The pharmacokinetic and pharmacodynamic interaction between propafenone and lidocaine

Ujhelyi, Michael R.; O'Rangers, Eleanor A.; Fan, Chunyan; Kluger, Jeffrey; Pharand, Chantal; Chow, Moses S. S.

doi:10.1038/clpt.1993.7

Cited by 26 publications

(8 citation statements)

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“…The inhibitors of CYP2C19 (omeprazole) and CYP2D6 (propafenone) have little if any effect on intravenous lignocaine (Noble et al 1994;Ujhelyi et al 1993). Interestingly, although CYP3A4 is responsible for the formation of monoethylglycinexylidide in vitro, our study group has previously shown that erythromycin and itraconazole, both strong inhibitors of CYP3A4, have practically no effect on the pharmacokinetics of intravenous lignocaine (Isohanni et al 1998).…”

Section: Discussionmentioning

confidence: 99%

Effect of Erythromycin and Itraconazole on the Pharmacokinetics of Oral Lignocaine

Isohanni¹,

Neuvonen

Olkkola³

1999

Pharmacology & Toxicology

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Absiruct: Lignocaine is metabolized by cytochrome P450 3A4 enzyme (CYP3A4), and has a moderate to high extraction ratio resulting in oral bioavailability of 30%. We have studied the possible effect of two inhibitors of CYP3A4, erythromycin and itraconazole, on the pharmacokinetics of oral lignocaine in nine volunteers using a cross-over study design. The subjects were given erythromycin orally (500 mg three times a day), itraconazole (200 mg once a day) or placebo for four days. On day 4, each subject ingested a single dose of 1 mg/kg of oral lignocaine. Plasma samples were collected until 10 hr and concentrations of lignocaine and its major metabolite, monoethylglycinexylidide were measured by gas chromatography. Both erythromycin and itraconazole increased the area under the lignocaine plasma concentration-time curve [AUC(O-m)] and lignocaine peak concentrations by 40-70% (P<0.05). Compared to placebo and itraconazole, erythromycin increased monoethylglycinexylidide peak concentrations by approximately 40% (P

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Section: Discussionmentioning

confidence: 99%

Effect of Erythromycin and Itraconazole on the Pharmacokinetics of Oral Lignocaine

Isohanni¹,

Neuvonen

Olkkola³

1999

Pharmacology & Toxicology

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“…It is known that liver or heart failure (Thomson et al, 1973) possibly right to left cardiac shunts (Bokesch et al, 1987;Burrows et al, 1991), or the concurrent administration of phenobarbital (Heinonen, 1966) or propafenone (Ujhelyi et al, 1993) will alter the pharmacokinetics of lignocaine. To the authors' knowledge, these attributes did not apply to the present study population.…”

Section: Discussionmentioning

confidence: 99%

The pharmacokinetics of lignocaine in humans during a computer‐controlled infusion

Dyck

Wallace

et al. 1997

European Journal of Pain

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Several types of chronic pain syndromes are effectively treated with sodium channel blockers such as lignocaine. Further investigation of this therapeutic modality would be facilitated by refinement of the parameters describing lignocaine distribution and elimination. This would allow precise lignocaine infusion by a computer-controlled infusion to attain and maintain stable target lignocaine concentrations. Arterial blood samples were obtained at frequent intervals during a computer-controlled infusion of lignocaine in 12 adult human volunteers. Plasma lignocaine concentrations of 1, 2, 3, 4 and 5 microg/ml were targeted for 15 min at each concentration. A three-compartment mammillary pharmacokinetic model best described the resulting concentration vs time profile. A population pharmacokinetic analysis was performed using three different techniques; the two-stage, pooled and mixed effects modelling. There was marked overshoot of the plasma concentration above the target prior to refinement of the pharmacokinetic parameters. The best parameters of a three-compartment mammillary model fit to the measured concentration using the pooled data approach were: V(1) = 7.44, V(2) =11.5 and V(3) = 97.71; Cl(1) = 0.585, Cl(2) = 2.23 and Cl(3) =1.64 l/min. Similarly calculated parameters using NONMEM were V(1) = 6.99, V(2) =12.2 and V(3) =1341; Cl(1) = 0.703, Cl(2) =1.24 and Cl(3) =1.49 l/min. The addition of age as a covariate of the pharmacokinetic parameters improved the model in both cases. Height, lean body mass and body surface area as covariates of the pharmacokinetic parameters did not improve the predicted value of the model. Prospective testing of the pharmacokinetic parameters will be required to define whether they function well. The refinement of pharmacokinetic parameters for the computer-controlled intravenous infusion of lignocaine will facilitate further research in pain therapy. Published lignocaine pharmacokinetic values have a relatively large central volume of distribution, and hence, when implemented as a computer-controlled infusion, result in dramatic overshoot shortly after targeting a higher plasma concentration. In light of the long-lasting pain relief provided by sodium channel blockade in neuropathic pain states, overshoot of plasma concentrations must be avoided if the concentration vs effect relationship is to be defined.

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“…[ [23][24][25][26] Two studies with a dosage of 150 mg three times per day but no identical PK parameters were reported:…”

Section: Reasons For Exclusion Referencesmentioning

confidence: 99%

The Effect of CYP2D6 Phenotypes on the Pharmacokinetics of Propafenone: A Systematic Review and Meta-Analysis

et al. 2022

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Propafenone (PPF) is a class 1C antiarrhythmic agent mainly metabolized by cytochrome (CYP) 2D6, CYP1A2, and CYP3A4. Previous studies have shown that CYP2D6 polymorphism influences the pharmacokinetics (PK) of PPF. However, the small sample sizes of PK studies can lead to less precise estimates of the PK parameters. Thus, this meta-analysis was performed to merge all current PK studies of PPF to determine the effects of the CYP2D6 phenotype more accurately on the PPF PK profile. We searched electronic databases for published studies to investigate the association between the PPF PK and CYP2D6 phenotype. Four PK-related outcomes were included: area under the time–concentration curve (AUC), maximum concentration (Cmax), apparent clearance (CL/F), and half-life (t1/2). A total of five studies were included in this meta-analysis (n = 56). Analyses were performed to compare PK parameters between poor metabolizers (PMs) versus extensive metabolizers (EMs). PPF has a non-linear pharmacokinetics; therefore, analyses were performed according to dose (300 mg and 400 mg). At 300 mg, the AUC mean (95% CI), Cmax, and t1/2 of PPF in PMs were 15.9 (12.5–19.2) µg·h/mL, 1.10 (0.796–1.40) µg/mL, and 12.8 (11.3–14.3) h, respectively; these values were 2.4-, 11.2-, and 4.7-fold higher than those in the EM group, respectively. At 400 mg, a comparison was performed between S- and R-enantiomers. The CL/F was approximately 1.4-fold higher for the R-form compared with the S-form, which was a significant difference. This study demonstrated that CYP2D6 metabolizer status could significantly affect the PPF PK profile. Adjusting the dose of PPF according to CYP2D6 phenotype would help to avoid adverse effects and ensure treatment efficacy.

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The pharmacokinetic and pharmacodynamic interaction between propafenone and lidocaine

Cited by 26 publications

References 0 publications

Effect of Erythromycin and Itraconazole on the Pharmacokinetics of Oral Lignocaine

Effect of Erythromycin and Itraconazole on the Pharmacokinetics of Oral Lignocaine

The pharmacokinetics of lignocaine in humans during a computer‐controlled infusion

The Effect of CYP2D6 Phenotypes on the Pharmacokinetics of Propafenone: A Systematic Review and Meta-Analysis

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