Impaired intrinsic chiral inversion activity of ibuprofen in rats with adjuvant-induced arthritis

Uno, Satoshi; Uraki, Misato; Kono, Hiroshi; Ikuta, Hiroyuki; Kawase, Atsushi; Iwaki, Masaya

doi:10.1080/00498250802483768

Cited by 3 publications

(1 citation statement)

References 33 publications

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“…Ibuprofen (IB) as a model compound of 2-APA undergoes unidirectional chiral inversion of the inactive R-enantiomer to the active S-enantiomer in rats (Kaiser et al, 1976). We previously demonstrated that the intrinsic chiral inversion rate constant of IB and the metabolic degradation rate constants decreased in AA rats compared with those of control rats in freshly isolated rat hepatocytes (Uno et al, 2008). This in vivo study was carried out to clarify the effects of AA inflammation on the stereoselective pharmacokinetics of R-IB and S-IB and chiral inversion of IB after intravenous administration to rats.…”

Section: Introductionmentioning

confidence: 99%

Stereoselective Pharmacokinetics and Chiral Inversion of Ibuprofen in Adjuvant-induced Arthritic Rats

2016

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2-Arylpropionic acid (2-APA) nonsteroidal anti-inflammatory drugs are commonly used in racemic mixtures () for clinical use. 2-APA undergoes unidirectional chiral inversion of the in vivo inactive -enantiomer to the active-enantiomer. Inflammation causes the reduction of metabolic activities of drug-metabolizing enzymes such as cytochrome P450 (P450) and UDP-glucuronosyltransferase. However, it is unclear whether inflammation affects the stereoselective pharmacokinetics and chiral inversion of 2-APA such as ibuprofen (IB). We examined the effects of inflammation on the pharmacokinetics of -IB and-IB after intravenous administration of -IB,-IB, and -IB to adjuvant-induced arthritic (AA) rats, an animal model of inflammation. The plasma protein binding of-IB, glucuronidation activities for -IB and-IB, and P450 contents of liver microsomes in AA rats were determined. Total clearance (CL) of IB significantly increased in AA rats, although the glucuronidation activities for IB, and P450 contents of liver microsomes decreased in AA rats. We presumed that the increased CL of IB in AA rats was caused by the elevated plasma unbound fraction of IB due to decreased plasma albumin levels in AA rats. Notably, CL of -IB but not-IB significantly increased in AA rats after intravenous administration of -IB. These results suggested that AA could affect drug efficacies after stereoselective changes in the pharmacokinetics of-IB and -IB.

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Section: Introductionmentioning

confidence: 99%

Stereoselective Pharmacokinetics and Chiral Inversion of Ibuprofen in Adjuvant-induced Arthritic Rats

2016

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In Vitro Liver Systems to Study Induction/Inhibition: Prediction of In Vivo Metabolism and Drug–Drug Interactions

Kono

Iwaki

2012

Encyclopedia of Drug Metabolism and Interactions

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This chapter was the review focused on the evaluation systems for metabolic stability, CYP inhibition and induction not only in the selection process of development candidates including lead optimizations in drug discovery but also to support a design of clinical studies in drug development. In the former process, the advanced in vitro systems have been developed, associating with an inevitable paradigm shift from the throughput to the quality. The similar trend has been gradually transmitted to the prediction of clearance and DDI. The predictions appeared to be in the movement from the basic models to the more mechanistic models including PBPK.

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Stereoselective hepatic disposition of ibuprofen in the perfused liver of rat with adjuvant-induced arthritis

2016

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1. The effects of adjuvant-induced arthritis (AA) on the stereoselective hepatic disposition and chiral inversion of "profens" have scarcely been investigated. Ibuprofen (IB) undergoes unidirectional chiral inversion from R-IB to S-IB and is metabolized to IB-glucuronide (IB-Glu). 2. We used an in situ perfused rat liver system to clarify the effects of inflammation on the metabolic activities and chiral inversion of IB without protein binding. 3. After dosing of R-IB, AA had minimal effect on the elimination of R-IB from the perfusate. Larger amounts of S-IB-Glu than R-IB-Glu were observed in the bile at the dose of 2.4 and 4.8 μmol. However, after dosing of S-IB, the elimination of S-IB from the perfusate in AA rats was delayed, indicating a significant decrease in the hepatic clearance in AA rats. The cumulative biliary excretion of S-IB-Glu in AA rats was promoted after dosing with S-IB. There was little difference between the chiral inversion ratios of the control and AA rats. 4. The present study demonstrated that AA results in the delayed elimination of S-IB, the active form, without changes to the chiral inversion ratio. Thus, further attention to the altered stereoselective pharmacokinetics of IB during inflammation is required.

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Impaired intrinsic chiral inversion activity of ibuprofen in rats with adjuvant-induced arthritis

Cited by 3 publications

References 33 publications

Stereoselective Pharmacokinetics and Chiral Inversion of Ibuprofen in Adjuvant-induced Arthritic Rats

Stereoselective Pharmacokinetics and Chiral Inversion of Ibuprofen in Adjuvant-induced Arthritic Rats

In Vitro Liver Systems to Study Induction/Inhibition: Prediction of In Vivo Metabolism and Drug–Drug Interactions

Stereoselective hepatic disposition of ibuprofen in the perfused liver of rat with adjuvant-induced arthritis

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