L-Arginine Reverses Alterations in Drug Disposition Induced by Spinal Cord Injury by Increasing Hepatic Blood Flow
- 1 December 2007
- journal article
- Published by Mary Ann Liebert Inc in Journal of Neurotrauma
- Vol. 24 (12), 1855-1862
- https://doi.org/10.1089/neu.2007.0375
Abstract
High hepatic extraction drugs--such as phenacetin, methylprednisolone, and cyclosporine--exhibit an increased bioavailability after acute spinal cord injury (SCI) due to an impaired clearance. For these drugs, metabolic clearance depends on hepatic blood flow. Thus, it is possible that pharmacokinetic alterations can be reversed by increasing liver perfusion. Therefore, we evaluated the effect of L-arginine, a nitric oxide precursor, on the pharmacokinetics of a prototype drug with high hepatic extraction, and on hepatic microvascular blood flow (MVBF) after acute SCI. Pharmacokinetics of i.v. phenacetin was studied in rats 24 h after a severe T-5 spinal cord contusion; animals being pretreated with L-arginine 100 mg/kg i.v. or vehicle. MVBF was assessed under similar experimental conditions using laser Doppler flowmetry. SCI significantly altered phenacetin pharmacokinetics. Clearance was significantly reduced, resulting in a prolonged half-life and an increase in bioavailability, while volume of distribution was decreased. Pharmacokinetic alterations were reversed when injured rats were pretreated with L -arginine. It was also observed that L-arginine significantly increased hepatic MVBF in injured rats, notwithstanding it exhibited a limited effect on sham-injured animals. Our data hence suggest that L-arginine is able to reverse SCI-induced alterations in phenacetin pharmacokinetics due to an impaired hepatic MVBF, likely by increased nitric oxide synthesis leading to vasodilation. Further studies are warranted to examine the potential usefulness of nitric oxide supplementation in a clinical setting.Keywords
This publication has 34 references indexed in Scilit:
- Understanding Drug Disposition Alterations Induced by Acute Spinal Cord Injury: Role of Injury Level and Route of Administration for Agents Submitted to Extensive Liver MetabolismJournal of Neurotrauma, 2006
- Cardiovascular Alterations After Spinal Cord Injury: An OverviewCurrent Medicinal Chemistry-Cardiovascular & Hematological Agents, 2004
- Neuroprotective Effects ofl -Arginine Administration after Cortical Impact Injury in Rats: Dose Response and Time WindowJournal of Pharmacology and Experimental Therapeutics, 2003
- Methylprednisolone and Acute Spinal Cord InjurySpine, 2001
- Molecular mechanism of cGMP-mediated smooth muscle relaxationJournal of Cellular Physiology, 2000
- Relative Importance of Flow versus Pressure in Splanchnic Perfusion during Cardiopulmonary Bypass in RabbitsAnesthesiology, 2000
- Role of nitric oxide in the regulation of the hepatic microcirculation in vivoJournal of Hepatology, 1997
- Pilot Study of the Pharmacokinetics of Methylprednisolone After Single and Multiple Intravenous Doses of Methylprednisolone Sodium Succinate and Methylprednisolone Suleptanate to Healthy VolunteersThe Journal of Clinical Pharmacology, 1994
- Comparison of population pharmacokinetic models for gentamicin in spinal cord-injured and able-bodied patientsAntimicrobial Agents and Chemotherapy, 1993
- Paracetamol and PhenacetinDrugs, 1986