Aranzazu González

Hydrosoluble fiber (Plantago ovata husk) and levodopa II: Experimental study of the pharmacokinetic interaction in the presence of carbidopa

Levodopa combined with carbidopa constitutes one of the most frequent medication in the treatment of Parkinsons disease. Plantago ovata husk (water-soluble fiber) improves levodopa absorption conditions, but when this drug is administered with carbidopa, fiber could reduce its effectiveness. The purpose of this study is to investigate whether the presence of P. ovata husk modifies in rabbits the bioavailability and other pharmacokinetic parameters of levodopa (20 mg/kg) when administered by the oral route with carbidopa (5 mg/kg). We have also studied whether pharmacokinetic modifications are fiber-dose dependent (100 and 400 mg/kg). When levodopa and carbidopa were administered with 100 mg/kg P. ovata husk, the value of AUC for levodopa diminishes 29.7% (sign, n=6, P<0.05) and Cmax 28.1% (sign, n=6, P<0.05) in relation to the values obtained when these drugs were administered without fiber. If the dose of fiber was 400 mg/kg, the decrease was smaller: 20.4% for AUC (no significant difference) and 24.6% for Cmax (sign, n=6, P<0.05), that may indicate an inhibitory action of AADC by the fiber or any of its partial hydrolysis products. On the other hand, since certain time on, levodopa concentrations are always higher in the groups that receive fiber: 210 min with 100 mg/kg and 150 min with 400 mg/kg. The administration of P. ovata husk with levodopa/carbidopa to patients with Parkinson disease could be beneficial and in particular in those patients who also suffer constipation due to an improvement of levodopa kinetic profile with higher final concentrations, a longer plasma half-life and lower Cmax.

Hydrosoluble fiber (Plantago ovata husk) and levodopa I: experimental study of the pharmacokinetic interaction.

Fiber therapy could be used in patients with Parkinson disease to reduce the symptoms of gastrointestinal disorders; however, it could interact with levodopa reducing its effectiveness. In this experimental study we have investigated whether the presence of Plantago ovata husk (water-soluble fiber) modifies in rabbits the bioavailability and other pharmacokinetic parameters of levodopa (20 mg/kg) when administered by the oral route at the same time. We have also studied whether pharmacokinetic modifications are fiber-dose dependent (100 and 400 mg/kg). The extent of levodopa absorbed when administering 100 mg/kg of fiber (AUC=43.4 mug min ml(-1)) is approximately the same as when levodopa is administered alone (AUC=47.1 microg min ml(-1)); however, Cmax is lower (1.04 versus 1.43 microg ml(-1)). Results obtained indicate that fiber at the higher dose increases the extent of levodopa absorbed (AUC=62.2 microg min ml(-1)), being the value of Cmax similar (1.46 microg ml(-1)). The value of tmax increases from 10 min when levodopa is administered alone to 20 min when the animals receive fiber. On the other hand, since certain time on, levodopa concentrations are always higher in the groups that receive fiber: 60 min with 100 mg/kg fiber and 20 min with 400 mg/kg fiber. Fiber also increases the mean residence time (MRT). P. ovata husk administration with levodopa could be beneficial, not only in patients with constipation, due to: lower adverse reactions (lower values of Cmax) and longer and more stable effects (higher final concentrations and more time in the body).

Influence of two dietary fibers in the oral bioavailability and other pharmacokinetic parameters of ethinyloestradiol.

Dietary fibers are widely used in hypoglycaemic, hypolipidemic, slimming diets. It is probable that their ingestion coincides with the oral administration of drugs and a modification of their pharmacokinetics can appear. In the present study, the influence of two soluble fibers (guar gum and psyllium) was evaluated on the pharmacokinetics of ethinyloestradiol (EE) when they were administered together to female rabbits via the oral route. Three groups of rabbits were used. All animals received 1 mg/kg of EE; this compound was administered alone in the control group and with 3.5 g of guar gum or psyllium in the other two groups. When guar gum was administered, there was a decrease in the extent of EE absorbed, but no change was observed in the rate of absorption. When psyllium was administered, the extent of EE absorbed increased slightly and the rate of absorption was slower.

Effects of slowed gastrointestinal motility on levodopa pharmacokinetics

Autonomic disorders are often seen in Parkinsons 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 Parkinsons 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 (20:5mg/kg) and the anticholinergic biperiden (100 microg/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.

Evolution of the bioavailability and other pharmacokinetic parameters of levodopa (with carbidopa) in rabbits

Levodopa pharmacokinetics show important inter- and intraindividual differences when it is administered by the oral route. As a result of fluctuating drug plasma concentrations, patients may develop motor fluctuations and dyskinesias. Therefore, it is important to perform studies on levodopa pharmacokinetics in the same individual. The aim of this study was to contribute to a better knowledge of the evolution of the pharmacokinetics of levodopa administered with carbidopa. The study involved the oral administration of 20/5 mg/kg levodopa/carbidopa to rabbits for two different time periods (7 or 14 days), due to the fact that inhibition of aromatic L-amino-acid decarboxylase by carbidopa is not immediate. After 7 days of treatment, the levodopa AUC increased by 12.6% from day 1 (range: 114.2-150.7 microg.min/ml) to day 7 (range: 131.1-166.0 microg.min/ml) and C(max) increased by 9.6% (range: 1.90-2.86 microg/ml on day 1 and 2.12-3.13 microg/ml on day 7). After 14 days of treatment, the increase in AUC was 17.0% (range: 119.6-160.1 microg.min/ml on day 1 and 142.9-172.7 microg.min/ml on day 14) and C(max) increased by 6.5% (range: 2.29-2.96 microg/ml on day 1 and 2.41-3.07 microg/ml on day 14). The values obtained for C(min) (sample obtained immediately before levodopa/carbidopa administration) in both groups increased progressively with the duration of the treatment. C(max) and AUC values were very similar after 7 or 14 days of treatment. The time needed for C(min) stabilization was slightly higher, because we found significant differences until day 11 of treatment.