Pharmacokinetic analysis of absorption and metabolism of dopamine and a dopamine prodrug in dogs

摘要

AbstractPharmacokinetic compartment models were constructed to describe the absorption and metabolism of dopamine (DA) and DA prodrug, N‐(N‐acetyl‐L‐methionyl)0,0‐bis(ethoxycarbonyl) dopamine(1). Plasma concentrations of DA, DA‐SO4. and DOPAC after oral administration of DA to dogs, were analysed using the pharmacokinetic model assuming the contribution of first‐pass metabolism for the formation of DA‐SO4and DOPAC, Though plasma concentration of DA was quite different from that of DA‐SO4or DOPAC, these data were simultaneously analysed with a good fitting curve. The apparent absorption rate constant of DA(K1) was proved to be much smaller than the apparent formation rate constants of DA‐SO4(K2) or DOPAC(K3). It was found that the compartment model is useful for the evaluation of absorption and metabolic inactivation of DA. Plasma concentration of DA, N‐(N‐acetyl‐L‐methionyl)dopamine(2), DA‐SO4, and DOPAC after oral administration of1were simultaneously analysed using the compartment model including the first‐pass metabolism and two‐fraction dissolution process. Good fitting curves were obtained. The apparent formation rate constant of2(K4) is larger than that of DA‐SO4(K5) or DOPAC(K6); thus it was shown that two protective groups of1reduced the metabolism of DA and2specially played an important role to the reduction of first‐pass metabolism. From these results, it was found to be possible to give a pharmacokinetic interpretation for the mechanism of red