Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

Backman, Janne T.; Filppula, Anne M.; Niemi, Mikko; Neuvonen, Pertti J.

doi:10.1124/pr.115.011411

Cited by 191 publications

(171 citation statements)

References 537 publications

(474 reference statements)

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“…Furthermore, the pharmacokinetics of pioglitazone are not affected by the SLCO1B1 c.521T.C polymorphism, indicating that pioglitazone is not a substrate of OATP1B1 (Kalliokoski et al, 2008). Therefore, pioglitazone can be used as a selective probe substrate to study the function of CYP2C8 in vivo (Tornio et al, 2012;Backman et al, 2016). The average 2.1-fold increase in pioglitazone AUC by clopidogrel in the current study is in agreement with the results of earlier drug interaction studies between pioglitazone and CYP2C8 inhibitors (Deng et al, 2005;Jaakkola et al, 2005;Tornio et al, 2008).…”

Section: Discussionsupporting

confidence: 90%

Clopidogrel Markedly Increases Plasma Concentrations of CYP2C8 Substrate Pioglitazone

Itkonen

Tornio

Neuvonen

et al. 2016

Drug Metabolism and Disposition

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The glucose-lowering drug pioglitazone undergoes hepatic CYP2C8-mediated biotransformation to its main metabolites. The antiplatelet drug clopidogrel is metabolized to clopidogrel acyl-b-D-glucuronide, which was recently found to be a strong time-dependent inhibitor of CYP2C8 in humans. Therefore, we studied the effect of clopidogrel on the pharmacokinetics of pioglitazone. In a randomized crossover study, 10 healthy volunteers ingested either 300 mg of clopidogrel on day 1, and 75 mg on days 2 and 3, or placebo. Pioglitazone 15 mg was administered 1 hour after placebo and clopidogrel on day 1. Plasma concentrations of pioglitazone, clopidogrel, and their main metabolites were measured up to 72 hours. Clopidogrel increased the area under the plasma concentration-time curve (AUC 0-' ) of pioglitazone 2.1-fold [P < 0.001, 90% confidence interval (CI) 1.8-2.6] and prolonged its half-life from 6.7 to 11 hours (P = 0.002). The peak concentration of pioglitazone was unaffected but the concentration at 24 hours was increased 4.5-fold (range 1.6-9.8; P < 0.001, 90% CI 3.17-6.45) by clopidogrel. The M-IV-to-pioglitazone AUC 0-' ratio was 49% (P < 0.001, 90% CI 0.40-0.59) of that during the control phase, indicating that clopidogrel inhibited the CYP2C8-mediated biotransformation of pioglitazone. Clopidogrel increases the exposure to pioglitazone by inhibiting its CYP2C8-mediated biotransformation. In consequence, use of clopidogrel may increase the risk of fluid retention and other concentration-related adverse effects of pioglitazone.

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Section: Discussionsupporting

confidence: 90%

Clopidogrel Markedly Increases Plasma Concentrations of CYP2C8 Substrate Pioglitazone

Itkonen

Tornio

Neuvonen

et al. 2016

Drug Metabolism and Disposition

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“…Although CYP2C8 is a minor CYP member and only involved in the metabolism of approximately 5% of small molecule drugs, its clinical significance has been increasingly recognized (Backman et al, 2016;Lai et al, 2009;Totah and Rettie, 2005). In particular, CYP2C8 plays an important role in repaglinide pharmacokinetics, where polymorphic expression of CYP2C8 is associated with reduced repaglinide plasma concentrations (Niemi et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

CYP2C8-mediated interaction between repaglinide and steviol acyl glucuronide: In vitro investigations using rat and human matrices and in vivo pharmacokinetic evaluation in rats

Zhou

Wang

et al. 2016

Food and Chemical Toxicology

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“…Moreover, the low bioavailability could be caused by following reasons; a) PT, an efficient anticancer drug act as substrate for drug efflux pump transporter i.e. Pglycoprotein (P-gp) and multidrug resistance protein (MRP-2), these P-gp and MRP-2 with substrate, inhibits oral absorption of PT by excreting it into intestinal lumen [8,13], b) PT follows the widespread pre-systemic first pass metabolism in liver and gut by involvement of cytochrome enzymes (CYP3A and CYP2C8) [8,14]. C) Lower elimination half-life (t1/2el) [15].…”

Section: Introductionmentioning

confidence: 99%

Investigation of Effect of Phospholipids on Physical and Functional Characterization of Paclitaxel Liposomes

Tatode

Patil²,

Umekar³

et al. 2017

Int J Pharm Pharm Sci

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Objective: Aim of the present investigation was to determine the effect of various synthetic grades of phospholipids on paclitaxel liposomes (PTL). Methods:The PTL formulations using various grades of phospholipids were prepared by film hydration method. The prepared PTL formulations were physicochemically characterized by entrapment efficiency (EE, %w/w), vesicular size and particle size distribution. These formulations were also characterized for function parameters such as in vitro release and hemolytic toxicity assay. Results:The synthetic grades of phospholipids significantly influenced PTL formulations. The stoichiometric ratio (1:1) between CH and various synthetic phospholipids was found to be optimized one, from rest of the ratios. The characterization confirmed the formation of PTL. The EE was observed to be high (86.67%) as increasing the ratios between CH and phospholipids but then declined suddenly as further increasing the ratio. The best liposomal formulations showed that the spherical shape was found to be within size ranging from<10 µm, with a higher rate and extent of the release, ~86.22% of paclitaxel from PTL formulation. The results of the hemolytic toxicity study demonstrated that PTL formulations with a ratio (1:1) exhibited a significantly lower hemolytic toxicity (2.70%), compared to all formulations. Conclusion:The result revealed the excellent effect of phospholipids on paclitaxel liposomes. The paclitaxel liposomes prepared with CH: PL90G ratio (1:1) was found to be optimized one. The entrapment efficiency, particle size distribution, in vitro release and hemolytic activity with this ratio shown to be excellent as compared to other ratios.

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Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

Cited by 191 publications

References 537 publications

Clopidogrel Markedly Increases Plasma Concentrations of CYP2C8 Substrate Pioglitazone

Clopidogrel Markedly Increases Plasma Concentrations of CYP2C8 Substrate Pioglitazone

CYP2C8-mediated interaction between repaglinide and steviol acyl glucuronide: In vitro investigations using rat and human matrices and in vivo pharmacokinetic evaluation in rats

Investigation of Effect of Phospholipids on Physical and Functional Characterization of Paclitaxel Liposomes

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