Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization.

@article{Prueksaritanont2002GlucuronidationOS,
  title={Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization.},
  author={Thomayant Prueksaritanont and Raju Subramanian and Xiaojun Fang and Bennett Ma and Yue Qiu and Jiunn Huei Lin and Paul G. Pearson and Thomas A. Baillie},
  journal={Drug metabolism and disposition: the biological fate of chemicals},
  year={2002},
  volume={30 5},
  pages={
          505-12
        }
}
The active forms of all marketed hydroxymethylglutaryl (HMG)-CoA reductase inhibitors share a common dihydroxy heptanoic or heptenoic acid side chain. In this study, we present evidence for the formation of acyl glucuronide conjugates of the hydroxy acid forms of simvastatin (SVA), atorvastatin (AVA), and cerivastatin (CVA) in rat, dog, and human liver preparations in vitro and for the excretion of the acyl glucuronide of SVA in dog bile and urine. Upon incubation of each statin (SVA, CVA or… Expand
Metabolic fate of pitavastatin, a new inhibitor of HMG-CoA reductase: similarities and difference in the metabolism of pitavastatin in monkeys and humans
TLDR
Overall metabolism is different compared with humans owing to the extensive oxidative metabolism of pitavastatin and its lactone in monkey, and results implied that lactonization is a common pathway for drugs such as 5-hydroxy pentanoic acid derivatives. Expand
ACYL-COENZYME A FORMATION OF SIMVASTATIN IN MOUSE LIVER PREPARATIONS
TLDR
Results provide direct experimental evidence that SVA (and conceivably other statins as well) is able to form an acyl-CoA thioester, possibly by microsomal long-chain acyl CoA synthetase(s), leading to formation of two parallel metabolic pathways. Expand
Effects of fibrates on metabolism of statins in human hepatocytes.
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The results suggest that there is a potential difference between fibrates in their ability to affect the pharmacokinetics of statins, and among statins in their susceptibility to metabolic interactions with GFZ in humans. Expand
Atorvastatin Glucuronidation Is Minimally and Nonselectively Inhibited by the Fibrates Gemfibrozil, Fenofibrate, and Fenofibric Acid
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Based on unbound fibrate concentrations at the inlet to the liver, these data predict a small increase in atorvastatin AUC (∼1.2-fold) after gemfibrozil coadministration and no interaction with fenofibrate. Expand
Generation of Human Chiral Metabolites of Simvastatin and Lovastatin by Bacterial CYP102A1 Mutants
TLDR
It is demonstrated that CYP102A1 mutants can be used to produce human metabolites, especially chiral metabolites, of simvastatin and lovastatin, which are used to treat hyperlipidemia and hypercholesterolemia. Expand
Comparative Hepatic and Intestinal Metabolism and Pharmacodynamics of Statins
TLDR
Compared with in vitro drug transporter and clinical data, the findings are applicable for use in comparative systems pharmacology modelling to predict the pharmacokinetics and pharmacological effects of statins at different dosages. Expand
Metabolic properties of the acid and lactone forms of HMG-CoA reductase inhibitors
TLDR
It is demonstrated that CYP-mediated metabolism of lactones is also a common metabolic pathway for statins and that the CYP3A4- mediated metabolism of the lactone forms clearly will need to be taken into account in assessing mechanistic aspects of drug–drug interaction involving statins. Expand
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Neither the acute cellular injury nor glucuronidation-driven irreversible protein binding in vitro is predictive of the drug-induced hepatopathy. Expand
Rosuvastatin: a new inhibitor of HMG-CoA reductase for the treatment of dyslipidemia
  • R. Rosenson
  • Medicine
  • Expert review of cardiovascular therapy
  • 2003
TLDR
Rosuvastatin has the longest terminal half-life of the statins and is only minimally metabolized by the cytochrome P450 (CYP 450) enzyme system with no significant involvement of the 3A4 enzyme and the absence of clinically significant drug interactions between rosuvastatin and other drugs known to inhibit CYP 450 enzymes. Expand
P-glycoprotein Has Differential Effects on the Disposition of Statin Acid and Lactone Forms in mdr1a/b Knockout and Wild-Type Mice
TLDR
It is suggested that mouse P-glycoprotein does not affect the lactone-acid interconversion or liver-plasma distribution, and P- glycoprotein plays a limited role in restricting the brain penetration of the acid forms of atorvastatin, pravastsatin, simvastAT, lovastatin and atorVastatin lactone. Expand
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