Toxicokinetics of isoprene in rodents and humans.

A physiological toxicokinetic model (PT model) was developed for inhaled isoprene in mouse, rat and man. Partition coefficients blood:air and tissue:blood were determined in vitro by a headspace method. Parameters of a saturable isoprene metabolism in B6C3F1 mice, Sprague-Dawley rats and volunteers were obtained from gas uptake experiments in closed systems, analyzed by means of a two-compartment model. Incorporation of these parameters into the PT model revealed that isoprene was metabolized not only in the liver but also in extrahepatic organs. Endogenous production of isoprene in man was quantified from experiments with volunteers breathing into a closed system. The PT model was validated for mice, rats and humans by comparing simulated values with data determined by other authors.

Local tissue tolerability of meloxicam, a new NSAID: indications for parenteral, dermal and mucosal administration.

Meloxicam is a new non-steroidal anti-inflammatory drug (NSAID) which has potent anti-arthritic activity and a reduced potential to induce gastric irritation in animals. The present series of animal studies investigated the local and/or systemic tolerance of meloxicam formulations: intravenous, intramuscular and subcutaneous injections, eye-drops, gel and suppositories. The concentration and formulations were as intended for therapeutic use in man. An in vitro haemolysis test demonstrated that the parenteral formulation of meloxicam produced only minimal haemolysis. In comparison, NSAIDs such as piroxicam, ketoprofen and indomethacin showed comparable haemolysis only after dilution. Diclofenac and ibuprofen caused considerable haemolysis even when diluted. In all studies, the local tolerance of meloxicam was good and did not differ from placebo, even when administered daily for 4 weeks. Few abnormal histopathological findings indicative or organ toxicity were observed. There were only small, transient macroscopic changes at the site of administration, with no striking histopathological changes directly attributable to meloxicam. Intramuscular piroxicam and diclofenac, however, resulted in development of an extensive, solitary necrotic area. Other formulations tested were also very well tolerated. In conclusion, all meloxicam formulations tested exhibited excellent tissue tolerability. Therefore, meloxicam appears to be suitable for parenteral, dermal and mucosal administration.

A pharmacokinetic model to describe toxicokinetic interactions between 1,3-butadiene and styrene in rats: predictions for human exposure.

Co-exposure to vapours of 1,3-butadiene and styrene occurs in the styrene-butadiene polymer manufacturing industry. Both compounds are biotransformed during a first step by cytochrome P450-dependent mono-oxygenases to epoxides--intermediates which are proven carcinogens. In a previous publication, we reported that metabolism of butadiene in rats was inhibited by simultaneous exposure to styrene, whereas butadiene had no effect on the kinetics of styrene. In order to translate these results into conditions of human exposure, we developed a physiologically based pharmacokinetic (PBPK) model, which is presented here. Maximal metabolic rates (Vmax) and Ostwald's partition coefficients were obtained using liver microsomes and tissues from rat and man. Apparent Michaelis (Km) and inhibition (Ki) constants were derived from previously published data on rats and were considered to be species-independent. The model was used to simulate human exposure to atmospheric mixtures of 5 and 15 ppm butadiene with 0.20 and 50 ppm styrene. It predicts that the presence of styrene significantly inhibits butadiene metabolism in man: At exposures up to 15 ppm, the amounts of butadiene metabolized can be expected to be reduced to 81 and 63% with co-exposure to styrene at 20 and 50 ppm, respectively.