Creatine kinase elevation caused by a combination of fluvastatin and telmisartan in a patient heterozygous for the CYP2C9*3 and ABCC2 -24C &gt; T variants: a case report

Schwabedissen, Henriette E. Meyer zu; Siegmund, Werner; Kroemer, Heyo K.; Rollnik, Jens D.

doi:10.1186/1756-0500-7-688

Cited by 10 publications

(8 citation statements)

References 15 publications

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“…Carriers of the TC genotype of SLCO1B1 rs4149056 (T>C) variant who are treated with amlodipine (CYP3A4 inhibitor) experienced a 90% increased simvastatin AUC compared with subjects not treated with amlodipine and wild-type for rs4149056 [87]. A similar scenario was reported with other two case reports (see Supplementary Table 1) [88,89].…”

Section: Ddgis and Challenges In Clinical Practicesupporting

confidence: 81%

Drug–drug–gene interactions and adverse drug reactions

2019

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The economic and health burden caused by adverse drug reactions has increased dramatically in the last few years. This is likely to be mediated by increasing polypharmacy, which increases the likelihood for drug-drug interactions. Tools utilized by healthcare practitioners to flag potential adverse drug reactions secondary to drug-drug interactions ignore individual genetic variation, which has the potential to markedly alter the severity of these interactions. To date there have been limited published studies on impact of genetic variation on drug-drug interactions. In this review, we establish a detailed classification for pharmacokinetic drug-drug-gene interactions, and give examples from the literature that support this approach. The increasing availability of real-world drug outcome data linked to genetic bioresources is likely to enable the discovery of previously unrecognized, clinically important drug-drug-gene interactions.

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Section: Ddgis and Challenges In Clinical Practicesupporting

confidence: 81%

Drug–drug–gene interactions and adverse drug reactions

2019

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“…Another study showed that the CYP2C9 polymorphism was related to the risk for fluvastatin-induced adverse drug reactions (ADRs). 12) In addition, this study also found an increased risk of ADRs when carriers of CYP2C9 variant alleles were given CYP2C9 inhibiting medicines concomitantly. A subsequent case report found that an elevation of the muscle tissue biomarker creatine kinase in a Caucasian patient genotyped as CYP2C9*1/*3 appeared to be caused by a DDI between fluvastatin and telmisartan, and a normalization was noticed after switching from telmisartan to candesartan.…”

mentioning

confidence: 53%

“…8) cines concomitantly. 12) Ohno et al 7) and Hisaka et al 8) have reported that careful attention needs to be paid to the co-administration of CYP3A4 inhibitors when using statins that are mainly metabolized by CYP3A4. It has also been reported that fluvastatin should be considered to be a good choice for patients who need to be treated by CYP3A4 inhibitors such as calcineurin inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Co-administration of Fluvastatin and CYP3A4 and CYP2C8 Inhibitors May Increase the Exposure to Fluvastatin in Carriers of CYP2C9 Genetic Variants

Mukai

Narita

Ohashi

et al. 2017

Biological & Pharmaceutical Bulletin

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Fluvastatin, which is one of the hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins), is primarily metabolized by CYP2C9 and to a lesser extent by CYP3A4 and CYP2C8. Predictions of drug-drug interactions (DDI) are important for the safety of combination therapies with statins, in particular drugs that are metabolized by CYP3A4. Little information is available regarding drug interactions with fluvastatin. Since CYP2C9 is a polymorphic enzyme, we investigated the effect of DDI via CYP2C9, CYP3A4, and CYP2C8 on fluvastatin pharmacokinetics by using a validated prediction method in relation to CYP2C9 variants. The predicted increases in the area under the concentration-time curve (AUC) ratios of fluvastatin in carriers with CYP2C9*1/*2, CYP2C9*1/*3, CYP2C9*2/*2, CYP2C9*2/*3, and CYP2C9*3/*3 versus that found in carriers with CYP2C9*1/*1 were 1.16, 1.35, 1.37, 1.65, and 2.06, respectively. Our in silico model predicted that administration of fluvastatin in conjunction with the potent inhibitors that completely inhibited CYP3A4 and CYP2C8 in carriers with the CYP2C9*3/*3 variant would cause a 3.23- and 2.60-fold increase in the AUC ratios, respectively, when compared to that for the carriers with the CYP2C9*1/*1 taking fluvastatin alone. We also predicted the effect of telmisartan when coadministered with fluvastatin. Our prediction results showed that the interaction between telmisartan and fluvastatin via CYP enzymes were negligible in clinical situations.

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“…Co-administration of FLU with telmisartan for several years resulted in mild myotoxicity as well as exhibited significant spinal motor neuron loss in vitro at lower concentrations as compared to other statins. [37,38] Incidence of hepatotoxicity was observed more frequently with FLU than the other statins [39] . These toxicities act as preliminary signals and future evaluations are certainly needed to confirm them and quantify these possible risks.…”

Section: In Silico Toxicity Predictionmentioning

confidence: 98%

“…The present in silico toxicity studies indicate carcinogenicity toxicity profile for rat male FDA none vs carcinogen toxicity model (Table S1) that might answer the increased incidence of thyroid follicular cells adenomas and carcinomas in males . Co‐administration of FLU with telmisartan for several years resulted in mild myotoxicity as well as exhibited significant spinal motor neuron loss in vitro at lower concentrations as compared to other statins . Incidence of hepatotoxicity was observed more frequently with FLU than the other statins .…”

Section: M1 and M2 ([M + H] + M/z 508) (Sulphation Of Hydroxylated Flu)mentioning

confidence: 99%

Identification and characterization of fluvastatin metabolites in rats by UHPLC/Q‐TOF/MS/MS and in silico toxicological screening of the metabolites

Chavan¹,

Kalariya²,

Nimbalkar

et al. 2017

J. Mass Spectrom.

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The present study reports the in vivo and in vitro identification and characterization of metabolites of fluvastatin, the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, using liquid chromatography-mass spectrometry (LC-MS). In vitro studies were conducted by incubating the drug with human liver microsomes and rat liver microsomes. In vivo studies were carried out by administration of the drug in the form of suspension to the Sprague-Dawley rats followed by collection of urine, faeces and blood at different time points up to 24 h. Further, samples were prepared by optimized sample preparation method, which includes freeze liquid extraction, protein precipitation and solid phase extraction. The extracted and concentrated samples were analysed using ultrahigh-performance liquid chromatography-quadruple time-of-flight tandem mass spectrometry. A total of 15 metabolites were observed in urine, which includes hydroxyl, sulphated, desisopropyl, dehydrogenated, dehydroxylated and glucuronide metabolites. A few of the metabolites were also present in faeces and plasma samples. In in vitro studies, a few metabolites were observed that were also present in in vivo samples. All the metabolites were characterized using ultrahigh-performance liquid chromatography-quadruple time-of-flight tandem mass spectrometry in combination with accurate mass measurement. Finally, in silico toxicity studies indicated that some of the metabolites show or possess carcinogenicity and skin sensitization. Several metabolites that were identified in rats are proposed to have toxicological significance on the basis of in silico evaluation. However, these metabolites are of no human relevance. Copyright © 2017 John Wiley & Sons, Ltd.

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Creatine kinase elevation caused by a combination of fluvastatin and telmisartan in a patient heterozygous for the CYP2C9*3 and ABCC2 -24C > T variants: a case report

Cited by 10 publications

References 15 publications

Drug–drug–gene interactions and adverse drug reactions

Drug–drug–gene interactions and adverse drug reactions

Co-administration of Fluvastatin and CYP3A4 and CYP2C8 Inhibitors May Increase the Exposure to Fluvastatin in Carriers of CYP2C9 Genetic Variants

Identification and characterization of fluvastatin metabolites in rats by UHPLC/Q‐TOF/MS/MS and in silico toxicological screening of the metabolites

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