Pharmacokinetics Of Levamisole Research Articles

Pharmacokinetics and therapeutic efficacy of levamisole in Ascaridia galli experimentally infected ducks

This study investigated the pharmacokinetics and therapeutic efficacy of levamisole (LVS) after intravenous (i.v.) and oral administrations to healthy and Ascaridia galli-infected ducks by developing an infection model. Twenty-four two-week old ducklings were experimentally infected with A. galli. The ducks were monitored for the development of infection and after 8 weeks they were administered with LVS at a single dose of 30 mg/kg by oral or i.v. administration. Sixteen healthy ducks were subjected to the same treatment and served as control. Serial blood samples were taken for LVS determination with HPLC-UV and pharmacokinetic analysis was carried out based on the non-compartmental approach. The LVS therapeutic efficacy was determined 1 week post drug administration by intestinal worm count at necropsy. In vivo data on development of ascariasis in ducks showed that 8 weeks post inoculation the number of eggs per gram of feces reached at least 100 in each bird. After a single dose of LVS, no parasites were recovered upon necropsy. Results of the pharmacokinetic study showed no statistical differences between infected and non-infected birds for both routes of administration. The mean oral bioavailability was slightly below 50% in both experimental groups. In conclusion, the pharmacokinetics of LVS in ducks was not affected by experimentally-induced ascariasis. A single dose of LVS was found to be efficient against experimental ascariasis in ducks induced by in field isolates of A. galli.

Pharmacokinetics and pharmacodynamics of single and multiple-dose levamisole in belugas (Huso huso): Main focus on immunity responses

The pharmacokinetics of levamisole were determined in the belugas after single intravascular (IV), and single and multiple-dose oral by feed administrations. Also, the effect of levamisole (LVM) on the stress and immune responses of belugas were assessed. One hundred-fourteen healthy belugas in 4 different groups received single LVM administration at the doses of 50 and 100 mg/kg via IV and oral routes. A separate group of 24 belugas were administered oral LVM at the dose of 100 mg/kg for 5 days. Blood samples were collected at different time points after administrations to measure plasma concentrations of LVM by a validated high-performance liquid chromatography (HPLC) assay. For immunological evaluations, a total of 126 belugas received 50 and 100 mg/kg LVM via medicated feed for 5 days or served as the control without any medication; blood samples were recovered on day 0, 1, 3, 5, 7, 10, and 14 to measure hemolytic activity of the complement system (HAC50), serum lysozyme activity, serum antibacterial activity, glucose, cortisol, total protein, albumin and C3 contents. In the single-dose administration, quantified LVM concentrations were dose-dependent and the oral bioavailability was in the range of 43.2–49.6%. In the multiple-dose administration, the peak plasma concentration at the steady state was 45.2 mg/ml, and accumulation ratio was calculated as 3.6. In the immunological study, LVM especially at the dose of 100 mg/kg increased HAC50, lysozyme and antibacterial activity in the sera of treated fish. No significant effect of LVM on glucose and albumin content was observed, but cortisol levels decreased and C3 content was increased, more significantly by LVM at the dose of 100 mg/kg. Our results indicate that LVM is well absorbed after oral administration and reached to concentrations that can affect stress indicators and improve immune responses in belugas.

Pharmacokinetics and Tissue Residence of Various Doses of Levamisole in Crucian Carp at Different Water Temperatures

The pharmacokinetics of levamisole in crucian carp, including the absorption, distribution, and clearance rates in different tissues, were studied at different temperatures and doses for the theoretical basis of proper usage and withdrawal time. The fish were divided into three groups denoted A, B and C. The A and B groups were treated once at a dosage of 5 mg/kg levamisole, at 19 ± 1°C and 26 ± 1°C water temperature, respectively. The C group was treated at a dosage of 20 mg/kg levamisole at 19 ± 1°C water temperature. Then plasma, muscle, hepatopancreas, and kidney tissues samples were collected and pretreated, then measured using an ultra performance liquid chromatography-ultraviolet method. Plasma data were analyzed using DAS 3.0 pharmacokinetics software. Total area under the curve (AUC0-t) and elimination half-life (t1/2z) had a negative correlation with water temperature, and a positive correlation with dosage. Apparent volume of distribution (Vz) and total clearance rate (CLz) was positively correlated with temperature, and a negatively correlated with dosage. Levamisole was absorbed quickly to reach its peak concentration. The drug concentration and residence time in hepatopancreal and kidney were considerably higher and longer respectively than in the muscle and plasma suggesting that the hepatopancreas and kidney may be important metabolic organs for levamisole.

Pharmacokinetics of levamisole in broiler breeder chickens

The pharmacokinetics of levamisole was studied in 20 broiler breeder chickens (chickens that give eggs to breed broilers). A single dose of levamisole (40 mg/kg) was administered orally or intravenously to chickens before the onset of egg production, prelay (age = 22 weeks), and repeated at the peak of egg production (age = 32 weeks). A high-pressure liquid chromatographic with ultraviolet detection method (HPLC-UV) was used for quantification of levamisole in plasma. Using compartmental analysis, levamisole followed a three-compartmental open model with mean values of alpha = 0.1224 and 0.4968, beta = 0.01663 and 0.01813, gamma = 0.002 and 0.002/min at the prelay and at the peak of egg production periods, respectively. The mean values for volume of distribution at steady state (V(ss)), determined by compartmental analysis, were significantly different for prelay and peak of egg production (8.358 and 13.581 mL/kg), respectively.

Intra-arterial pharmacokinetics and pulmonary first-pass of levamisole in rabbits

The pharmacokinetics of levamisole after intra-arterial administration of 12.5, 16 and 20 mg kg−1 was investigated in rabbits. After compartmental analysis, the disposition of levamisole was well described by a two-compartment open model with mean values ± sd of: α= 0.1650 ± 0.0839, 0.1611 ± 0.0298, 0.2312 ± 0.0540 min −1, and β= 0.0118 ± 0.0022, 0.0125 ± 0.0026, 0.0120 ± 0.0024 min −1, for the three doses studied, respectively. There were no dose-related differences (one-way analyses of variance (ANOVA), P≤ 0.05) in α,β , total body clearance ( Cl) and volume of distribution at steady state (Vss ). The AUC increased significantly with the doses (249.7, 376.7 and 562.5 μ g min ml −1). After non-compartmental analysis there were no significant differences in plasma elimination rate constant ( λ), MRT and Vssas a function of dose, but these differences were significant for Cl, between 16 and 20 mg kg −1, and AUC (one-way ANOVA, P≤ 0.05). The two-way ANOVA showed no significant differences between the values obtained for the three doses when λ–β , Cl, Vssand Vawere compared while AUC showed significant changes. On the other hand, the pharmacokinetic analysis (compartmental and non-compartmental) showed significant differences in AUC, Cl, Vssand Va, but there were no significant differences when λ– β were compared. The slow clearance of levamisole by rabbit lung compared to a high pulmonary blood flow rate makes the possibility of significant first-pass lung metabolism unlikely in this animal species.

Pharmacokinetics of levamisole in sheep after intravenous administration

The pharmacokinetics of levamisole at doses of 5, 7.5 and 10 mg/kg were determined after its intravenous administration to eighteen healthy Merino sheep. Using compartmental analysis, the disposition of the drug best fitted a two-compartmental open model. The mean values for the compartmental volume of distribution at steady state (Vss) were 2.034 ± 0.23I, 2.347 ± 0.720 and 2.001 ± 0.367 I/kg for each dose, respectively, and values obtained using the statistical moment theory were 2.141 ± 0.269, 2.390 ± 0.536 and 2.140 ± 0.345 l/kg for each dose, respectively. There were no dose-related differences (one-way ANOVA) in the constants describing distribution and elimination phases (α and β) or Vss, but significant differences were detected in the total body clearance (Cl) and the area under the plasma concentration-time curve (AUC). After non-compartmental analysis, no significant differences were found when the parameters λ (the linear terminal slope) and Vss were compared, but significant differences were detected in Cl and AUC. There were no significant differences between the values obtained using the compartmental and non- compartmental analysis when λ-β, Cl, Vss and AUC were compared.

Pharmacokinetics of levamisole in rabbits after intravenous administration

A compartmental and non-compartmental pharmacokinetic study was carried out on rabbits after intravenous (i.v.) administration of levamisole at the three dose rates: 12.5, 16.0 and 20.0 mg/kg body weight. Using compartmental analysis, the disposition of levamisole best fitted a two-compartmental open model with mean values of alpha = 0.1278, 0.1019 and 0.1282 min-1; beta = 0.0139, 0.0126 and 0.0124 min-1; A = 6.24, 5.27 and 10.58 micrograms/ml and B = 2.14, 3.83 and 5.08 micrograms/ml for each dose, respectively. The statistical moment theory was mainly used for non-compartmental analysis. Values for mean residence time (MRT) of 69.2, 71.7 and 73.1 min were obtained for each dose. The mean values for volume of distribution at steady state (Vd(ss)), determined by compartmental analysis, were 3879, 3279 and 2735 ml/kg for each dose, and values obtained using the statistical moment theory were 3760, 3015 and 2943 ml/kg; there were no statistically significant differences using Student's paired t-test. Identical conclusions were obtained using both methods when the parameters beta, AUC and Cl were compared.

Effect of parasitism with Nematodirus battus on the pharmacokinetics of levamisole, ivernectin and netobimin

The pharmacokinetics of levamisole, ivermectin and netobimin administered orally and by subcutaneous injection were compared in lambs exposed to a moderate challenge with Nematodirus battus and in parasite naive lambs. There were no significant differences ( P > 0.05) in the bioavailability of any of the anthelmintics tested between parasitized and non-parasitized animals. Levamisole reduced nematode faecal egg output by more than 99% when administered by either route. Ivermectin was also highly effective (>99%). Orally administered netobimin reduced egg output by more than 98% seven days after administration. However egg output was only reduced by 89% 21 days after administration, suggesting poor activity against the early parasitic stages of N. battus. Netobimin was not effective against N. battus when administered by the subcutaneous route and this was probably because very low plasma concentrations of its active albendazole metabolites were achieved.

Novel assay and pharmacokinetics of levamisole and p-hydroxylevamisole in human plasma and urine.

A new gas chromatographic method was developed for the quantification of levamisole in human plasma and urine, using a nitrogen-phosphorus flame ionization detector. The adsorption of the drug onto glass was prevented by treating the glassware with a siliconizing agent. The sensitivity of the assay was 10 ng ml-1 and as low as 2 ng ml-1 can be detected in plasma. The urinary metabolite p-hydroxylevamisole was analysed by high performance liquid chromatography with ultraviolet detection. The sensitivity of this assay was 0.50 micrograms ml-1. Plasma and urinary concentrations of levamisole were determined in 10 healthy volunteers including seven men and three women following the administration of a single 150 mg dose of levamisole. Levamisole was rapidly absorbed (tmax 1.5 h), giving a peak plasma concentration of 716.7 +/- 217.5 ng ml-1. The plasma elimination half-life of levamisole was 5.6 +/- 2.5 h. Only 3.2 +/- 2.9 per cent of the oral dose was recovered as unchanged drug in the urine, suggesting the importance of clearance of levamisole by routes other than the kidney, and most probably by hepatic metabolism. The urinary concentrations of p-hydroxylevamisole were determined before and after hydrolysis of the urine samples with beta-glucuronidase, and the level of conjugation of the metabolite with glucuronic acid was then estimated. Cumulative recovery of the metabolite accounted for 1.6 +/- 1.1 per cent and 12.4 +/- 5.5 per cent of the oral dose of levamisole before and after hydrolysis, respectively, indicating that p-hydroxylation is a relatively important route of metabolism of levamisole, and that the p-hydroxylated metabolite is excreted mainly in conjugation with glucuronic acid. Except for the absorption rate of levamisole which is approximately twice as rapid in women as in men, there is no marked difference in the pharmacokinetics of levamisole between healthy men and women.

Pharmacokinetics of levamisole in healthy subjects and cancer patients.

Eleven healthy volunteers (six men, five women) and twelve cancer patients (six men, six women) were given single oral doses (2.5 mg/kg body weight) of levamisole, an immunostimulant agent. In a second experiment eleven healthy et volunteers (six men, five women) and twelve cancer patients (six men, six women) were given single oral doses (5 mg/kg body weight) of levamisole. The levamisole concentrations in plasma (24 h blood sampling) were measured by gas chromatography after extraction. A mono-compartment open model was proposed, and some parameters were calculated. The main results from these two experiments are: the drug was absorbed well, the peak levels of levamisole in the plasma were reached after 1.0 – 2.0 hrs and ranged between 0,8 (μg and 1.6 μg/ml with the 2.5 mg and 5 mg/kg body weight doses respectively (concentrations requiredin vitro to produce an immunological effect); the plasma half-life of levamisole calculated from the decline in the concentration curves varied between 3.3 h and 5.1 h; the absorbed fractions were 0.7 and clearance 310 ml/min; twenty-four hours after medication, the levamisole concentrations in plasma were only 6 % of the peak levels.