Pharmacokinetics of Methylprednisolone Succinate, Methylprednisolone, and Lidocaine in the Normal Dog and During Hemorrhagic Shock

Toutain, P. L.; Autefage, A.; Oukessou, M.; Alvinerie, M.

doi:10.1002/jps.2600760708

Cited by 10 publications

(7 citation statements)

References 17 publications

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“…This has potential clinical consequences, as an increase in drug blood levels may result in excessive concentrations associated with side effects. Phenacetin half-life was also significantly increased by spinal shock, as previously reported for MPSS after severe hemorrhagic shock (Toutain et al, 1987). It should be noted that half-life depends on clearance, but also on volume of distribution (Rowland and Tozer, 1989).…”

Section: Meaning Of Pharmacokinetic Alterationssupporting

confidence: 54%

“…It should be noted that methylprednisolone, which is a neuroprotector agent widely used in SCI, is also a drug submitted to high hepatic extraction. In fact, methylprednisolone is administrated as its prodrug, methylprednisolone sodium succinate (MPSS), which is biotransformed to the active molecule (Toutain et al, 1987;Ferry et al, 1994). MPSS and phenacetin share the property of high hepatic extraction.…”

Section: Rationale For Using Phenacetin Pharmacokinetics and Laser-domentioning

confidence: 99%

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L-Arginine Reverses Alterations in Drug Disposition Induced by Spinal Cord Injury by Increasing Hepatic Blood Flow

Vertiz-Hernandez¹,

Castañeda‐Hernández²,

Martínez-Cruz³

et al. 2007

Journal of Neurotrauma

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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.

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Section: Meaning Of Pharmacokinetic Alterationssupporting

confidence: 54%

Section: Rationale For Using Phenacetin Pharmacokinetics and Laser-domentioning

confidence: 99%

L-Arginine Reverses Alterations in Drug Disposition Induced by Spinal Cord Injury by Increasing Hepatic Blood Flow

Vertiz-Hernandez¹,

Castañeda‐Hernández²,

Martínez-Cruz³

et al. 2007

Journal of Neurotrauma

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“…Lidocaine concentrations decreased rapidly in this study with a half-life of 1.0 h similar to the 1.1 h seen in pigs (Mets et al, 1993) and anesthetized horses (Feary et al, 2006) but less than the 2.6 h in hydrated camels (Ben-Zvi et al, 1995) and 2.1 h in dogs (Toutain et al, 1987). The clearance of lidocaine in cows from this study (2531 mL ⁄ hAEkg) is greater than the 246 mL ⁄ hAEkg for camels (Ben-Zvi et al, 1995) but less than then the 3120 mL ⁄ hAEkg for fed horses (Engelking et al, 1987).…”

supporting

confidence: 72%

“…, 2006) but less than the 2.6 h in hydrated camels (Ben‐Zvi et al. , 1995) and 2.1 h in dogs (Toutain et al. , 1987).…”

Section: Plasma Pharmacokinetic Parameters Of Intravenously Administmentioning

confidence: 93%

Pharmacokinetics of lidocaine after intravenous administration to cows

Cox

Wilson

Doherty

2011

Vet Pharm & Therapeutics

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“…The reduced total body clearance observed in our experiments, although not statistically significant, favours this hypothesis. In other studies in animal models of hemorrhagic shock a reduced liver flow was also proposed as the mechanism for the decreased clearance for midazolam [ 11, methylprednisolone succinate [26] and prednisolone [I41 in the dog, and lidocaine in the rhesus monkey [7].…”

Section: Discussionmentioning

confidence: 99%

The influence of hemorrhagic shock on the pharmacokinetics and the analgesic effect of morphine in the rat

Paepe

Belpaire

Rosseel

et al. 1998

Fundamemntal Clinical Pharma

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The influence of hemorrhagic shock (removal of 30% of the blood volume) on the pharmacokinetics and the analgesic effect of morphine was investigated in conscious rats. Plasma concentrations of morphine after a bolus injection (5 mg/kg) are higher in the shock animals, which is attributed to a small decrease in clearance (-22%; P > 0.05) and a significant decrease in distribution volume (-33%; P < 0.05) of the drug. The areas under the plasma concentration-time curve of the metabolite morphine-3-glucuronide (M3G) are significantly higher (+237%; P < 0.01) in the shock rats, which is probably explained by a decreased distribution and renal excretion. The analgesic effect of morphine was evaluated using the tail-flick test during a continuous infusion (10 mg/kg/h) with measurement of the plasma concentrations of morphine and M3G. Data from these experiments show higher plasma concentrations of morphine (+33%; P < 0.05) and M3G (+66%; P > 0.05) during shock, and a significantly increased analgesic effect (+43%; P < 0.05). Our data suggest that the increased analgesic effect of morphine during hemorrhagic shock can most likely be explained by pharmacokinetic changes resulting in higher morphine concentrations.

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Pharmacokinetics of Methylprednisolone Succinate, Methylprednisolone, and Lidocaine in the Normal Dog and During Hemorrhagic Shock

Cited by 10 publications

References 17 publications

L-Arginine Reverses Alterations in Drug Disposition Induced by Spinal Cord Injury by Increasing Hepatic Blood Flow

L-Arginine Reverses Alterations in Drug Disposition Induced by Spinal Cord Injury by Increasing Hepatic Blood Flow

Pharmacokinetics of lidocaine after intravenous administration to cows

The influence of hemorrhagic shock on the pharmacokinetics and the analgesic effect of morphine in the rat

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