Pharmacokinetics of methylprednisolone aceponate(MPA) in rats (I): Absorption, distribution, metabolism, excretion and accumulation after single and repeated subcutaneous administration to rats.
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Pharmacokinetics of methylprednisolone aceponate(MPA) was investigated after subcutaneous administration of [6-<SUP>14</SUP>C-methyl]-MPA to rats.<BR>1. The radioactivity in the plasma reached Cmax at 0.3 h, and disappeared from the plasma with a half-life of 1 h. AUC and plasma levels in male rats were 2-fold higher than those in females.<BR>2. Binding to plasma protein in vitro and in vivo accounted for 94%.<BR>3. The radioactivity distributed rapidly and widely to tissues. Most tissues, especially liver and kidney, showed higher conc. than in the blood. The maximum was found within 1 h, and disappeared almost completely from tissues by 120 h. The disappearance from the blood of male rats was slow (T<SUB>1/2</SUB> in the last phase:> 150 h). Though the conc. in tissues showed higher values in male than female, the C<SUB>tissues</SUB>/C<SUB>blood</SUB> were similar in both sex.<BR>4. During the repeated subcutaneous administration, the conc. in tissues of female rats showed no accumulation. In male rats, the conc. in tissues, especially in the blood, raised by the repeated administration. The increase of the conc in tissues was caused by the higher blood level, and the accumulation in tissues was not found. Excretion to urine and feces was complete.<BR>5. The conc. in fetus was lower than that in maternal plasma, and showed practically no transfer to milk.<BR>6. The excretion of the radioactivity into urine and feces within 120 h were 2 ?? 6% and 90 ?? 96% of the dose, respectively. The biliary excretion was 80% (-24 h). About 15% of the radioactivity in the bile underwent enterohepatic recirculation.<BR>7. MPA was not found in the plasma already at 15 min, and the main metabolites in the plasma were methylprednisolone-17-propionate (MP-17P, female, male), methylprednisolone (female) and highly polar unidentified metabolites (male). Most of radioactivity excreted to the bile consisted of a major metabolite identified as sulfate conjugate of MP-17P (female;> 90%, male;> 20%). Several unidentified metabolites were found in male rats.
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