Biliary secretion of felodipine metabolites in man after intravenous [14C]felodipine

Sutfin, T A; Lind, Tore; Gabrielsson, M; Regårdh, C G

doi:10.1007/bf02336677

Cited by 14 publications

(4 citation statements)

References 13 publications

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“…Dihydropyridine derivatives undergo rapid and extensive hepatic oxidative metabolization by cytochrome P 450 enzymes, 10 giving rise to pyridine analogues that are pharmacologically inactive and further biotransformation including ester cleavage. 11 Also, these drugs are more or less light-sensitive. Their degradation pathways depend on the kind of irradiation: UV light gives rise to the nitropyridine derivative, while visible light produces the nitrosopyridine analogue.…”

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confidence: 99%

Electrochemical Oxidation of 4‐Methyl‐1,4‐dihydropyridines in Protic and Aprotic Media. Spin Trapping Studies

Núñez‐Vergara¹,

Sturm²,

Álvarez‐Lueje³

et al. 1999

J. Electrochem. Soc.

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This work reports the electrochemical oxidation of a new series of 4‐methyl‐1,4‐dihydropyridine derivatives with platelet activation factor antagonistic activity. Differential pulse and cyclic voltammetry studies on a glassy carbon electrode showed an irreversible single peak due to the oxidation of the dihydropyridine ring via two electrons. Rotating disk electrode studies show a linear dependence between the current and the rotating rate, indicating that the oxidation process is diffusion‐controlled. Calculated diffusion coefficients did not exhibit significant differences between the derivatives. Voltammetric apparent normalpKnormala values for the protonation‐deprotonation equilibrium of the N‐heterocyclic nitrogen are compared with 4‐phenyl substituted 4‐aryl‐1,4‐dihydropyridine (1,4-DHP) derivatives. Based on voltammetric experiments on glassy carbon electrodes, it is seen that the potential peak values are directly related to the electron density on the dihydropyridine ring, wherein C-5 substituent with electron‐withdrawing character produces the most oxidizable 1,4-DHP derivative. The oxidation mechanism follows the general pathway: electron, H+ , electron, H+ , with formation of an unstable cation radical in the first step. A one‐electron oxidation intermediate was confirmed with controlled potential electrolysis and electron spin resonance experiments. On applying N‐benzilydene‐t‐butylamine‐N‐oxide as the spin trap, the unstable radical intermediates from the oxidation of 4‐methyl‐1,4‐dihydropyridine derivatives were intercepted. Comparison of the electron spin resonance spectra of the nitroxide spin adducts revealed no significant differences in the splitting constants of the radicals. © 1999 The Electrochemical Society. All rights reserved.

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confidence: 99%

Electrochemical Oxidation of 4‐Methyl‐1,4‐dihydropyridines in Protic and Aprotic Media. Spin Trapping Studies

Núñez‐Vergara¹,

Sturm²,

Álvarez‐Lueje³

et al. 1999

J. Electrochem. Soc.

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“…This has implications for DDI risk assessment at the site of action. Felodipine is predominantly metabolized by CYP3A4, less than 0.1% is secreted in the bile and less than 0.5% is excreted unchanged in urine and metabolized to dehydrofelodipine 42,43 . In this model, fm CYP3A4 is assumed as 100% (worst case) to show the sensitivity of the diseased population to DDI predictions.…”

Section: Discussionmentioning

confidence: 99%

“…Felodipine is predominantly metabolized by CYP3A4, less than 0.1% is secreted in the bile and less than 0.5% is excreted unchanged in urine and metabolized to dehydrofelodipine. 42,43 In this model, fm CYP3A4 is assumed as 100% (worst case) to show the sensitivity of the diseased population to DDI predictions. However, a small change in fm CYP3A4 will hugely impact the AUC ratio and level of DDIs.…”

Section: Prospective Simulations and Potential Applications Of Ced Po...mentioning

confidence: 99%

Physiologically based pharmacokinetic modeling for development and applications of a virtual celiac disease population using felodipine as a model drug

Salem

Nimavardi

Tompson

et al. 2023

CPT Pharmacom & Syst Pharma

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In celiac disease (CeD), gastrointestinal CYP3A4 abundance and morphology is affected by the severity of disease. Therefore, exposure to CYP3A4 substrates and extent of drug interactions is altered. A physiologically‐based pharmacokinetic (PBPK) population for different severities of CeD was developed. Gastrointestinal physiology parameters, such as luminal pH, transit times, morphology, P‐gp, and CYP3A4 expression were included in development of the CeD population. Data on physiological difference between healthy and CeD subjects were incorporated into the model as the ratio of celiac to healthy. A PBPK model was developed and verified for felodipine extended‐release tablet in healthy volunteers (HVs) and then utilized to verify the CeD populations. Plasma concentration‐time profile and PK parameters were predicted and compared against those observed in both groups. Sensitivity analysis was carried out on key system parameters in CeD to understand their impact on drug exposure. For felodipine, the predicted mean concentration‐time profiles and 5th and 95th percentile intervals captured the observed profile and variability in the HV and CeD populations. Predicted and observed clearance was 56.9 versus 56.1 (L/h) in HVs. Predicted versus observed mean ± SD area under the curve for extended release felodipine in different severities of CeD were values of 14.5 ± 9.6 versus 14.4 ± 2.1, 14.6 ± 9.0 versus 17.2 ± 2.8, and 28.1 ± 13.5 versus 25.7 ± 5.0 (ng.h/mL), respectively. Accounting for physiology differences in a CeD population accurately predicted the PK of felodipine. The developed CeD population can be applied for determining the drug concentration of CYP3A substrates in the gut as well as for systemic levels, and for application in drug–drug interaction studies.

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“…Felodipine (CAS 72509-76-3)i sadihydropyridine calcium-channel blockerw ithh igh selectivity fort he smoothm uscle of the arterialresistancevessels,a nd hasno effecton the heart in therapeuticconcentrations [1].Felodipine iscompletelyabsorbed in the gastrointestinaltract.However,the absolutebioavailability of felodipine extended release( ER)f ormulation afteroral administration wasapproximately15 %. The lowabsolutebioavailability wasduetothe high first-pass effect of pre-systemicelimination of felodipine [2].Biliary secretion isaminorr outeo fe limination of felodipine,a s approximately7 0%o fagiven dosei sexcreted asmetabolitesin the urine and 10%i sexcreted in the feces [3,4].Inthe doserange from 5mgto40mg,felodipine has linearpharmacokineticc haracteristics [2,5,6].Following multiple dosing of felodipine,the accumulation is minimalbased on C max and AUC [7,8].The main metabolicenzyme forfelodipine metabolismisCYP3A4, and the primary metabolitei sdehydrofelodipine,a compound without vasodilating activity [9,10].Therei s astrong correlation between plasmafelodipine concentration and reduction in diastolicb lood pressure( DBP) in hypertensivep atients [11].Duetoa45 %to60 %d ecreaseinfelodipine clearanceand the resulting increase in systemicexposure,the initialrecommended dosef or elderlys ubjects and patients withcongestiveh eart failureo rhepaticimpairmentisr educed from 5mgo nce dailyt o2.5 mg oncedaily [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of felodipine extended-release tablets in healthy Taiwanese subjects: a retrospective review

Hsiao

Hsu³

2011

Arzneimittelforschung

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The objective of this study was to investigate the pharmacokinetics of felodipine (CAS 72509-76-3) in healthy male Taiwanese subjects. This is a retrospective review of five felodipine pharmacokinetic studies completed in Taiwan. A total of 100 evaluable healthy Taiwanese males were enrolled in these studies. The subjects received 5 mg (n = 80) or 10 mg (n = 20) of Plendil? (felodipine extended-release tablets; felodipine ER) once daily for 6 days. The mean ? SD tmax, ss, Cmax, ss and AUC? of dose normalized to 10 mg felodipine was 3.32 ? 1.33 h, 13.12 ? 5.34 nmol/L and 136.33 ? 63.18 nmol ? h/L, respectively. By using Kolmogorov-Smirnov?s test and probit plots, the results indicated that the frequency distribution of AUC/dose, Cmin/ dose and CL/F was bimodal. Compared to data from the literature, the mean Cmax, ss and AUC? of 5 mg felodipine in healthy young Taiwanese subjects were similar to or slightly lower than data from Swedish, Danish, Turkish and Canadian studies in healthy young subjects who received 10 mg felodipine. Comparable Cmax values and approximately 30% lower AUC values were observed when comparing the 5 mg Taiwanese data to data in healthy elderly German subjects who also received 5 mg felodipine. Taiwanese subjects might have lower CYP3A4 activity to metabolize felodipine, which is similar to the phenomenon observed with nifedipine.

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Biliary secretion of felodipine metabolites in man after intravenous [14C]felodipine

Cited by 14 publications

References 13 publications

Electrochemical Oxidation of 4‐Methyl‐1,4‐dihydropyridines in Protic and Aprotic Media. Spin Trapping Studies

Electrochemical Oxidation of 4‐Methyl‐1,4‐dihydropyridines in Protic and Aprotic Media. Spin Trapping Studies

Physiologically based pharmacokinetic modeling for development and applications of a virtual celiac disease population using felodipine as a model drug

Pharmacokinetics of felodipine extended-release tablets in healthy Taiwanese subjects: a retrospective review

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