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Effect of first-pass hepatic metabolism on the disposition of levamisole after intravenous administration in rabbits

Irma VillanuevaPharmacology Area, Department of Pharmacology, Toxicology, Nursing and Physical Therapy, Veterinary Faculty, University of Leon, 24071 León, Spain.

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M. José DiezPharmacology Area, Department of Pharmacology, Toxicology, Nursing and Physical Therapy, Veterinary Faculty, University of Leon, 24071 León, Spain.

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Juan J. GarcíaPharmacology Area, Department of Pharmacology, Toxicology, Nursing and Physical Therapy, Veterinary Faculty, University of Leon, 24071 León, Spain.

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M. Nélida FernándezPharmacology Area, Department of Pharmacology, Toxicology, Nursing and Physical Therapy, Veterinary Faculty, University of Leon, 24071 León, Spain.

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Ana M. SahagúnPharmacology Area, Department of Pharmacology, Toxicology, Nursing and Physical Therapy, Veterinary Faculty, University of Leon, 24071 León, Spain.

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Ana SierraPharmacology Area, Department of Pharmacology, Toxicology, Nursing and Physical Therapy, Veterinary Faculty, University of Leon, 24071 León, Spain.

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Matilde SierraPharmacology Area, Department of Pharmacology, Toxicology, Nursing and Physical Therapy, Veterinary Faculty, University of Leon, 24071 León, Spain.

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Abstract

Objective—To evaluate the contribution of first-pass hepatic metabolism of levamisole on levamisole disposition in rabbits.

Animals—30 male New Zealand White rabbits.

Procedures—Rabbits were randomly placed into 2 groups. Rabbits in the first group received levamisole via the marginal ear vein at the following 3 doses: 12.5, 16, and 20 mg/kg (5 rabbits for each dose). Rabbits of the second group received levamisole via the jejunal vein at the same doses (5 rabbits each). During the following 240-minute period, plasma samples were obtained and quantified for levamisole concentrations by reversed-phase high-performance liquid chromatography.

Results—No significant differences were found between pharmacokinetic parameters calculated by compartmental or noncompartmental analysis. Mean hepatic extraction ratio ranged from –0.044 to 0.017 and from 0.020 to 0.081 when area under the plasma concentration-time curve values were obtained after compartmental or noncompartmental analysis, respectively. After compartmental analysis, plasma concentration decreased bi-exponentially. Mean pharmacokinetic parameter values were as follows for each dose (12.5, 16, and 20 mg/kg, respectively): after levamisole administration via the marginal ear vein, volume of distribution at steady state (Vss) = 4.26, 4.33, and 3.20 L/kg; total body clearance (Cl) = 49.04, 43.77, and 39.26 mL/kg·min; and half-life associated with β-phase (t1/2β) = 77.93, 85.39, and 69.79 minutes. After levamisole administration via the jejunal vein, Vss = 4.38, 2.85, and 2.97 L/kg; Cl = 48.14, 42.40, and 39.69 mL/kg·min; and t1/2b = 101.9, 76.71, and 76.13 minutes.

Conclusions—Levamisole has a low degree of hepatic extraction in rabbits. (Am J Vet Res 2003;64: 1283–1287)

Abstract

Objective—To evaluate the contribution of first-pass hepatic metabolism of levamisole on levamisole disposition in rabbits.

Animals—30 male New Zealand White rabbits.

Procedures—Rabbits were randomly placed into 2 groups. Rabbits in the first group received levamisole via the marginal ear vein at the following 3 doses: 12.5, 16, and 20 mg/kg (5 rabbits for each dose). Rabbits of the second group received levamisole via the jejunal vein at the same doses (5 rabbits each). During the following 240-minute period, plasma samples were obtained and quantified for levamisole concentrations by reversed-phase high-performance liquid chromatography.

Results—No significant differences were found between pharmacokinetic parameters calculated by compartmental or noncompartmental analysis. Mean hepatic extraction ratio ranged from –0.044 to 0.017 and from 0.020 to 0.081 when area under the plasma concentration-time curve values were obtained after compartmental or noncompartmental analysis, respectively. After compartmental analysis, plasma concentration decreased bi-exponentially. Mean pharmacokinetic parameter values were as follows for each dose (12.5, 16, and 20 mg/kg, respectively): after levamisole administration via the marginal ear vein, volume of distribution at steady state (Vss) = 4.26, 4.33, and 3.20 L/kg; total body clearance (Cl) = 49.04, 43.77, and 39.26 mL/kg·min; and half-life associated with β-phase (t1/2β) = 77.93, 85.39, and 69.79 minutes. After levamisole administration via the jejunal vein, Vss = 4.38, 2.85, and 2.97 L/kg; Cl = 48.14, 42.40, and 39.69 mL/kg·min; and t1/2b = 101.9, 76.71, and 76.13 minutes.

Conclusions—Levamisole has a low degree of hepatic extraction in rabbits. (Am J Vet Res 2003;64: 1283–1287)