First-pass metabolism of lidocaine in the anesthetized rabbit. Contribution of the small intestine.
It is assumed that, in vivo, the liver is the organ responsible for the first-pass metabolism of lidocaine. To assess in vivo whether the intestine and the lungs contribute with the liver to the first-pass metabolism of lidocaine, groups of anesthetized rabbits (N = 6/group) received lidocaine into the thoracic aorta (10 mg/kg), a jugular vein (10 mg/kg), a mesenteric vein (20 mg/kg), and into the duodenum (20 mg/kg). Serial blood samples were withdrawn from the abdominal aorta. The area under lidocaine plasma concentration-time curve [AUCL(O-infinity)] corrected by the dose, when injected into the jugular vein, was equal to that estimated when injected into the thoracic aorta, but was larger than the AUCL(O-infinity) corrected by the dose of lidocaine injected into a mesenteric vein [i.e. 0.0047 +/- 0.0005 vs. 0.0030 +/- 0.0004 min/ml, respectively (p < 0.05)]. Moreover, the latter was greater (p < 0.05) than the AUCL(O-infinity) corrected by the dose of lidocaine instilled into the duodenum (0.0024 +/- 0.0003 min/ml). Liver and intestinal extractions of lidocaine were 36 and 20%, respectively. Oral systemic bioavailability was 0.49. The metabolites of lidocaine, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), were only detected when lidocaine was administered before the liver or the intestine. In in vitro studies, incubation of lidocaine in the supernatant of the 10,000g of epithelial cells of the intestine, liver, and lungs decreased lidocaine concentrations at the following rates: liver > intestine approximately lungs. MEGX and GX could be measured in the liver, but only MEGX in the small intestine and lung. It is concluded that the intestine contributes with the liver to the first-pass metabolism of lidocaine.
Lê
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KT
Department of Pharmacology, Faculty of Medicine, University of Montréal, Québec, Canada.
Maurice
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H
du Souich
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P
D000758:Anesthesia; D000818:Animals; D001013:Aorta, Thoracic; D001711:Biotransformation; D004848:Epithelium / Q000378:metabolism; D007275:Injections, Intravenous; D007421:Intestine, Small / Q000378:metabolism*; D007601:Jugular Veins; D008012:Lidocaine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism* / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008297:Male; D008642:Mesenteric Veins; D011817:Rabbits
D008012:Lidocaine; C001306:glycinexylidide; C001173:monoethylglycinexylidide