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

Vertiz-Hernandez, Antonio; Castañeda‐Hernández, Gilberto; Martínez-Cruz, Angelina; Cruz-Antonio, Leticia; Grijalva, Israel; Guı́zar-Sahagún, Gabriel

doi:10.1089/neu.2007.0375

Cited by 19 publications

(14 citation statements)

References 37 publications

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“…55 Riluzole is an intermediate hepatic extraction drug whose hepatic metabolism would be decreased by lower hepatic blood flow, similar to methylprednisolone and cyclosporine A. 2) Concomitant medications that are CYP 1A2 substrates, inducers, or inhibitors would affect the metabolism of riluzole by CYP 1A2.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacology of riluzole in acute spinal cord injury

Chow

Teng

Toups

et al. 2012

SPI

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Object The aim of this paper was to characterize individual and population pharmacokinetics of enterally administered riluzole in a Phase 1 clinical trial of riluzole as a neuroprotective agent in adults 18–70 years old with acute spinal cord injury (SCI). Methods Thirty-five individuals with acute SCI, American Spinal Injury Association Impairment Scale Grades A–C, neurological levels from C-4 to T-12, who were enrolled in the Phase 1 clinical trial sponsored by the North American Clinical Trials Network for Treatment of Spinal Cord Injury, received 50 mg riluzole twice daily for 28 doses. The first dose was administered at a mean of 8.7 ± 2.2 hours postinjury. Trough plasma samples were collected within 1 hour predose, and peak plasma samples were collected 2 hours postdose on Days 3 and 14 of treatment. Riluzole concentrations were quantified by high-performance liquid chromatography assay. The data were analyzed for individual and population pharmacokinetics using basic structural and covariate models. The pharmacokinetic measures studied were the peak concentration (Cmax), trough concentration (Cmin), systemic exposure (AUC0–12), clearance (CL/F), and volume of distribution (V_F) normalized by the bioavailability (F). Results The Cmax and AUC0–12 achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher CL and larger V. The pharmacokinetics of riluzole (Cmax, Cmin, AUC0–12, CL, and V) changed during the acute and subacute phases of SCI during the 14 days of therapy. It was consistently observed in patients at all clinical sites that Cmax, Cmin, and AUC0–12 (128.9 ng/ml, 45.6 ng/ml, and 982.0 ng × hr/ml, respectively) were significantly higher on Day 3 than on Day 14 (76.5 ng/ml, 19.1 ng/ml, and 521.0 ng × hr/ml, respectively). These changes resulted from lower CL (49.5 vs 106.2 L/hour) and smaller V (557.1 vs 1297.9/L) on Day 3. No fluid imbalance or cytochrome P 1A2 induction due to concomitant medications was identified during the treatment course to account for such increases in V and CL, respectively. Possible mechanisms underlying these changes are discussed. Conclusions This is the first report of clinical pharmacokinetics of riluzole in patients with SCI. The Cmax and AUC0–12 achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher clearance and larger volume of distribution in SCI patients. The finding in SCI patients of an increase in the clearance and distribution of riluzole between the 3rd and 14th days after SCI, with a lower plasma concentration of riluzole on the 14th day, stresses the importance of monitoring changes in drug metabolism after SCI in interpreting the safety and efficacy of therapeutic drugs that are used in clinical trials in SCI. Clinical trial registration no.: NCT00876889.

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Section: Discussionmentioning

confidence: 99%

“…14,15,41 Based on the knowledge of SCI effects on the pharmacokinetics of drugs reported in the past 26 years (1985-2011), 3,14,18,23,27,35,39,44,[46][47][48]55 we may anticipate the following alterations of pharmacokinetics of riluzole in patients with acute SCI from that in healthy individuals.…”

Section: Alterations Of Pharmacokinetics Of Drugs In Scimentioning

confidence: 99%

Pharmacology of riluzole in acute spinal cord injury

Chow

Teng

Toups

et al. 2012

SPI

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“…30,43,49 Experimental studies have shown that increasing hepatic microvascular blood flow through nitric oxide-mediated vasodilation using L-arginine, a nitric oxide precursor, could ameliorate PK alterations at this level. 50 …”

Section: Altered Pkmentioning

confidence: 99%

Spinal cord injury sequelae alter drug pharmacokinetics: an overview

et al. 2011

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Study design: Literature review. Objectives: Critical review of the literature published on the physiological alterations caused by spinal cord injury (SCI) and their effect on the pharmacokinetic parameters of commonly employed drugs. The review introduces the most recent treatment protocols of a variety of drugs, enabling the modern clinician to apply efficacious and cost-effective solutions to the pharmacological treatment of SCI patients. Methods: Studies published in international indexed journals up to January 2011 were selected from the PubMed database. Results: The review evaluated the sequelae of SCI and their effect on pharmacological processes. The results demonstrated that these alterations affected the pharmacokinetics of drugs commonly administered to SCI patients, such as antibiotics, muscle relaxants, immunosuppressants and analgesics. Conclusion: There are multiple etiologies to SCI and patients present with varying degrees of impairment. Factors such as level of injury and completeness of the injury create a very heterogeneous population within the SCI community. The heterogeneity of this population creates a problem when trying to standardize pharmacokinetic (PK) parameters. It is because of this that specific physiological alterations must be linked to changes in PK and be identified within the clinical setting. This relationship between physiology and PK enables the clinician to be alert for possible pharmacological complications in individual patients based on their clinical manifestations. Future research should aim to develop rigorous therapeutic guidelines tailored to the diverse manifestations of SCI so as to provide effective, affordable and safe pharmacotherapy.Spinal Cord (2011) 49, 955-960;

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“…Sildenafil citrate, a type 5 specific phosphodiesterase inhibitor, prevents the breakdown of cGMP and potentiates the effect of NO on vascular smooth muscle (16). L-arginine, a substrate of NO, increases hepatic and limb blood flow (17,18). The present study was undertaken as a pilot study to investigate whether vitamin E, l-arginine, or sildenafil citrate treatment has a potential to increase the blood flow of uterine radial arteries and to improve endometrial growth in patients with a thin endometrium.…”

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confidence: 99%