Pharmacokinetics of lidocaine and its active metabolites in dogs

Wilcke, J. R.; Davis, Lloyd; Neff-Davis, C. A.; Koritz, G. D.

doi:10.1111/j.1365-2885.1983.tb00454.x

Cited by 30 publications

(34 citation statements)

References 9 publications

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“…Emesis usually occurred three to six times beginning at 3-4 h after initiation of infusion in all dogs. Consistent with the findings reported previously, 28,29,38 primary and secondary products of the N-dealkylation pathway, namely MEGX and GX, were the principal metabolites detected in canine plasma. C b /C p ratios of LD were found to be similar on day 1 (0.91 ( 0.13) and day 10 (0.94 ( 0.12) (p ) 0.715).…”

Section: Resultssupporting

confidence: 93%

“…In addition, preliminary studies in noninstrumented dogs, which were given a 5-min infusion of unlabeled LD (2 mg/kg), established that t 1/2 , V dss , and Cl p values of LD were not different from those values obtained on day 1 (data not shown). Mean values obtained in our instrumented dogs (Table 2) were also comparable to those previously reported by other investigators: t 1/2 , 45-91 min; 29,43,44 Cl p , 30-40 mL/min/kg; 29,43,44 and V dss , 2.18 L/kg. 43 Disposition kinetics of other compounds such as ICG 45 and mibefradil, 46 both of which are almost completely removed by the liver, were also not altered after surgical implantation of catheters and flow probes.…”

Section: Discussionsupporting

confidence: 87%

“…25,26 Second, dogs and humans share similar metabolic profiles, 27 with N-dealkylation products being the major metabolites detected in plasma. 28,29 Third, the instrumented dog model permits direct, continuous monitoring of hepatic arterial and portal venous blood flows during the whole course of LD infusion. Together with simultaneous blood sampling from the carotid artery and the portal and hepatic veins, this model allows accurate and reliable determination of transhepatic fluxes of LD in an intact conscious animal.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Intravenous Infusion of Lidocaine on Its Pharmacokinetics in Conscious Instrumented Dogs

Ngo

Tam

Tawfik

et al. 1997

Journal of Pharmaceutical Sciences

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In this study, potential alterations in hepatic blood flow, plasma protein binding, hepatic tissue binding, and enzyme activities induced by LD iv infusion of lidocaine (LD) were evaluated using a chronically instrumented dog model. Four conscious female mongrel dogs (19.0-23.5 kg) were each given, on days 1 and 10, a 5-min infusion of a mixture of unlabeled LD at approximately 2 mg/kg and 14C-labeled LD at approximately 25 microCi and, on day 8, a 12-h constant rate iv infusion of LD (approximately 76 microg/kg/min). During LD infusion, there was a 11-79% increase in total hepatic blood flow, mainly due to a 1.6-9.2-fold increase in hepatic arterial flow. Despite similar blood clearance (27.5 +/- 6.0 mL/min/kg vs 27.5 +/- 3.5 mL/min/kg), volume of distribution at steady state (1.38 +/- 0.08 L/kg vs 1.36 +/- 0.17 L/kg), and free fraction values of LD between days 1 and 10 (p > 0.05), intrinsic clearance values were consistently reduced (1224 +/- 859 mL/ min/kg vs 285 +/- 104 mL/min/kg; p = 0.034). Furthermore, hepatic tissue uptake of LD and/or its metabolites was less on day 10 than on day 1 (39.7 +/- 14.5 micromol vs 30.1 +/- 15.1 micromol; p = 0.072). The extent of N-dealkylation of LD to MEGX was unaltered, whereas sequential biotransformation of MEGX was impaired. Hence, these findings suggested that LD infusion led to a reduction of hepatic intrinsic clearance, although the change was not significant enough to alter its conventional kinetic parameters.

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Section: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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Effects of Intravenous Infusion of Lidocaine on Its Pharmacokinetics in Conscious Instrumented Dogs

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Tam

Tawfik

et al. 1997

Journal of Pharmaceutical Sciences

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“…A few procedures for the determination of lidocaine and metabolites in plasma using high-performance liquid chromatography with UV detection have been described [6][7][8][9][10]. The limit of quantification (LOQ) ranged from 50 ng ml −1 to 800 ng ml −1 .…”

Section: Introductionmentioning

confidence: 99%

Determination of lidocaine and its two N-desethylated metabolites in dog and horse plasma by high-performance liquid chromatography combined with electrospray ionization tandem mass spectrometry

Maes

Weiland

Sandersen

et al. 2007

Journal of Chromatography B

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A sensitive method for the quantification of lidocaine and its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), in animal plasma using high-performance liquid chromatography combined with electrospray ionization mass spectrometry is described. The sample preparation includes a liquid-liquid extraction with methyl tert-butylmethyl ether after addition of 2 M sodium hydroxide. Ethylmethylglycinexylidide (EMGX) is used as an internal standard. For chromatographic separation, an ODS Hypersil column was used. Isocratic elution was achieved with 0.01 M ammonium acetate and acetonitrile as mobile phases. Good linearity was observed in the range of 2.5-1000 ng ml −1 for lidocaine in both dog and horse plasma. For MEGX, linear calibration curves were obtained in the range of 5-1000 ng ml −1 and 20-1000 ng ml −1 for dog and horse plasma, respectively. In dog and horse plasma good linearity was observed in the range of 200-1500 ng ml −1 for GX. The limit of quantification (LOQ) in dog plasma for lidocaine, MEGX and GX was set at 2.5 ng ml −1 , 20 ng ml −1 and 200 ng ml −1 , respectively. For horse plasma a limit of quantification of 2.5 ng ml −1 , 5 ng ml −1 and 200 ng ml −1 was achieved for lidocaine, MEGX and GX, respectively. In dog plasma, the limit of detection (LOD) was found to be 0.8 ng ml −1 , 2.3 ng ml −1 and 55 ng ml −1 for lidocaine, MEGX and GX, respectively. In horse plasma the LOD's found for lidocaine, MEGX and GX, were 1.1 ng ml −1 , 0.5 ng ml −1 and 13 ng ml −1 , respectively. The method was shown to be of use in pharmacokinetic studies after application of a transdermal patch in dogs and after an intravenous infusion in horses.

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“…On the other hand, a 2.5-fold difference would seem unlikely. Similar studies of lidocaine pharmacokinetics in dogs (who apparently lack plasma pseudoesterase activity), reveal unexplained clearances of from 40 to 41 ml/min/kg [23,24], values also in excess of estimated hepatic blood flow. Although plasma pseudoesterases have been reported to be high in horses [25], they would not be likely contributors to lidocaine intravascular biotransformation (unlike procaine), for li docaine does not contain ester linkages.…”

Section: Discussionmentioning

confidence: 70%

Antipyrine and Lidocaine Are Cleared Faster in Horses than in Humans: Acetaminophen May Be Handled Similarly

Engelking¹,

Löfstedt

Blyden

et al. 1987

Pharmacology

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The following studies were designed to evaluate plasma elimination kinetics of intravenously administered antipyrine, acetaminophen and lidocaine among 9 healthy adult horses and 9 healthy drug-free humans (3 each per drug group), in order to compare potential species differences in drug-metabolizing ability. Acetaminophen is largely biotransformed in humans by hepatic glucuronide and sulfate conjugation, whereas both antipyrine and lidocaine are oxidized by hepatic microsomal mixed-function oxidases. Thus, plasma clearances of these drugs are thought to reflect differences in hepatic oxidative and conjugative activity, and possibly hepatic blood flow in the case of lidocaine. Results showed that mean ( ± SD, n = 3) acetaminophen clearance was similar in both horses (4.84 ± 0.637 ml/min/kg) and humans (4.68 ± 0.691 ml/min/kg). However, antipyrine clearance was 10 times greater in horses (5.83 ± 2.21 ml/min/kg) than in humans (0.536 ± 0.110 ml/min/kg), which may reflect enhanced hepatic microsomal activity in horses. Although lidocaine clearance in humans was similar to estimated hepatic blood flow (20.6 ± 5.81 ml/min/kg), clearance in horses was more than 2 times greater (52.0 ± 11.7 ml/min/kg). The cause of the higher clearance of lidocaine in horses (like dogs) remains unexplained, and may involve significant metabolism of lidocaine at extrahepatic, extravascular sites, for intravascular degradation and renal excretion of intact lidocaine in horses was negligible. Although precise biochemical mechanisms underlying pharmacokinetic parameters for these drugs in horses were not determined, it is nonetheless concluded from antipyrine results that horses may have an enhanced ability (compared with humans) to clear drugs from the circulation that are primarily metabolized in the liver by phase I oxidative reactions. On the other hand, drugs (like acetaminophen) which require biotransformation by hepatic glucuronide and sulfate conjugation, may be handled similarly in horses and humans.

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Pharmacokinetics of lidocaine and its active metabolites in dogs

Cited by 30 publications

References 9 publications

Effects of Intravenous Infusion of Lidocaine on Its Pharmacokinetics in Conscious Instrumented Dogs

Effects of Intravenous Infusion of Lidocaine on Its Pharmacokinetics in Conscious Instrumented Dogs

Determination of lidocaine and its two N-desethylated metabolites in dog and horse plasma by high-performance liquid chromatography combined with electrospray ionization tandem mass spectrometry

Antipyrine and Lidocaine Are Cleared Faster in Horses than in Humans: Acetaminophen May Be Handled Similarly

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