Stereoselective metabolic pathways of ketoprofen in the rat: Incorporation into triacylglycerols and enantiomeric inversion

Carabaza, Assumpta; Suesa, Nuria; Tost, Digna; Pascual, Jordi Alberich; Gómez, Manel; Gutiérrez, M.T.; Ortega, Elvira; Montserrat, Xavier; García, Antonio Abellán; Mis, R.; Cabré, Francesc; Mauleón, David; Carganico, Germano

doi:10.1002/(sici)1520-636x(1996)8:2<163::aid-chir1>3.0.co;2-k

Cited by 24 publications

(7 citation statements)

References 29 publications

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“…In most therapeutic preparations ketoprofen exists as a racemic mixture, despite the S-enantiomer alone being responsible for the inhibition of prostaglandin synthesis (Hayball et al 1992;Suesa et al 1993). Stereospecific protein binding (Dubois et al 1993;Sakai et al 1996;Zhivkova & Russeva 1998) and liver metabolism (Carabaza et al 1996) have been reported for ketoprofen, but the ability of the enantiomers to alter the renal secretion of other compounds has not been examined. If the R-enantiomer of ketoprofen was an inhibitor of the renal tubular secretion of methotrexate, this would represent an example of the administration of an inactive enantiomer, as part of a racemic mixture, contributing to a clinically significant drug±drug interaction.…”

Section: Introductionmentioning

confidence: 99%

Effect of ketoprofen and its enantiomers on the renal disposition of methotrexate in the isolated perfused rat kidney

Karpf

Kirkegaard

Evans

et al. 2003

Journal of Pharmacy and Pharmacology

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Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit the renal tubular secretion of methotrexate. However, the relative contribution of the active S- and inactive R-enantiomers is unknown. This study examined the effect of racemic ketoprofen and its enantiomers on the renal disposition of methotrexate in the isolated perfused rat kidney (IPK). Nineteen kidneys were divided between a control and three treatment groups. Controls were perfused with methotrexate alone (25 micrograms mL-1, n = 5) over three 30-min periods. Treatment groups were perfused with methotrexate (25 micrograms m-1) for the first period, followed by a second period of methotrexate (25 micrograms mL-1) plus R- (n = 5), S- (n = 5) or RS-ketoprofen (n = 4) at 25 micrograms mL-1, and a third period of methotrexate (25 micrograms mL-1) plus R-, S- or RS-ketoprofen (50 micrograms mL-1). Perfusate and urine were collected over 10-min intervals. Methotrexate was measured by HPLC and its binding in perfusate by ultrafiltration. The clearance ratio (CR) for methotrexate was obtained by dividing the renal clearance by the product of its fraction unbound and the glomerular filtration rate. During control experiments, there was no significant change in the CR over 90 min. R-, S- and RS-ketoprofen at 50 micrograms mL-1 reduced the CR of methotrexate significantly, but there was no difference between the three groups. While the enantiomers of ketoprofen reduced the renal excretion of methotrexate, the interaction was not enantioselective.

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Section: Introductionmentioning

confidence: 99%

Effect of ketoprofen and its enantiomers on the renal disposition of methotrexate in the isolated perfused rat kidney

Karpf

Kirkegaard

Evans

et al. 2003

Journal of Pharmacy and Pharmacology

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“…Then we tried Carabaza et al's method26: oxalyl chloride was added to a solution of MA in methylene chloride, the solution was stirred for 1 h under an argon atmosphere and then evaporated to an oily residue with a stream of argon. The residue was added dropwise into a stirred solution of sodium Coenzyme A in H 2 O adjusted to pH 8.9 with 0.5 M NaOH.…”

Section: Discussionmentioning

confidence: 99%

Study on the metabolic mechanism of chiral inversion of S‐Mandelic acid in vitro

et al. 2011

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Mandelic acid (MA) is generally used as a biological indicator of occupational exposure to styrene, which is classified as a class of hazardous environmental pollutants. It was found to undergo one-directional chiral inversion (S-MA to R-MA) in Wistar and Sprague-Dawley rats in vivo. This study was aimed to explore the metabolic mechanism of chiral inversion of S-MA in vitro. S-MA was converted to R-MA in rat hepatocytes, whereas MA enantiomers remained unchanged in acidic and neutral phosphate buffers, HepG2 cells, and intestinal flora. In addition, the synthesized S-MA-CoA thioester was rapidly racemized and hydrolyzed to R-MA by rat liver homogenate and S9, cytosolic and mitochondrial fractions. The data suggest that chiral inversion of S-MA may involve the hydrolysis of S-MA-CoA, and its metabolic mechanism could be the same as that of 2-arylpropionic acid (2-APA) drugs.

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“…This was shown for R-fenoprofen, which was incorporated into glycerolipids in vivo and in vitro by both hepatocytes and adipocytes but was not the seen for the S-enantiomer [50][51][52]. In addition to fenoprofen this stereospecific incorporation of profens such as e.g., ibuprofen [53] and ketoprofen [54] seems to be selective for the R-form and can lead to the accumulation of these metabolites in tissue. It would also seem that e.g., the R-, but not the S-enantiomer of fenoprofen was responsible for the stereospecific inhibition of triacylglycerol biosynthesis in isolated rat hepatocytes and adipocytes [52].…”

Section: Hybrid Triglyceride Formationmentioning

confidence: 93%

Minimizing the DILI potential of carboxylic acid-containing drugs: a perspective

Weidolf,

Wilson

2023

Med Chem Res

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Drugs containing carboxylic acid moieties are associated with a range of toxicities, some related directly to their pharmacology and others to the metabolites that they produce on undergoing biotransformations that reduce biological activity and enhance excretion. The reactions involved in metabolism include a wide range of conjugations to the carboxylic acid moiety plus modifications to the spacers used to attach them to the main body of the drug. Here we provide a metabolic perspective on the biotransformations that have been found to occur with drugs that contain a carboxylic acid and discuss the potential of these to cause toxicity. Based on our current understanding of the metabolism of carboxylic acid-containing drugs we then consider approaches that may mitigate toxicity.

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Stereoselective metabolic pathways of ketoprofen in the rat: Incorporation into triacylglycerols and enantiomeric inversion

Cited by 24 publications

References 29 publications

Effect of ketoprofen and its enantiomers on the renal disposition of methotrexate in the isolated perfused rat kidney

Effect of ketoprofen and its enantiomers on the renal disposition of methotrexate in the isolated perfused rat kidney

Study on the metabolic mechanism of chiral inversion of S‐Mandelic acid in vitro

Minimizing the DILI potential of carboxylic acid-containing drugs: a perspective

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