Effect of age on gastrointestinal and hepatic first-pass effects of levodopa in rats

Abstract

Presystemic elimination of levodopa (20 mg kg-1) has been studied in 5- to 104-week-old male Wistar rats. The gastrointestinal and hepatic contribution to the overall first-pass effect was estimated separately after the drug had been administered intravenously, orally and intraportally. The contribution of the gut to the overall first-pass effect of this drug was greater than that of the liver in any age-group of the rats. Both the overall and intestinal first-pass effects of levodopa were greatest in 11-week-old rats and relatively small in both young (between weeks 5 and 7) and aged (between weeks 52 and 104) rats. In contrast, the hepatic first-pass effect did not show any significant age-dependent change. Age-related change in the jejunal blood flow could not explain the unique age-dependence in the intestinal first-pass metabolism of levodopa. However, the present age-dependence in the oral systemic availability of this drug between adult (11 weeks) and aged (52 to 104 weeks) rats was found to be similar to the tendency that has been reported between normal adult subjects and aged patients with Parkinson's disease.

Aging Biology and Geriatric Clinical Pharmacology

“…The increased bioavailability of levodopa reported in older parkinsonian subjects was considered to be secondary to delayed gastric emptying (Evans et al, 1981a). In rats, the agerelated increase in levodopa bioavailability was thought to be intestinal and unrelated to changes in hepatic metabolism or splanchnic blood flow (Iwamoto et al, 1987). In summary, there are many age-related changes that potentially may increase or decrease bioavailability and the food effect of orally administered drugs.…”

Decarboxylation of l-Dopa in the Rat Isolated Vascularly Perfused Small Intestine: Contribution to Systemic Elimination and Dose-dependent First Pass Effect

“…In these experiments the area under the plasma concentration time curves (AUC) for L-dopa was found to increase nonlinearly with the dose. The contribution of the rat liver in the overall first pass effect of L-dopa was found to be smaller than that of the intestine (Iwamoto et al 1987). Therefore, the non-linear L-dopa kinetics in-vivo can be attributed to the marked dose-dependent intestinal first pass effect observed in the in-vitro experiments.…”

Gut bacterial deamination of residual levodopa medication for Parkinson’s disease

“…DHPPA is a phenolic acid (a molecule in the class polyphenols), and recent findings demonstrated an association between bacterial-derived polyphenol metabolites and gut transit times in humans [27]. Levodopa is mainly absorbed in the proximal small intestine, but significant amounts can reach the distal part of the intestinal tract [17], and these levels increase with age [28]. As levodopa is taken orally, the first intestinal site where anaerobic bacteria such as C. sporogenes (Clostridium Cluster I) can encounter relevant levels of levodopa is the ileum.…”