Plasma levels of levodopa, total dopamine, and residual amounts of levodopa and its metabolites at the administered site were analyzed following administration of single 100-mg doses of levodopa in solution into isolated segments of the duodenum, jejunum, and ileum of the dog. The largest area under the plasma concentration-time curve (AUC) of levodopa during the 1.0-hr study was obtained following administration in the duodenum, followed by the jejunum and ileum. In addition, the residual amounts of levodopa and its metabolites detected at the administration sites were: ileum, 23% jejunum, 7%; and duodenum, <1%. The largest AUC of total dopamine was obtained following administration in the jejunum, followed by the ileum and duodenum. This order was consistent with the order of levodopa decarboxylase enzyme activity reported previously. Therefore, it can be concluded that the major absorption site of levodopa in the intestine resides in the upper small intestine. Levodopa in lo-, 50-, and 100-mg doses was administered into isolated duodenal segments. The AUC of levodopa increased nonlinearly with increasing dose. Negligible amounts of both levodopa and its metabolites were observed in the segment at !.O hr after administration, indicating that the duodenal absorption of levodopa was not saturable within the dose range tested.
Keyphrases 0 Levodopa-absorption and metabolism, intestinal segments, dogs, bioavailability, dosage form design 0 Dosage form design-bioavailability of levodopa, absorption and metabolism in dog intestinal segments Bioavailability-levodopa, dosage form design, absorption and metabolism in dog intestinal segments It was previously reported (1) that the reduced bioavailability of levodopa following oral administration was primarily due to levodopa metabolism by levodopa decarboxylase in the intestinal tissue, with the most enzyme activity in the jejunum and the least in the duodenum. The present investigation attempted to validate these findings by a study of levodopa absorption from intestinal segments.
EXPERIMENTAL
Major Absorption Site of Levodopa in Intestine of Dogs-Nine healthy male mongrel dogs, 11.1-13.9 kg, were fasted for -16 hr and anesthetized with 25-mg/kg iv doses of pentobarbital sodium. They were divided into three equal groups according to the segment to be ligated. After the dog was fixed on its back, a laparotomy was performed on each dog, and a 20-cm segment of the duodenum, the jejunum, or the ileum was ligated. A single 100-mg dose of levodopa was injected as a 1% solu-tion' into the ligated segment of each dog. Blood samples were withdrawn with a heparinized syringe from the brachial or femoral vein.
. 1 The 0.2,0.5, and 1% levodopa solutions were prepared by dissolving Ievodopa in the buffer solution containing 0.2% sodium bicarbonate and 0.5% polyvinyl acetate (-pH 8.0).
2 Total dopamine = unconjugated dopamine + conjugated dopamine.