokinetics of tenoxicam after a single oral dose of 20 mg has been studied in 12 patients with various degrees of decreased renal function. Unchanged tenoxicam and its 5'OH-metabolite in plasma and urine were determined by HPLC. The mean areas under the plasma concentration-time curve (138 +/- 53 micrograms/ml X h) and terminal half-lives in patients with impaired renal function did not differ from values previously reported in normal volunteers, nor did the peak concentration of tenoxicam. The half-life of 5'OH-tenoxicam and unchanged tenoxicam where the same. The urinary excretion of 5'OH-tenoxicam fell with decreasing renal function. Thus no dosage adjustment should be necessary and the usual daily dose of tenoxicam may be administered once daily also to patients with renal failure.