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

Pharmacokinetic 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-SO4 and DOPAC, Though plasma concentration of DA was quite different from that of DA-SO4 or 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 of 1 were 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 of 2(K4) is larger than that of DA-SO4(K5) or DOPAC(K6); thus it was shown that two protective groups of 1 reduced the metabolism of DA and 2 specially 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 reduction of first-pass metabolism of DA.