M. José Diez

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).

Pharmacokinetics of doxycycline in sheep after intravenous and oral administration

The pharmacokinetics of doxycycline were investigated in sheep after oral (PO) and intravenous (IV) administration. The IV data were best described using a 2- (n = 5) or 3- (n = 6) compartmental open model. Mean pharmacokinetic parameters obtained using a 2-compartmental model included a volume of distribution at steady-state (V(ss)) of 1.759+/-0.3149L/kg, a total clearance (Cl) of 3.045+/-0.5264mL/kg/min and an elimination half-life (t(1/2beta)) of 7.027+/-1.128h. Comparative values obtained from the 3-compartmental mean values were: V(ss) of 1.801+/-0.3429L/kg, a Cl of 2.634+/-0.6376mL/kg/min and a t(1/2beta) of 12.11+/-2.060h. Mean residence time (MRT(0-infinity)) was 11.18+/-3.152h. After PO administration, the data were best described by a 2-compartment open model. The pharmacokinetic parameter mean values were: maximum plasma concentration (C(max)), 2.130+/-0.950microg/mL; time to reach C(max) (t(max)), 3.595+/-3.348h, and absorption half-life (t(1)/(2k)(01)), 36.28+/-14.57h. Non-compartmental parameter values were: C(max), 2.182+/-0.9117microg/mL; t(max), 3.432+/-3.307h; F, 35.77+/-10.20%, and mean absorption time (MAT(0-infinity)), 25.55+/-15.27h. These results suggest that PO administration of doxycycline could be useful as an antimicrobial drug in sheep.

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.

Hypoglycemic and Hypolipidemic Potential of a High Fiber Diet in Healthy versus Diabetic Rabbits

The aim of this study was to investigate potential hypoglycaemic and hypolipidemic effects of Plantago ovata husk included in the diet, in healthy and diabetic rabbits. We also examined the effects of this fiber in other biochemical parameters. Two groups of 18 rabbits were used. The first group was fed with standard chow and the second with chow supplemented with Plantago ovata husk (3.5 mg/kg/day). On day 14 diabetes mellitus was induced by the intravenous administration of alloxan (80 mg/kg). After an oral glucose load (3 g), glucose, insulin, and other biochemical parameters were determined on day 14 (healthy rabbits) and on day 28 (diabetic rabbits). In healthy rabbits, fiber did not modify glucose or insulin levels but decreased significantly total cholesterol, LDL-cholesterol, atherogenic index, and glycosylated hemoglobin. In diabetic rabbits, fiber was more beneficial in mild diabetics than in severe diabetics with significant decreases in glucose levels and increases in insulin concentrations. In these animals fiber caused an important reduction in cholesterol, indicating a beneficial effect of Plantago ovata husk in diabetic rabbits. Although further studies in patients are necessary, we think that Plantago ovata husk offers interesting perspectives to be administered to patients with diabetes mellitus.

The hydrosoluble fiber Plantago ovata husk improves levodopa (with carbidopa) bioavailability after repeated administration

The influence of treatment duration (7 or 14 days) with Plantago ovata husk/levodopa/carbidopa in the bioavailability and other pharmacokinetic parameters of levodopa were evaluated in rabbits. Fiber was administered at two different doses, 100 and 400 mg/kg, and the dosage of levodopa/carbidopa was 20:5 mg/kg. These doses were administered once a day. When 100 mg/kg of fiber was administered, the mean AUC value obtained for levodopa increased 20.2% from day 1 to day 7, and 27.2% from day 1 to day 14; C(max) was 8.6% higher on day 7 and 11.7% higher on day 14. When administering 400 mg/kg of fiber, the increase in AUC values was 17.6% on day 7 and 24.9% on day 14, and that of C(max) 11.1% on day 7 and 11.3% on day 14. The concentration determined immediately before drug administration (C(min)) increased progressively with the duration of treatment, and the highest increase (53.2%) was observed on day 14 with 100 mg/kg of fiber. There was also a delay in levodopa elimination (higher MRT and lower Cl) in a fiber-dose dependent manner. In summary, we found that there was an improvement in the extent of levodopa absorbed with higher final concentrations and that levodopa elimination was slower with the administration of P. ovata husk.

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.

Effects of Plantago ovata Husk on Levodopa (with Carbidopa) Bioavailability in Rabbits with Autonomic Gastrointestinal Disorders

Gastrointestinal dysfunction is common in Parkinsons disease. Fiber therapy could be used to reduce the symptoms of gastrointestinal motility disorders. In a previous study, we showed that slowed gastrointestinal motility modified levodopa pharmacokinetics: area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) decreased and the elimination was delayed. In this study, we evaluated whether or not the hydrosoluble fiber Plantago ovata husk is useful in improving levodopa pharmacokinetics in rabbits with autonomic gastrointestinal disorders induced by the administration of the anticholinergic biperiden. Levodopa + carbidopa (20:5 mg/kg), biperiden (100 μg/kg), and P. ovata husk (at two different doses: 100 and 400 mg/kg) were administered orally to rabbits for two periods of time (7 or 14 days). In all groups of animals, the AUC values were approximately 50% higher on the final day of treatment than on day 1. Cmax was also higher, with the greater increase at the 400 mg/kg dose of fiber, which resulted in a boost of approximately 35%. On day 1 of treatment and with both doses of fiber, AUC values were very similar to those obtained in previous work in rabbits with normal gastrointestinal motility, but the Cmax was lower. However, after 7 or 14 days, the AUC values were higher, but Cmax remained lower. The greatest differences were observed in plasma concentration before drug administration (Cmin), for which the highest increase was obtained with the dose of 400 mg/kg fiber on day 14 of treatment (349.8%). P. ovata husk could be beneficial in patients with Parkinsons disease because it regulates stool transit in the intestine and because it improves levodopa pharmacokinetics when gastrointestinal peristalsis is slowed. These changes could lead to a possible delay in the onset of dyskinesias and to changes in prognosis.

Bioavailability of a commercial formulation of ivermectin after subcutaneous administration to sheep

OBJECTIVE To evaluate bioavailability and other pharmacokinetic variables of a commercial formulation of ivermectin after IV administration to sheep. ANIMALS 6 healthy adult sheep. PROCEDURES A single dose of a commercial formulation of ivermectin (200 microg/kg) was administered IV to each sheep. After a washout period of 3 weeks, each sheep was administered ivermectin by SC injection. Plasma samples were obtained for up to 36 and up to 42 days after IV and SC administration, respectively. Ivermectin concentrations were quantified by use of high-performance liquid chromatography with fluorescence detection. RESULTS Results obtained indicated that after IV administration, ivermectin is cleared slowly from plasma, tends to distribute and accumulate in the peripheral compartment, and is slowly eliminated from the body. After SC administration, noncompartmental analysis revealed that bioavailability of ivermectin is nearly complete (98.20%), has a slow mean absorption time of 0.96 days, and reaches a maximum plasma concentration of 19.55 ng/mL at 3.13 days. CONCLUSIONS AND CLINICAL RELEVANCE The commercial formulation of ivermectin used in this study can be administered SC to sheep on the basis of a nearly complete bioavailability. In addition, the maximum plasma concentration and interval from SC injection until maximum plasma concentration is obtained are higher than those reported by other authors who used other routes of administration.