Simultaneous Quantitation of Lidocaine and Its Four Metabolites by High-performance Liquid Chromatography: Application to studies on In Vitro and In Vivo Metabolism of Lidocaine in Rats

Kawai, Ryoji; Fujita, Satoshi; Suzuki, Tomohiko

doi:10.1002/jps.2600741116

Cited by 38 publications

(15 citation statements)

References 29 publications

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“…Since the effective duration of lidocaine in circulation is short (< 2 hrs) [25], the impact of delayed but sustained ectopic discharges, which start 13 to 24 hrs post injury [21,32,33], on Ca v α 2 δ 1 expression could not be studied in our experimental settings. The temporal blockade of injury-induced Ca v α 2 δ 1 upregulation in DRG and spinal dorsal horn indicates that brief local application of high concentrations of lidocaine did not cause irreversible toxic effects in DRG and spinal dorsal horn, at least for the cells expressing Ca v α 2 δ 1 .…”

Section: Discussionmentioning

confidence: 99%

Injury discharges regulate calcium channel alpha-2-delta-1 subunit upregulation in the dorsal horn that contributes to initiation of neuropathic pain

Boroujerdi

Kim

Lyu

et al. 2008

Pain

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Previous studies have shown that peripheral nerve injury in rats induces increased expression of the voltage gated calcium channel (VGCC) alpha-2-delta-1 subunit (Ca v α 2 δ 1 ) in spinal dorsal horn and sensory neurons in dorsal root ganglia (DRG) that correlates to established neuropathic pain states. To determine if injury discharges trigger Ca v α 2 δ 1 induction that contributes to neuropathic pain initiation, we examined allodynia onset and Ca v α 2 δ 1 levels in DRG and spinal dorsal horn of spinal nerve ligated rats after blocking injury induced neural activity with a local brief application of lidocaine on spinal nerves before the ligation. The lidocaine pretreatment blocked ligation-induced discharges in a dose-dependent manner. Similar pretreatment with the effective concentration of lidocaine diminished injury-induced increases of the Ca v α 2 δ 1 in DRG and abolished that in spinal dorsal horn specifically, and resulted in a delayed onset of tactile allodynia post injury. Both dorsal horn Ca v α 2 δ 1 upregulation and tactile allodynia in the lidocaine pretreated rats returned to levels similar to that in saline pretreated controls two weeks post the ligation injury. In addition, preemptive intrathecal Ca v α 2 δ 1 antisense treatments blocked concurrently injury-induced allodynia onset and Ca v α 2 δ 1 upregulation in dorsal spinal cord. These findings indicate that injury induced discharges regulate Ca v α 2 δ 1 expression in the spinal dorsal horn that is critical for neuropathic allodynia initiation. Thus, preemptive blockade of injury-induced neural activity or Ca v α 2 δ 1 upregulation may be a beneficial option in neuropathic pain management.

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Section: Discussionmentioning

confidence: 99%

Injury discharges regulate calcium channel alpha-2-delta-1 subunit upregulation in the dorsal horn that contributes to initiation of neuropathic pain

Boroujerdi

Kim

Lyu

et al. 2008

Pain

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“…(14) using a nonlinear least-square program (Kawai et al, 1985); estimates of Ko, Bmax, and Keq were obtained.…”

Section: Discussionmentioning

confidence: 99%

Regional Brain Measurement of B_max and K_D with the Opiate Antagonist Cyclofoxy: Equilibrium Studies in the Conscious Rat

Kawai¹,

Carson²,

Dunn³

et al. 1991

J Cereb Blood Flow Metab

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Summary: Brain distribution of the opiate receptor antag onist, cycIofoxy (CF), was evaluated at equilibrium in rats. A combination of i. v. injection and constant i. v. infusion was used to administer CF over a wide dose range (2.4-450 nmol/rat). Kinetic simulations and exper imental results showed that this administration schedule accomplishes "true" tissue-blood equilibrium of CF within 60 min. To estimate the receptor-ligand binding parameters, we assumed that the CF concentration at the receptor site is identical to that in plasma water at equi librium, and can be calculated from measured blood data after corrections for radiolabeled metabolites and plasma protein binding. This assumption was supported by CSF and plasma water measurements at equilibrium. Regional Kn, Bmax, and a nonspecific tissue binding equilibrium constant (Keq) were estimated by fitting the tissue and plasma water concentrations to a single receptor model; the estimated values were 1.4-2.9 nM, 15-74 pmol/g of tissue, and 5.2-8.0, respectively. They are in good agree-

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“…A concentration of lidocaine and of its primary (OH-lidocaine and MEGX) and secondary (OHof lidocaine (1 mg/kg in 0.9% NaCl) was injected into the femoral vein. Twelve rats submitted to two subsequent ether anesthesia MEGX and GX) metabolites were determined using HPLC following a modification of the procedure described by Kawai et al 24 Briefly, were used as controls (C). Control and IRI rats were sacrificed 20 (n Å 3), 40 (n Å 3), 80 (n Å 3), and 120 minutes (C; n Å 3 and 25 mL tocaine, 100 mmol/L (used as internal standard), 1 mL 1 mol/L Na 2 CO 3 , and 7 mL ethyl acetate were added to 1-mL aliquot IRI; n Å 5) after lidocaine injection, and blood drawn by aortic puncture.…”

Section: Methodsmentioning

confidence: 99%

“…(Drawn from published data. 24,28 ) 37ЊC; thereafter, 0.1 to 0.3 mg microsomal protein was added (final volume 345 mL) and incubated for 30 minutes at 37ЊC. The reaction was stopped by adding 20 mL perchloric acid at 60%.…”

Section: Fig 1 Pathways Of Lidocaine Metabolism In Rat (mentioning

confidence: 99%

The monoethylglycinexylidide test does not correctly evaluate lidocaine metabolism after ischemic liver injury in the rat

Leclercq

1997

Hepatology

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Although the monoethylglycinexylidide (MEGX) test de-activity of various cytochrome P-450 enzymes. [1][2][3] For clinical fined as a single determination of MEGX plasma concentra-application, the time-consuming repetitive determinations, tion after lidocaine injection has been proposed as a liver usually by high-performance liquid chromatography (HPLC) function test, some discrepancies appeared in assessing the of lidocaine plasma concentrations, were replaced by a single quality of liver donor for transplantation as well as the severity point measurement of one of its metabolites, the monoethylof liver disease. The present study used a severe ischemia-glycinexilidide (MEGX) with a convenient fluorescence poreperfusion liver injury (IRI) in rat to evaluate the various larization immunoassay (FPIA). 4 This test found many applifactors able to influence the level of MEGX. The metabolism cations in adult and pediatric hepatology [5][6][7][8][9][10] ; however, its of lidocaine was studied on microsomes isolated from intact initial relevance in the evaluation of organ viability before rats and from rats submitted to this liver injury. A significant transplantation has not been confirmed by subsequent studreduction of the various pathways transforming lidocaine but ies. 3,[11][12][13] In a preliminary study, we also observed that in a also MEGX was demonstrated. Lidocaine inhibited the MEGX well-defined model of severe liver injury produced in rat by transformation both in intact and injured liver microsomes. a period of ischemia followed by reperfusion, paradoxical In vivo, plasma MEGX concentrations, determined by high-results were obtained as MEGX value above the normal was performance liquid chromatography (HPLC), were lower in concomitant with a lethal injury within the next 24 hours. 14 IRI than in controls up to 80 minutes after lidocaine injection Although there are some differences in lidocaine metabolism but not later. By contrast, using the usual commercial fluores-between rat and man, 15 this model of liver injury could be cence polarization immunoassay (FPIA), MEGX concentra-used to critically test two assumptions about the MEGX test tions were paradoxically higher in IRI than in controls. More-that have not been confirmed experimentally. The first one over, MEGX values obtained using FPIA were threefold higher is that the determination of MEGX concentration at a single in controls and ninefold higher in IRI than with HPLC. It was time point is a reliable index of the lidocaine metabolism. shown that these differences were related to the detection by This could probably be questioned, because MEGX is only FPIA of free and mainly of conjugated hydroxy-MEGX that one of the metabolites of lidocaine and is itself submitted accumulated in plasma from rats submitted to an IRI. These to further transformations. Indeed, in humans, lidocaine is data emphasize the complexity of factors influencing the ap-mainly deethylated to MEGX and is, to a lesser extent, hypearance and disappearance of MEGX because of delayed d...

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Simultaneous Quantitation of Lidocaine and Its Four Metabolites by High-performance Liquid Chromatography: Application to studies on In Vitro and In Vivo Metabolism of Lidocaine in Rats

Cited by 38 publications

References 29 publications

Injury discharges regulate calcium channel alpha-2-delta-1 subunit upregulation in the dorsal horn that contributes to initiation of neuropathic pain

Injury discharges regulate calcium channel alpha-2-delta-1 subunit upregulation in the dorsal horn that contributes to initiation of neuropathic pain

Regional Brain Measurement of B_max and K_D with the Opiate Antagonist Cyclofoxy: Equilibrium Studies in the Conscious Rat

The monoethylglycinexylidide test does not correctly evaluate lidocaine metabolism after ischemic liver injury in the rat

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Simultaneous Quantitation of Lidocaine and Its Four Metabolites by High-performance Liquid Chromatography: Application to studies on In Vitro and In Vivo Metabolism of Lidocaine in Rats

Cited by 38 publications

References 29 publications

Injury discharges regulate calcium channel alpha-2-delta-1 subunit upregulation in the dorsal horn that contributes to initiation of neuropathic pain

Injury discharges regulate calcium channel alpha-2-delta-1 subunit upregulation in the dorsal horn that contributes to initiation of neuropathic pain

Regional Brain Measurement of Bmax and KD with the Opiate Antagonist Cyclofoxy: Equilibrium Studies in the Conscious Rat

The monoethylglycinexylidide test does not correctly evaluate lidocaine metabolism after ischemic liver injury in the rat

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Regional Brain Measurement of B_max and K_D with the Opiate Antagonist Cyclofoxy: Equilibrium Studies in the Conscious Rat