The Pharmacokinetic Interaction Study between Carvedilol and Bupropion in Rats

Abrudan, Maria Bianca; Gheldiu, Ana Maria; Neag, Maria Adriana; Vlase, Laurian

doi:10.1159/000453619

Cited by 8 publications

(9 citation statements)

References 18 publications

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“…Other PK drug-drug interaction studies between carvedilol and CYP450 inhibitors, including ketoconazole [30], cilostazol [31], ticlopidine [32], glipizide [33,] and bupropion [34] showed an increase in the carvedilol plasma levels in rats to a similar extent as that created by citalopram in the present study. Moreover, there are few clinical trials that evaluated carvedilol PKs after co-administration with fluoxetine [35] and paroxetine [36].…”

Section: Discussionsupporting

confidence: 80%

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Inhibitory Effect of Citalopram on the Pharmacokinetics of Carvedilol in Rats and in vitro Models

Abrudan

Popa²,

Gheldiu³

et al. 2017

Pharmacology

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Background/Aims: The aim of this study was to investigate the drug-drug interaction between carvedilol and citalopram based on carvedilol metabolism in vitro and his pharmacokinetics (PKs) in vivo after the oral administration of the single drug and both drugs, and reveal citalopram effects on the PKs of carvedilol. Methods: Each rat was cannulated on the femoral vein, prior to being connected to BASi Culex ABC®. Carvedilol was orally administrated in rats (3.57 mg/kg body weight [b.w.]) in the absence of citalopram or after a pre-treatment with multiple oral doses of citalopram (1.42 mg/kg b.w.). Plasma concentrations of carvedilol were determined using high-performance liquid chromatography-MS at the designated time points after drug administration, and the main PK parameters were calculated by noncompartmental analysis. In addition, effects of citalopram on the metabolic rate of carvedilol were investigated using rat-pooled liver microsome incubation systems. Results: During co-administration, significant increases of the area under the plasma concentration-time curve as well as of the peak plasma concentration were observed. The rat-pooled liver microsome incubation experiment indicated that citalopram could decrease the metabolic rate of carvedilol. Conclusion: Citalopram co-administration led to a significant alteration of carvedilol's PK profile in rats; it also demonstrated, in vitro, these effects could be explained by the existence of a drug-drug interaction mediated by CYP2D6 inhibition.

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Section: Discussionsupporting

confidence: 80%

“…Carvedilol plasma concentrations were determined by validated liquid chromatography - mass spectrometry method [20,34]. …”

Section: Methodsmentioning

confidence: 99%

Inhibitory Effect of Citalopram on the Pharmacokinetics of Carvedilol in Rats and in vitro Models

Abrudan

Popa²,

Gheldiu³

et al. 2017

Pharmacology

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“…e pharmacokinetic parameters of single-dose carvedilol changed in hepatic fibrosis when a CCl4 hepatic fibrosis model was used to study the antifibrosis and pharmacokinetic effects of carvedilol, which are manifested as delayed clearance and drug accumulation. is is thought to result from the decrease of CYP2D6 expression in the hepatic blood flow and liver [39,40]. e C max and AUC alteration in this study might have been affected by changes in drug absorption, and the delayed MRT might have been the result of drug clearance [41,42].…”

Section: Discussionmentioning

confidence: 77%

Comparative Pharmacokinetic Study of Taxifolin after Oral Administration of Fructus Polygoni Orientalis Extract in Normal and Fibrotic Rats by UPLC-MS/MS

Wei

Chen

et al. 2019

Evidence-Based Complementary and Alternative Medicine

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Fructus polygoni orientalis (FPO) is widely used in clinical practice in China, especially in treatment of liver diseases including viral hepatitis, liver fibrosis, and liver cirrhosis. However, its pharmacokinetic (PK) alterations in liver fibrotic rats have rarely been reported. To study whether taxifolin, one of the main flavonoids in FPO can be absorbed into blood after oral administration of FPO extract and to compare the differences in pharmacokinetic parameters of taxifolin to normal and liver fibrotic rats induced by porcine serum (PS), a UPLC-MS/MS method was developed and validated for determination of taxifolin in rat plasma using puerarin as the internal standard (IS). All validation parameters met the acceptance criteria according to regulatory guidelines. The results indicated that after treatment of rats with PS alone for 12 weeks, the liver fibrotic model group was built successfully. The taxifolin can be absorbed into the blood after oral administration of the FPO extract. The Cmax of taxifolin was 1940 ± 502.2 ng/mL and 2648 ± 208.5 ng/mL (p<0.05), the AUC0∼t of taxifolin was 4949.7 ± 764.89 h·ng/mL and 6679.9 ± 734.26 h·ng/mL (p<0.05), the AUC0∼∞ of taxifolin was 5049.4 ± 760.7 and 7095.2 ± 962.3 h·ng/mL (p<0.05), and the mean residence time (MRT) of taxifolin was 2.46 ± 0.412 h and 3.17 ± 0.039 h (p<0.05) in the normal and fibrotic model groups, respectively. These results confirmed that the pharmacokinetic parameters of taxifolin are altered in liver fibrosis, manifested as Cmax, AUC0∼t, AUC0∼∞, and the mean residence time (MRT). It suggested that it is essential to consider the characteristics of pharmacokinetics after oral administration of FPO in liver disease patients.

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“…Furthermore, there are few studies that showed pharmacokinetic drug-drug interactions between carvedilol and CYP2D6 inhibitors, like fluoxetine [32] and paroxetine [33]. Recently, some preclinical studies proving drug-drug interactions between carvedilol and sertraline [34], citalopram [20] and bupropion [35] were published. The in vitro results presented in this study are consistent with the ones resulted from in vivo studies, the inhibitory effect of these antidepressants being therefore proved in both in vitro and in vivo studies.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic interactions study between carvedilol and some antidepressants in rat liver microsoms – a comparative study

Abrudan

Popa

Gheldiu

et al. 2019

Medicine and Pharmacy Reports

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Background and aims. Cardiovascular diseases and depressive disorders are some of the most frequent diseases. The probability of concomitant prescription of antihypertensive and antidepressive medication is increasing. The aim of this study was to investigate the enzyme inhibition by bupropion, sertraline and fluvoxamine on the metabolism of carvedilol using rat pooled liver microsomes and to assess the importance of these interactions from the pharmacokinetic mechanism point of view. Methods. Two substrate concentrations (0.5 and 1 μM) and four inhibitor concentrations (0, 0.1, 0.75 and 1.5 μM) were used for each tested inhibitor. Results. The results of the in vitro experiments showed a significant decrease of the metabolic rate of carvedilol to 4'-hydroxyphenyl carvedilol, for all tested inhibitors, when the inhibitor was added to the incubation mixture containing the substrate. Moreover, an increase of the area under the concentration-time curve for carvedilol was observed after incubation with each tested inhibitor compared with the control state (no inhibitor). The most potent inhibitor was sertraline, followed by fluvoxamine and bupropion. Conclusion. The co-administration of tested antidepressants led to a significant alteration of carvedilol’s metabolism in vitro. CYP2D6 inhibition is the main pharmacokinetic mechanism that can explain these drug-drug interactions, with possible clinical implications.

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The Pharmacokinetic Interaction Study between Carvedilol and Bupropion in Rats

Cited by 8 publications

References 18 publications

Inhibitory Effect of Citalopram on the Pharmacokinetics of Carvedilol in Rats and in vitro Models

Inhibitory Effect of Citalopram on the Pharmacokinetics of Carvedilol in Rats and in vitro Models

Comparative Pharmacokinetic Study of Taxifolin after Oral Administration of Fructus Polygoni Orientalis Extract in Normal and Fibrotic Rats by UPLC-MS/MS

Pharmacokinetic interactions study between carvedilol and some antidepressants in rat liver microsoms – a comparative study

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