Structural Characterization of in Vivo Rat Glutathione Adducts and a Hydroxylated Metabolite of Simvastatin Hydroxy Acid

Subramanian, Raju; Fang, Xiaojun; Prueksaritanont, Thomayant

doi:10.1124/dmd.30.3.225

Cited by 10 publications

(7 citation statements)

References 8 publications

(10 reference statements)

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“…There is a major early eluting unidentified radioactive peak in both chromatograms from the previously referenced studies which is devoid of UV absorbance at 238 nm (lmax of SV) or 239 nm, consistent with the loss of the diene chromophore. In addition, no pharmacological activity was observed by Cheng [5] for this early eluting metabolite which again is consistent with the findings for the dihydrotriol [17]. The minor metabolite, 6'b-hydroxymethyl-SVA reported by Vickers [7] was not observed in our study but this metabolite may have been metabolized further in our subjects to 6'b-COOH-SVA [18].…”

Section: Figuresupporting

confidence: 92%

Use of Entero‐Test, a simple approach for non‐invasive clinical evaluation of the biliary disposition of drugs

Guiney

Beaumont

Thomas

et al. 2011

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THE SUBJECT• Biliary secretion is often a major route of elimination of drugs and metabolites. Knowledge of the biliary disposition of a drug in man is important in understanding the contribution of this route to overall clearance and the potential for drug-drug interactions which may have clinical consequences. • Current methods for collecting human bile as part of drug disposition studies are invasive and complex, requiring intubation of the duodenum. As a result, limited data exist regarding the biliary elimination of many drugs and their metabolites. WHAT THIS STUDY ADDS• This proof of utility study clearly demonstrates that bile samples for drug and metabolite analysis can be collected simply, safely and cost-effectively from subjects using non-invasive technology.• Using such technology, the biliary disposition of simvastatin was evaluated successfully in healthy subjects. Qualitative metabolite data compared favourably with reported biliary data derived from intubated patients dosed with radiolabelled simvastatin.• This technique has substantial utility for early clinical evaluation of biliary disposition of drugs. AIMTo evaluate the non-invasive collection of bile from healthy human subjects for the qualitative characterization of the biliary disposition of a drug, using spectrometric techniques. METHODSTwenty subjects underwent non-invasive bile capture using a peroral string test (Entero-Test) device prior to and following a single oral dose of simvastatin (80 mg). The device, consisting of a weighted gelatin capsule containing a highly absorbent nylon string, was swallowed by each subject with the proximal end of the string taped to the face. Once the weighted string was judged to have reached the duodenum, gallbladder contraction was stimulated in order to release bile. The string was then retrieved via the mouth, and bile samples were analysed for drug-related material using spectrometric and spectroscopic techniques following solvent extraction. RESULTSNumerous metabolites of simvastatin were detected, and the major metabolites were consistent with those reported from studies where bile was collected using invasive techniques from patients dosed with [ 14 C]-simvastatin. CONCLUSIONSThe results from this study demonstrate the utility of deploying the Entero-Test in human studies to provide structural information on biliary metabolites. This can be readily applied in drug development studies, including those in the target patient population and may eliminate the need for more invasive sampling techniques.

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Section: Figuresupporting

confidence: 92%

Use of Entero‐Test, a simple approach for non‐invasive clinical evaluation of the biliary disposition of drugs

Guiney

Beaumont

Thomas

et al. 2011

Brit J Clinical Pharma

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“…1), all of which have been identified previously as notable metabolites in dog bile (Vickers et al, 1990a,b;Subramanian et al, 2002). An O-glucuronidated SVA metabolite (M4) was also identified, but …”

Section: Resultsmentioning

confidence: 99%

Use of the Entero-Test, a Novel Approach for the Noninvasive Capture of Biliary Metabolites in Dogs

Guiney

Beaumont²,

Thomas³

2010

Drug Metab Dispos

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ABSTRACT:Preclinical information on the biliary metabolites of a drug candidate is typically obtained through the collection of bile after surgical cannulation of the bile duct. In this study, we describe a novel approach using the Entero-Test, a simple device that facilitates the noninvasive sampling of duodenal bile. The Entero-Test was used to collect bile from six fasted dogs that had been dosed either orally with simvastatin (SV) or intravenously with simvastatin hydroxy acid (SVA), compounds that have been previously reported to undergo extensive metabolism and biliary secretion in the dog. The devices, consisting of a weighted gelatin capsule containing 90 cm of a highly absorbent nylon string, were swallowed by each dog with the proximal end of the string taped to the animal's face. Once the weighted string had reached the duodenum, gallbladder contraction was stimulated to release bile. Each bile-stained string was then retrieved via the mouth and, after solvent extraction, samples were analyzed for drug-related material by ultraperformance liquid chromatography-mass spectrometry and NMR spectroscopy. Numerous metabolites of SV and SVA were observed, and, in general, the major metabolites have been reported previously from studies with bile duct-cannulated animals dosed with

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“…Statins are converted to lactones from statin acids. Lactones are produced by uridine 5′-diphospho-glucuronosyltransferases, and may be responsible for the cytotoxic effects of statins [ 81 ]. Recently a comprehensive study investigated the effect of seven different statins on C2C12 myoblast cell lines [ 82 ].…”

Section: Statin-associated Muscle Symptomsmentioning

confidence: 99%

Statins, Muscle Disease and Mitochondria

Ramachandran

Wierzbicki

2017

JCM

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Cardiovascular disease (CVD) accounts for >17 million deaths globally every year, and this figure is predicted to rise to >23 million by 2030. Numerous studies have explored the relationship between cholesterol and CVD and there is now consensus that dyslipidaemia is a causal factor in the pathogenesis of atherosclerosis. Statins have become the cornerstone of the management of dyslipidaemia. Statins have proved to have a very good safety profile. The risk of adverse events is small compared to the benefits. Nevertheless, the potential risk of an adverse event occurring must be considered when prescribing and monitoring statin therapy to individual patients. Statin-associated muscle disease (SAMS) is by far the most studied and the most common reason for discontinuation of therapy. The reported incidence varies greatly, ranging between 5% and 29%. Milder disease is common and the more serious form, rhabdomyolysis is far rarer with an incidence of approximately 1 in 10,000. The pathophysiology of, and mechanisms leading to SAMS, are yet to be fully understood. Literature points towards statin-induced mitochondrial dysfunction as the most likely cause of SAMS. However, the exact processes leading to mitochondrial dysfunction are not yet fully understood. This paper details some of the different aetiological hypotheses put forward, focussing particularly on those related to mitochondrial dysfunction.

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Structural Characterization of in Vivo Rat Glutathione Adducts and a Hydroxylated Metabolite of Simvastatin Hydroxy Acid

Cited by 10 publications

References 8 publications

Use of Entero‐Test, a simple approach for non‐invasive clinical evaluation of the biliary disposition of drugs

Use of Entero‐Test, a simple approach for non‐invasive clinical evaluation of the biliary disposition of drugs

Use of the Entero-Test, a Novel Approach for the Noninvasive Capture of Biliary Metabolites in Dogs

Statins, Muscle Disease and Mitochondria

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