[Comparative enantioselectivity of the disposition of two non-steroidal anti-inflammatory agents, ketoprofen and carprofen, in man and animals]. / Enantiosélectivité comparée de la disposition de deux anti-inflammatoires non stéroïdiens, le kétoprofène et le carprofène, chez l'homme et l'animal.

After the administration of racemic ketoprofen and carprofen to man, both enantiomers of each compound exhibit similar plasma profiles. This contrasts with the rat where the active S(+) enantiomer is predominant. For carprofen, regardless of the route of administration, the R(-) enantiomer is predominant in the plasma of all investigated animal species. The S(+)/R(-) ratio of the "areas under the curves" during the time course of the kinetics, is: 0.60 in dogs, 0.53 in Yucatan micro-pigs, 0.48 in mini-goats, 0.67 in calves and 0.19 in horses. For ketoprofen, the S(+) enantiomer is predominant in dogs, cats and horses, with ratios of 30.3, 5.3 and 1.5, respectively, while R(-) is the predominant enantiomer in sheep. The interpretation of these inter-species differences can be supported by experimental evidence, however some informations are lacking and additional investigation is required. In the case of ketoprofen where S(+) is predominant in rats, dogs and horses, the metabolic chiral inversion from R(-) to S(+), which has been demonstrated in rats, may also take place in the latter two species. In addition, the well documented stereoselective clearance of the glucuronides, possibly in favour of the enantiomer S(+), may explain the lower body clearance of the R(-) enantiomer in sheep. For carprofen, no metabolic chiral inversion was shown in rats and dogs after administration of each enantiomer individually, but for this compound, stereoselective clearance of glucuronides has been demonstrated which may support the idea of a plasma concentration shift of the enantiomeric proportions vs time in favour of the R(-) enantiomer. Regardless of the possible biological mechanisms which are responsible for these inter-species differences, the existence of these differences gives rise to at least two important issues: The choice of animal species which can be used in the research of drugs destined for human therapeutics: the most pertinent animal species will be the one which demonstrates an enantiomeric plasma profile closest to that observed in man. The present data show that the ideal animal species from this respect has still to be identified. For application in veterinary therapeutics, a careful balance must be established between the requirement of favourable bioavailability of the active S(+) enantiomer and the potential of any possible chiral inversion of R(-) to generate hybrid molecules in meat and milk which in turn may lead to residues, the toxicity of which to the human consumer is still unknown.

The non-human primate: a possible model for human genetically determined polymorphisms in oxidative drug metabolism.

Genetic polymorphisms of drug oxidation are major determinants of interindividual variations in drug response and toxicity. Many animal models, including rats, have been used for clinical investigations of pharmacogenetics. However, because of large interspecies differences, these data are difficult to extrapolate to humans. We therefore phenotyped 64 non-human primates for debrisoquine and mephenytoin polymorphisms and identified poor metabolizers of both drugs. The frequency of poor metabolizers was 14% for debrisoquine (95% confidence limits, 6.5-25%) and 3% for mephenytoin (95% confidence limits, 0.5-10%). If family studies demonstrate a genetic basis for the two independent defects, this animal species could be used for in vivo and in vitro pharmacogenetic investigations.

Antifilarial activity of CGP 20,376 in chimpanzees (Pan t. troglodytes) naturally infected with Dipetalonema vanhoofi.

CGP 20,376, a benzthiazole and new antifilarial agent, was investigated at CIRMF in eight wild born chimpanzees naturally infected with Dipetalonema vanhoofi. Single oral doses (3.75, 7.5, 11 and 15 mg/kg) were administered. Drug levels during the first hour after administration were assessed in seven chimpanzees at 10 minute intervals in the blood. Levels of unchanged drug (CGP 20,376) were higher than those of its metabolite (CGP 20,308). However, there was considerable variation between individuals, although the results for each animal were consistent. Because of investigational limitations a complete drug profile could not be established. Unsheathed microfilariae of D. vanhoofi were monitored during the first hour following drug administration in seven chimpanzees. In five the microfilaraemia dropped to low counts within 10 minutes and remained below the initial values for the next 50 minutes while in two other chimpanzees it showed a more irregular reduction. Periodic microfilarial counts over the next 20 months, at roughly 30 day intervals, showed that three chimpanzees, treated with 7.5, 11 and 15 mg/kg respectively, remained free of circulating microfilariae from Day 1 to Day 600, the chimpanzee treated with 3.75 mg/kg remained microfilaremic and, in three chimpanzees low numbers of microfilariae reappeared within one year, whereas in the remaining ape they reappeared after one year. No major clinical adverse effects were observed, but liver function tests showed mild reversible changes at the 11 and 15 mg/kg doses. CGP 20,376 was therefore microfilaricidal, except for the lowest dose, and it was possibly macrofilaricidal in those chimpanzees which remained free of microfilariae for 600 days. Clinically CGP 20,376 was well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Cellular and biochemical characteristics of semen obtained from pubertal chimpanzees by masturbation.

Semen characteristics were studied in 6 wild-born chimpanzees with dental ages ranging approximately from 6 to 12 years. The animals formed 2 groups, early pubertal (EP, N = 3, 6-9 years) and late pubertal (LP, N = 3, 11-12 years). Mean body weight, testicular volume and serum androgen concentration were significantly lower in Group EP (32.2 +/- 1.6 kg, 34.0 +/- 7.7 cm3, 2.1 +/- 0.1 ng/ml) than in Group LP (55.7 +/- 5.7 kg, P less than 0.01; 100.5 +/- 11.9 cm3, P less than 0.01; 3.6 +/- 0.7 ng/ml, P less than 0.05). Ejaculates were obtained by masturbation in all subjects. The mean ejaculate volume was lower in Group EP (0.56 +/- 0.20 ml) than in Group LP (3.77 +/- 0.73 ml, P less than 0.01). In Group EP, 2 animals were azoospermic while the third produced semen with means of 57.1 x 10(6) spermatozoa per ml, 20% motility and 40% vitality. These values were low when compared with the mean values of Group LP (376 x 10(6) spermatozoa per ml, 67% motility and 78% vitality). Mean total sperm count was correlated with testicular volume (r = 0.84) and serum androgen concentration (r = 0.96). The mean concentrations of L-carnitine, fructose, citrate and acid phosphatase for the two groups were not significantly different; but, related to the differences in ejaculate volumes, their total amounts in total ejaculate were lower in Group EP than in Group LP. These results suggest that, in chimpanzees, mechanisms of seminal plasma production and ejaculation are functional early in the reproductive life and that the emission of spermatozoa occurs later.