Clinical phase I and pharmacokinetic study of S 16020, a new olivacine derivative: report on three infusion schedules.

S 16020, a new 9-OH olivacine derivative, is a novel topoisomerase II inhibitor with activity in cell lines presenting the classical multidrug resistance phenotype. This report summarizes, in addition to pharmacokinetic data, the whole phase I clinical experience of S 16020 using three different infusion schedules. Asthenia and skin toxicity were the main side effects. In an attempt to understand the skin toxicity mechanism, experiments in animals were performed, the results of which are reported. S 16020 showed rapid tumor necrotizing activity in some patients, with soft tissue metastases of epidermoïd tumors and pain at the tumor site. To document the side effects of S 16020 and tumor site reactions (pain, edema, inflammatory signs), inflammatory parameters and some cytokines were measured. In our patients there was no hemolysis and no detection of anti-S 16020 antibodies, confirming the absence of immunogenicity of the compound. Based on the overall data of the three infusion schedules of S 16020, the dose of 100 mg/m(2) over 3 h every 3 weeks was selected for phase II studies.

Assessment of drug exposure in rat dietary studies.

1. The objective of this study was to justify the evaluation of exposure of animals to chemical substances on the basis of only three blood samples taken during a 24-h period, but still with acceptable accuracy. 2. Fischer rats were fed a diet mixed with either paracetamol, 100 mg.kg-1 (short half-life compound), antipyrine, 100 mg.kg-1 (medium half-life compound), or phenylbutazone, 50 mg kg-1 (long half-life compound) for 3 weeks. It had been shown in a preliminary study that these compounds when administered at these dose levels did not influence feeding behaviour. At the end of 3 weeks, five rats were sampled every 3 h beginning and ending at 19.00 h (45 rats in total) and plasma concentrations were measured using h.p.l.c. 3. The area under the curve over 24 h (AUC24), calculated using all nine concentrations was considered to be the true AUC24. Subsequently, estimates of this parameter were made using different combinations of concentrations at three or even two selected time points. 4. For each compound, the highest concentration occurred at 07.00 h. It was shown that using the concentrations at 07.00, 10.00 and 16.00 h the estimate of the AUC24 was within 15% of the true value. 5. In comparison with a gavage study in the same rat (strain and age), bioavailability was lower in the diet study with relative bioavailabilities of 27, 22 and 61% for paracetamol, antipyrine and phenylbutazone, respectively. 6. In conclusion, drug exposure as expressed by AUC24 and Cmax can be accurately determined in rat studies using compound administration in the diet by measuring concentrations at three selected time points for compounds with elimination half-lives ranging from about 1 to 5 h.

Radioimmunoassays for a new angiotensin-converting enzyme inhibitor, zabicipril, and its active metabolite, zabiciprilat, in human plasma.

Zabicipril (Z), a new angiotensin-converting-enzyme inhibitor under development, is a prodrug that has to be deesterified in vivo to the active metabolite, zabiciprilat (ZT), to reach its antihypertensive pharmacological properties. Two radioimmunoassays have been developed for the measurement of both Z and ZT in human plasma. Anti-Z and anti-ZT antibodies were raised in rabbits against their respective lysine analogues conjugated to bovine serum albumin. [3H]Z and [3H]ZT were used as radioligands for the prodrug (Z) and the drug (ZT), respectively. Studies on anti-Z antiserum specificity showed no significant cross-reactivity (< 0.1%) with the active metabolite (ZT); similarly, Z is poorly recognized (0.5%) by the anti-ZT antiserum. Both antisera showed little cross-reaction (2%) with glucuronide metabolites. The sensitivities of the assays were 1 and 0.2 ng/mL for Z and ZT, respectively. Interassay coefficients of variation ranged from 9 to 12% for Z at 2-50 ng/mL and from 8 to 13% for ZT at 0.5-5 ng/mL. These assays were used to investigate the pharmacokinetic profile of both Z and its pharmacologically active metabolite ZT after intravenous infusion of Z in human volunteers.

Genetic transformation ofCatharanthus roseus G. Don byAgrobacterium rhizogenes.

Catharanthus roseus plantlets were inoculated with differentAgrobacterium rhizogenes strains. This plant species is known to produce secondary metabolites and axenic hairy-root cultures are an alternative to extraction of plant tissue for the compounds which are synthesized in roots. Hairy root lines were established from inoculations with the agropine strain 15834 and transformed plants were obtained after spontaneous regeneration. Phenotypic alterations of both the root system and the aerial parts were observed in transformed plants. All the tissues analyzed contained agropine and mannopine. T-DNA analysis confirmed the presence of TL- and TR-DNAs either as distinct inserts, or as a single and continuous insert including the region between TL and TR on pRi 15834.