Bioavailability and pharmacokinetics of an oral dopamine prodrug in dogs.
The bioavailability and pharmacokinetics of an oral dopamine prodrug, N-(N-acetyl-L-methionyl)O,O-bis(ethoxycarbonyl)dopamine (1), were examined in dogs, and the mechanism of its absorption and bioactivation was discussed. Compound 1 showed a plasma dopamine concentration that was several times higher than that of dopamine (DA) following oral administration to dogs, while the plasma concentrations of dopamine-30-sulfate (DA-SO4) and 3,4-dihydroxyphenylacetic acid (DOPAC) are lower in comparison with that of DA. The conversion of 1 to DA occurred in proportion to the dose administered. Compound 1 also showed a plasma DA concentration that was several times higher than that of other DA prodrugs reported hitherto. In dog plasma, in vitro, 1 was converted to its deethoxycarbonylated form, N-(N-acetyl-L-methionyl)dopamine (2), while other related compounds, N-(L-methionyl)dopamine (3), N-(L-methionyl)O,O-bis(ethoxycarbonyl)-dopamine (4), and O,O-bis(ethoxycarbonyl)dopamine (5), were rapidly converted to DA (however, 2 was stable in plasma). Bioavailability, based on the AUC of DA, 1, 2, and 5 following oral administration to dogs, increased in the following order: 1, 2, 5, and DA. Thus, it was shown that the two protective groups introduced in 1 served to reduce the first-pass metabolism of the DA moiety in the absorption process. It was also confirmed that 1 is converted to 2 or DA in blood, liver, and intestine.
Murata
K
K
Products Formulation Research Laboratory, Tanabe Seiyaku Company, Ltd., Osaka, Japan.
Noda
K
K
Kohno
K
K
Samejima
M
M
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D004285:Dogs; D004298:Dopamine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D004355:Drug Stability; D004386:Duodenum; D007267:Injections; D007408:Intestinal Absorption; D007441:Intubation, Gastrointestinal; D008642:Mesenteric Veins; D011355:Prodrugs
D011355:Prodrugs; D015102:3,4-Dihydroxyphenylacetic Acid; C052143:docarpamine; D004298:Dopamine