Effects of slowed gastrointestinal motility on levodopa pharmacokinetics

Abstract

Autonomic disorders are often seen in Parkinson's disease, with disturbances of the gastrointestinal tract occurring most frequently. These disorders, mainly a delay in gastric emptying and slowed gastrointestinal motility, can modify the pharmacokinetics and effectiveness of drugs used to treat Parkinson's disease and administered orally. In this study, we evaluated in a rabbit model the pharmacokinetics of levodopa (administered with carbidopa) in the context of gastrointestinal motility slowed by the administration of an anticholinergic drug. Levodopa + carbidopa (20:5 mg/kg) and the anticholinergic biperiden (100 μg/kg) were orally administered to rabbits over one of two time periods (7 or 14 days) to verify the stabilization of levodopa concentrations. The values of the area under the curve (AUC) and C max were higher on the final day of treatment with an increase in AUC of 25% on day 7 and 33.4% on day 14; for C max , the increase was 15% on day 7 and 12.8% on day 14. The values of AUC and C max were lower than those obtained when levodopa was administered to rabbits with normal gastrointestinal motility. The values obtained for C min (baseline sample obtained before administration) also increased with treatment duration (24% and 47.4% on days 7 and 14, respectively). These values were higher than those obtained in the absence of anticholinergic administration. We conclude that, under our experimental conditions of slowed gastrointestinal motility, levodopa absorption diminishes, and final concentrations and C min are higher than under conditions of normal motility.

Ghrelin prevents levodopa‐induced inhibition of gastric emptying and increases circulating levodopa in fasted rats

“…The present study showed that plasma dopamine levels were increased along with those of l ‐dopa with a peak elevation 15 min after orogastric l ‐dopa corresponding to the same time frame in which delayed gastric emptying was observed. Such a kinetic study is also consistent with other reports showing that l ‐dopa levels in the circulation peak around 15–20 min after orogastric treatment at doses of 5 and 15 mg kg −1 in rats 36 and 20 mg kg −1 in rabbits 39 . Elevation of circulating dopamine may play a role in the delayed gastric emptying.…”

Pharmaceutical quality of seven generic Levodopa/Benserazide products compared with original Madopar® / Prolopa®

“…Differences in the excipients used for generic formulations and the presence of impurities which may affect both the absorption and bioavailability of active ingredients in patients create a potential risk of “relative therapeutic in-equivalence” [15]. Furthermore, the intra-individual peculiarity of PD patients, such as slow absorption of the first orally administered dose of medication in the morning due to low gastric motility [23] makes the variability of blood concentrations from generic drugs unpredictable. Furthermore, PD patients often use multiple drugs e.g., dopamine agonists, monoamine oxydase inhibitors, anticholinergics, and psychotropics.…”

“…Furthermore, PD patients often use multiple drugs e.g., dopamine agonists, monoamine oxydase inhibitors, anticholinergics, and psychotropics. Since issues regarding drug-drug interactions are not addressed by bioequivalence studies, potential risks cannot be excluded [1,23]. Unpredictable blood concentrations also expose patients to a higher risk of concentration-dependent drug-drug interactions.…”

Pharmaceutical quality of seven generic levodopa/benserazide products compared with original Madopar®/Prolopa®

“…Furthermore, PD patients often use multiple drugs e.g., dopamine agonists, monoamine oxydase inhibitors, anticholinergics, and psychotropics. Since issues regarding drug-drug interactions are not addressed by bioequivalence studies, potential risks cannot be excluded [1,23]. Unpredictable blood concentrations also expose patients to a higher risk of concentrationdependent drug-drug interactions.…”