Statin Lactonization by Uridine 5′-Diphospho-glucuronosyltransferases (UGTs)

Schirris, Tom J.J.; Ritschel, Tina; Bilos, Albert; Smeitink, Jan A.M.; Rüssel, Frans G. M.

doi:10.1021/acs.molpharmaceut.5b00474

Cited by 43 publications

(40 citation statements)

References 37 publications

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“…Polymorphisms in UGT1A1 , 1A3 and 2B7 regions could contribute to myopathy caused by statins. Authors concluded that knowing these polymorphisms could be used to personalize statin therapy and improve their safety . Our patient was heterozygous for UGT2B7 and homozygous for UGT1A1 low‐activity alleles what also could have contributed to rosuvastatin toxicity.…”

Section: Discussionmentioning

confidence: 84%

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Rosuvastatin‐Induced Rhabdomyolysis – Possible Role of Ticagrelor and Patients’ Pharmacogenetic Profile

Kirhmajer

Šarinić

Šimičević

et al. 2018

Basic Clin Pharma Tox

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Up to the beginning of 2018, a total of eight cases describing rare but clinically important drug interactions between rosuvastatin and ticagrelor which resulted in rhabdomyolysis have been noted in the Global World Health Organization (WHO) adverse drug reaction (ADR) database (VigiBase) as well as in available literature. There are several possible factors which could contribute to the onset of rhabdomyolysis: old age, initially excessive rosuvastatin dose, drug-drug interactions (DDI) on metabolic enzymes (CYPs and UGTs) and drug transporter levels (ABCB1, ABCG2, OATP1B1) and pharmacogenetic predisposition. We reviewed all available cases plus the case of an 87-year-old female Croatian/Caucasian patient who developed rhabdomyolysis following concomitant treatment with rosuvastatin and ticagrelor. The results of the pharmacogenetic analysis indicated that the patient was a carrier of inactivating alleles CYP2C9*1/*3, CYP3A4*1/*22, CYP3A5*3/*3, CYP2D6*1/*4, UGT1A1*28/*28, UGT2B7 -161C/T, ABCB1 3435C/T and ABCB1 1237C/T which could have added to the interactions not only between ticagrelor and rosuvastatin but also other concomitantly prescribed medicines, such as amiodarone and proton pump inhibitors. In this case report, the possible multifactorial causes for rhabdomyolysis following concomitant use of rosuvastatin and ticagrelor such as old age, polypharmacy, renal impairment, along with pharmacogenetics will be discussed.

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Section: Discussionmentioning

confidence: 84%

“…The study performed by Schirris et al . showed that for six clinically relevant statins, only UGT1A1, 1A3 and 2B7 significantly contributed to their lactonization. Polymorphisms in UGT1A1 , 1A3 and 2B7 regions could contribute to myopathy caused by statins.…”

Section: Discussionmentioning

confidence: 99%

Rosuvastatin‐Induced Rhabdomyolysis – Possible Role of Ticagrelor and Patients’ Pharmacogenetic Profile

Kirhmajer

Šarinić

Šimičević

et al. 2018

Basic Clin Pharma Tox

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“…Considering that pitavastatin, rosuvastatin, and pravastatin are generally classified as statins metabolized poorly in humans (Shitara and Sugiyama, 2006), it is unlikely that metabolism accounts for the overestimation of K p,uu,V0 . However, a recent report suggested that pitavastatin undergoes lactonization by uridine 59-diphospho-glucuronosyltransferases more extensively than other statins (Schirris et al, 2015), which may explain, at least in part, the overestimation of K p,uu,V0 compared with K p,uu,ss (Fig. 3, A and B).…”

Section: Discussionmentioning

confidence: 94%

Comparison of Methods for Estimating Unbound Intracellular-to-Medium Concentration Ratios in Rat and Human Hepatocytes Using Statins

et al. 2017

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It is essential to estimate concentrations of unbound drugs inside the hepatocytes to predict hepatic clearance, efficacy, and toxicity of the drugs. The present study was undertaken to compare predictability of the unbound hepatocyte-to-medium concentration ratios (K) by two methods based on the steady-state cell-to-medium total concentration ratios at 37°C and on ice (K) and based on their initial uptake rates (K). Poorly metabolized statins were used as test drugs because of their concentrative uptake via organic anion-transporting polypeptides. K values of these statins provided less interexperimental variation than the K values, because only data at longer time are required for K K values for pitavastatin, rosuvastatin, and pravastatin were 1.2- to 5.1-fold K in rat hepatocytes; K values in human hepatocytes also tended to be larger than corresponding K To explain these discrepancies, theoretical values of K and K were compared with true K (K), considering the inside-negative membrane potential and ionization of the drugs in hepatocytes and medium. Membrane potentials were approximately -30 mV in human hepatocytes at 37°C and almost abolished on ice. Theoretical equations considering the membrane potentials indicate that K values for the statins are 0.85- to 1.2-fold K, whereas K values are 2.2- to 3.1-fold K, depending on the ratio of the passive permeability of the ionized to nonionized forms. In conclusion, K values of anions are similar to K when the inside-negative membrane potential is considered. This suggests that K is preferable for estimating the concentration of unbound drugs inside the hepatocytes.

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“…For rosuvastatin, the CL int,UGT was not determined in this study because rosuvastatin was reportedly more stable against UGTs than atorvastatin in the in vitro recombinant systems. 18…”

Section: Metabolic Clearance Of Oatp Substrate Drugs In Human Liver Mmentioning

confidence: 99%

Comparison of the Predictability of Human Hepatic Clearance for Organic Anion Transporting Polypeptide Substrate Drugs Between Different In Vitro–In Vivo Extrapolation Approaches

Izumi

Nozaki

Komori

et al. 2017

Journal of Pharmaceutical Sciences

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Prediction of human pharmacokinetic profiles of drug candidates is an essential step toward first-in-human studies. However, it remains difficult to quantitatively predict hepatic clearance, particularly when hepatic uptake is mediated by transporter(s). Using 15 organic anion transporting polypeptide (OATP) substrate drugs, we tested 3 in vitro-in vivo extrapolation (IVIVE) approaches to predict overall hepatic intrinsic clearance in vivo (CL). IVIVE approaches involved metabolic intrinsic clearance in human liver microsomes (CL) with or without hepatocyte-to-buffer maximum unbound concentration ratio (K) correction and uptake intrinsic clearance at 37°C (PS) in human hepatocyte suspensions. K and PS values were determined in 2 hepatocyte batches, and all tested compounds showed temperature-dependent uptake, consistent with the fact of transporter-mediated uptake. CL substantially underestimated CL. By multiplying CL by K values, the prediction performance was much improved; however, in vitro-in vivo correlation was poor. Among the IVIVE approaches, PS showed the most robust correlation with CL, and one of the hepatocyte batches could predict CL with a minimal empirical scaling factor. These results suggested IVIVE with hepatic uptake clearance determined in hepatocyte suspensions as one of the most practical approaches for predicting CL of OATP substrate drugs.

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Statin Lactonization by Uridine 5′-Diphospho-glucuronosyltransferases (UGTs)

Cited by 43 publications

References 37 publications

Rosuvastatin‐Induced Rhabdomyolysis – Possible Role of Ticagrelor and Patients’ Pharmacogenetic Profile

Rosuvastatin‐Induced Rhabdomyolysis – Possible Role of Ticagrelor and Patients’ Pharmacogenetic Profile

Comparison of Methods for Estimating Unbound Intracellular-to-Medium Concentration Ratios in Rat and Human Hepatocytes Using Statins

Comparison of the Predictability of Human Hepatic Clearance for Organic Anion Transporting Polypeptide Substrate Drugs Between Different In Vitro–In Vivo Extrapolation Approaches

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