Absorption of a novel prodrug of L-dopa, L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine (NB-355). In vitro and in situ studies.
Absorption mechanism and absorption site of a prodrug of L-DOPA, L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine (NB-355, 1) was investigated using rats. Prodrug 1 (0.5 mM) was taken up by intestinal tissue segments time-dependently in vitro at pH 6.0. However, the rate of uptake was less than that of L-dopa. Inhibitors of the amino acid active transport system (L-Phe, dinitrophenol, ouabain) had no effect on the uptake of prodrug 1. In the intestinal tissue segments, prodrug 1 was extensively hydrolyzed by diisopropylfluorophosphate-sensitive esterase(s). To characterize the absorption site, gastrointestinal tracts were ligated to make acute loops in situ and prodrug 1 or L-dopa was injected into the loops. L-dopa disappeared rapidly from the lumen of the jejunum. In contrast, prodrug 1 disappeared rapidly from the ileum rather than the duodenum or jejunum. From these results, it was suggested that prodrug 1 was slowly absorbed primarily from the lower small intestine.
Hisaka
A
A
Central Research Laboratories, Banyu Pharmaceutical Company, Ltd., Tokyo, Japan.
Kasamatsu
S
S
Takenaga
N
N
Ohtawa
M
M
D000818:Animals; D004140:Dinitrophenols / Q000494:pharmacology; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007531:Isoflurophate / Q000494:pharmacology; D007980:Levodopa / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D008297:Male; D010042:Ouabain / Q000494:pharmacology; D010649:Phenylalanine / Q000494:pharmacology; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats
D004140:Dinitrophenols; D011355:Prodrugs; C061031:L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine; D007531:Isoflurophate; D007980:Levodopa; D010649:Phenylalanine; D010042:Ouabain