Biomedical subjects
Publications and source records attributed to A Trouet.
Vinblastine-C4 acyl derivatives were synthesized by linking alkyl maleoyl or amino acid maleoyl compounds through an ester linkage at the C4 position of the vindoline moiety of vinblastine. The condensation of the above mentioned compounds was performed by the mixed anhydride method. Their synthesis, yields and physiochemical data are reported.
The experimental antitumor activity of new vinca analogues was evaluated in mice. Among the derivatives tested, compounds n.8 and 14 demonstrated good activity against the P388 leukemia. These analogues were further investigated in 3 human carcinomas xenografted in nude mice. Compound n.8 compared favourably with vinblastine in the MX1 xenograft. Derivative n.14 showed activity against HepG2 and MX1 xenografts. As expected, derivative n.14 showed no activity against the CX1 tumor. Because of their significant antitumor activity in different models, further development of these compounds in being considered.
The pharmacokinetics, metabolism and disposition of doxorubicin and daunorubicin were studied for periods up to 100 hr in rabbits with (group II) or without a biliary fistula (groups I and III) and with (group I) or without (groups II and III) ligatured ureters using high-performance liquid chromatography to separate parent drug and metabolites. The plasma decay of doxorubicin and daunorubicin was triexponential. Metabolites appearing in the plasma after doxorubicin and daunorubicin bolus i.v. injection were respectively doxorubicinol and daunorubicinol, the latter being the major compound after daunorubicin injection. The elimination of daunorubicin was faster than that of doxorubicin. No differences in the elimination were observed between the 3 groups. In bile, 21% of the injected dose of doxorubicin were excreted mainly as the parent drug and 60% of the injected dose of daunorubicin were excreted, mainly as daunorubicinol. Enterohepatic circulation did not affect the biliary excretion of both doxorubicin and daunorubicin. Ligature of ureters increased slightly the biliary excretion of doxorubicin. The hepatic clearance of daunorubicin was greater than that of doxorubicin. The total urinary excretion was not different between the II and III groups and amounted to 11.6 and 12.8% of the injected dose of doxorubicin and daunorubicin, respectively. Metabolic ratios of doxorubicinol/doxorubicin and daunorubicinol/daunorubicin were similar in bile and urine.
The pharmacokinetics of daunorubicinol (DOL), the main metabolite of daunorubicin (DNR), was studied in rabbits and compared to that of daunorubicin after an 8 mg/kg dose. High-performance liquid chromatography was used to separate parent drug and metabolites. The plasma disappearance of DNR and DOL was triexponential. DOL was the major species detected in plasma and urine. Both drugs had large volumes of distribution. About 70% of DNR or DOL were bound to plasma proteins and mainly to albumin. Pharmacokinetic parameters of DOL obtained after injection of DOL were different from those calculated for DNR and those calculated for DOL after injection of DNR. The total urinary excretions of DNR or DOL were similar and amounted to 25% of the dose. No conjugates were identified in urine after enzymatic treatment. No fluorescent drug was identified in the feces. Anthracyclines were degraded in vitro in rabbit feces. The rabbit seems to be a good model for the study of anthracycline pharmacokinetics as our results in rabbits after DNR injection were similar to those in human studies.
Vinblastine-23-oyl amino acid derivatives and the analog deoxy vinblastine derivative were synthesized by linking amino acid carbocyclic esters to the vinca-23-oyl moiety, through an amide linkage. Their experimental chemotherapeutic activities on P388, L1210 leukemias and 6C3HED lymphosarcoma in mice were evaluated in comparison to those of the parent alkaloids vinblastine, vincristine, and the semi-synthetic derivative vindesine. Further, their toxicities and plasmatic clearance are given. We have developed a method for conjugating vinca alkaloid to bovine serum albumin through a covalent and reversible linkage. The chemotherapeutic activity of this conjugate on P388 leukemia was assessed. This conjugate was found stable in blood and serum up to 48 hours. Lysosomal hydrolases liberate about 50 per cent of the tritiated drug after 48 hours.
The levels of doxorubicin, doxorubicinol and DOX aglycone achieved in plasma, urine and feces after i.v. administration of doxorubicin at 7.9 mg/kg into five New Zealand White rabbits were determined by high-performance liquid chromatography and fluorometry. The parent drug was the major compound found in the plasma. Doxorubicinol and DOX aglycone only appeared in trace amounts in the plasma. The plasma disappearance curves were triphasic with mean half-lives of 2 min, 18 min and 15 h for the alpha-, beta- and gamma-phases, respectively. Plasma protein binding was studied by ultracentrifugation and electrophoresis. Doxorubicin was mainly bound to albumin to an extent of 73.9%. The mean percentage of the administered dose excreted in the urine was 8.0%. Doxorubicinol and doxorubicin were the major compounds present in the urine with small amounts of DOX aglycone. Neither the parent drug nor any fluorescent metabolites were identified in the feces. The rabbit seems to be a good experimental model for the pharmacokinetics study of anthracyclines since the plasma and urine pharmacokinetics parameters and the extent of metabolism are similar in both humans and rabbits.
To gain a better understanding of the antibacterial and antiprotozoal activity of spiramycin as well as the characteristic conditions of cellular defence, we studied its accumulation and intracellular localization in cultured macrophages. Within two hours spiramycin in its active form is accumulated intracellularly by macrophages to a concentration 10 to 20 times that found in the extracellular medium; it is released slowly by the cells when they are incubated in antibiotic-free medium. After differential or isopycnic centrifugation, a bimodal localization of spiramycin was found; one part could be associated with the soluble cytosolic fraction and another with organelles sedimenting at a density of 1.17 g/ml, which represent part of the lysosomal population and perhaps the phagosomes.