RESUMEN
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.
Asunto(s)
Daunorrubicina/metabolismo , Doxorrubicina/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Animales , Bilis/metabolismo , Daunorrubicina/análogos & derivados , Daunorrubicina/sangre , Daunorrubicina/orina , Doxorrubicina/análogos & derivados , Doxorrubicina/sangre , Doxorrubicina/orina , Circulación Enterohepática , Femenino , Cinética , Modelos Biológicos , Conejos , Factores de TiempoRESUMEN
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.
Asunto(s)
Daunorrubicina/análogos & derivados , Daunorrubicina/metabolismo , Animales , Proteínas Sanguíneas/metabolismo , Cromatografía Líquida de Alta Presión , Daunorrubicina/orina , Heces/análisis , Semivida , Cinética , Masculino , Unión Proteica , ConejosRESUMEN
The stability of doxorubicin (DOX) and daunorubicin (DNR) in rabbit and human plasma, bile and urine and in rabbit faeces was studied in the presence or absence of light, and at body, room and cold room temperatures. Fluorescence was determined by spectrofluorimetry after normal and reversed phase HPLC. Under each set of conditions, DOX and DNR fluorescence decreased with time; the decrease was more rapid with DOX. As the parent drugs were degraded, apolar compounds were formed which behaved like 7-deoxyaglycones and generally did not compensate for the loss in fluorescence of the parent drug. The degradation of anthracyclines occurred even in the absence of light, was not due to bacterial contamination and was faster at higher pH or temperature. The rapid degradation of DOX and DNR in biological fluids at body temperature may have implications on the disposition of anthracyclines in vivo. Prior to analysis, biological fluids and solutions containing anthracyclines should be processed quickly at 4 degrees C, in the absence of light, and at a pH no greater than 6 to avoid degradation.
RESUMEN
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.