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Metabolic stereoisomeric inversion of ibuprofen in mammals.

Chen CS, Shieh WR, Lu PH, Harriman S, Chen CY.

Department of Pharmacognosy and Environmental Health Sciences, College of Pharmacy, University of Rhode Island, Kingston 02881.

Studies on the mechanism and enzymology of metabolic ibuprofen isomerization constituted the focus of this investigation. Comparative in vivo studies revealed that this biotransformation proceeded via a proton abstraction mechanism in all tested species of mammals, which is in agreement with the previous reports. Direct evidence supporting this conclusion stemmed from the in vitro epimerization of ibuprofen-CoA thioester in rat liver homogenates. Chemically synthesized (R)-ibuprofen-CoA thioester was rapidly transformed to its (S)-counterpart by subcellular hepatic preparations. Examination of this epimerase activity in various rat tissue homogenates indicated that this enzyme was highly tissue specific. This biochemical reaction mainly took place in the liver and kidney, whereas low levels of enzyme activity were associated with other tissues. Nevertheless, the liver and kidney homogenates failed to invert (R)-ibuprofen directly even in the presence of all the necessary cofactors. Presumably, the failure to characterize this bioconversion was due to the lack of enzymatic acyl-CoA synthesis in these homogenates. It is noteworthy that the '2-arylpropionyl-CoA epimerase' catalyzed the transformation from either direction and with high turnover rates. The catalytic efficiency of (S)-ibuprofen CoA epimerization appeared to be greater than that of the (R)-counterpart. These in vitro findings suggest that the step of acyl-CoA formation assume a pivotal role in controlling the stereoselectivity and efficiency of the in vivo metabolism. As the responsible acyl-CoA synthetase(s) in different species of animals may exert the reaction with different degrees of enantiomeric preference and efficiency, the resulting stereochemical outcome and metabolic rates of this bioinversion vary accordingly. Consequently, in guinea pigs, this biotransformation proceeds in both directions with nearly equal efficiency, whereas it is virtually unidirectional and slow in humans. Currently, the purification and characterization of this novel '2-arylpropionyl-CoA epimerase' from rat livers constitute the focus of this investigation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1859831&dopt=Abstract ibuprofen Motrin



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Sustained effects of endothelin-1 on rabbit, dog, and rat pulmonary circulations.

Barnard JW, Barman SA, Adkins WK, Longenecker GL, Taylor AE.

Department of Physiology, College of Medicine, University of South Alabama, Mobile 36688.

Effects of endothelin-1 (10(-8) M) on the pulmonary vascular resistance-compliance profile were examined in isolated blood-perfused rabbit, dog, and rat lungs using occlusion techniques. Capillary permeability was assessed by filtration coefficient (Kfc). Cyclooxygenase products were assessed by radioimmunoassay. In rabbit lungs, endothelin-1 increased all resistances except large vein; ibuprofen reversed the constriction. Endothelin-1 decreased total vascular compliance (CT), which was reversed by ibuprofen. Cyclooxygenase products were unchanged by endothelin-1 or endothelin-1 plus ibuprofen. In dog lungs, large vein resistance increased after endothelin-1; ibuprofen increased large arterial resistance. Endothelin-1 decreased CT and middle compartment compliance, and endothelin-1 plus ibuprofen decreased large vessel compliance (CLV). Ibuprofen reversed the endothelin-1 increase in plasma 6-oxo-prostaglandin F1 alpha. In rat lungs, ibuprofen reversed the endothelin-1 increase in small arterial resistance. Endothelin-1 decreased CLV, and endothelin-1 plus ibuprofen returned the compliance to baseline values. Ibuprofen potentiated the endothelin-1 increase in plasma prostanoids. Endothelin-1 plus indomethacin increased vascular resistance and blocked prostaglandin production. Kfc was increased only in rat lung after endothelin-1 plus ibuprofen. In summary, endothelin-1 increased pulmonary vascular resistance, which was attenuated by prostacyclin in dogs and rats. In rabbits, the resistance increase was reversed by ibuprofen.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1877674&dopt=Abstract ibuprofen Motrin



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Renal handling and effects of S(+)-ibuprofen and R(-)-ibuprofen in the rat isolated perfused kidney.

Cox PG, Moons WM, Russel FG, van Ginneken CA.

Department of Pharmacology, University of Nijmegen, The Netherlands.

1. The renal handling and effects of S(+)- and R(-)-ibuprofen have been studied in the isolated perfused kidney (IPK) of the rat. 2. Both ibuprofen enantiomers were extensively reabsorbed and accumulated in the kidney in a concentration-dependent manner. No pharmacokinetic differences were observed between the two enantiomers. 3. S(+)-ibuprofen concentrations ranging from 0.25 to 25 micrograms ml-1 (1.2 to 120 microM) caused a decrease in urinary flow, glomerular filtration rate (GFR) and electrolyte excretion. Urinary pH and excretion of glucose were not influenced. R(-)-ibuprofen concentrations ranging from 2.5 to 25 micrograms ml-1 (12 to 120 microM) also decreased urinary flow and electrolyte excretion. This decrease, however, was less than observed with S(+)-ibuprofen. GFR, urinary pH and glucose excretion were not affected by R(-)-ibuprofen. Prostaglandin E2 (PGE2) concentrations of 133 ng ml-1 reversed the effects on renal function of both enantiomers. 4. Very high S(+)- and R(-)-ibuprofen concentrations (greater than 400 micrograms ml-1) resulted in an increase in urinary flow and fractional excretion of sodium, chloride, potassium, glucose and calcium. 5. It is concluded that the pharmacokinetic behaviour of ibuprofen in the kidney is not stereoselective. Relatively high concentrations of both enantiomers increased the urinary flow and electrolyte excretion in a nonstereoselective manner. Lower concentrations of S(+)-ibuprofen decreased urinary flow and electrolyte excretion. The pharmacologically inactive R(-)-ibuprofen was also able to affect renal function in a similar way, but at different concentrations. These effects on renal function are probably caused by inhibition of PGE2 synthesis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1884108&dopt=Abstract ibuprofen Motrin



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Determination of the epimeric composition of ibuprofenyl-CoA.

Tracy TS, Hall SD.

Department of Medicine, Indiana University School of Medicine, Wishard Memorial Hospital, Indianapolis 46202.

Ibuprofen [racemic2-(4-isobutylphenyl)propionic acid] is a 2-arylpropionic acid nonsteroidal anti-inflammatory drug which undergoes unidirectional, R to S chiral inversion in vivo. It has been proposed that this chiral inversion phenomenon occurs via a coenzyme A (CoA) thioester intermediate. To characterize the formation and metabolism of this metabolic intermediate, ibuprofenyl-CoA, reference standards were needed and thus the CoA derivatives of (R)-, (S)-, and racemic ibuprofen were chemically synthesized. An HPLC assay employing a C18 reverse-phase column was developed to quantitate "total" ibuprofenyl CoA. Samples collected from this assay were then analyzed for ibuprofenyl-CoA epimeric composition by chiral chromatography employing a Chiral-AGP alpha 1-acid glycoprotein column. The applicability of these methods was demonstrated by assessing (R)- and (S)-ibuprofenyl-CoA hydrolysis and epimerization following incubation with rat liver homogenates. Rat liver homogenate catalyzed the complete and rapid epimerization of ibuprofenyl-CoA and the rate constants for (R)- and (S)-ibuprofenyl-CoA hydrolysis were equal. ATP and CoA were found to inhibit rat liver-catalyzed ibuprofenyl-CoA hydrolysis by 70-80% with no effect on epimerization. Additionally, it was demonstrated that traditional indirect ibuprofenyl-CoA assays which employ basic hydrolysis result in erroneous epimeric ratio determinations due to chemical epimerization.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1888016&dopt=Abstract ibuprofen Motrin



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Investigations of ibuprofen and paracetamol binding to lens proteins to explore their protective role against cataract.

Shyadehi AZ, Harding JJ.

Nuffield Laboratory of Ophthalmology, Oxford University, U.K.

There is evidence that ibuprofen and paracetamol can act as anti-cataract drugs. [14C]-Ibuprofen labelled at the methyl group of the propanoic acid moiety was synthesized. The labelled ibuprofen was found to bind non-covalently to alpha-crystallin but not to beta- and gamma-crystallin of the bovine lens. Labelled paracetamol binds to total lens soluble proteins. Both drugs penetrate into the lens cortex and nucleus within 24 hr. Affinity chromatographic studies suggest that the lipophilic isobutyl group of ibuprofen hinders binding to the lens proteins. Hence, in the light of weak binding of ibuprofen and paracetamol and strong binding of the ibuprofen analogue used in the affinity chromatography, it is suggested, in this paper, that the protection against cataract by these analgesics is possibly due to their metabolites interacting with the lens proteins.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1958225&dopt=Abstract ibuprofen Motrin



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Pharmacologic reduction in tumor necrosis factor activity of pulmonary alveolar macrophages.

Leeper-Woodford SK, Fisher BJ, Sugerman HJ, Fowler AA 3rd.

Department of Medicine, Virginia Commonwealth University/Medical College of Virginia, Richmond.

Tumor necrosis factor-alpha (TNF), an inflammatory cytokine released by macrophages, may be a mediator of lung injury during septicemia. We previously reported that the cyclooxygenase inhibitor ibuprofen and histamine receptor antagonists cimetidine (H2 antagonist) and diphenhydramine (H1 antagonist) attenuate lung injury and reduce circulating TNF surges during porcine sepsis. Since pulmonary alveolar macrophages (PAM) may participate in early sepsis by producing TNF, we hypothesized that the TNF activity of PAM is reduced by ibuprofen, cimetidine, and diphenhydramine. To test this, we examined changes in PAM-derived TNF bioactivity and cell viability of freshly isolated porcine PAM during exposure to bacterial endotoxin (LPS), ibuprofen, cimetidine, and diphenhydramine. The TNF activity (% L929 cytotoxicity of PAM conditioned medium) was elevated in LPS-stimulated PAM cultures (15 to 25% increase at 1 to 6 h and 40 to 43% increase at 6 to 48 h, compared with non-LPS-stimulated cultures), and ibuprofen (150 micrograms/ml) added with LPS decreased the TNF activity for 24 h (20 to 28% reduction at 1 to 24 h). Ibuprofen added 1 h after LPS was less effective in reducing the PAM-derived TNF activity (20 to 22% reduction at 2 to 6 h). Cimetidine (112 micrograms/ml) reduced the TNF activity of LPS-stimulated PAM cultures during the first 4 h of LPS exposure (15 to 24% decrease at 1 to 4 h). Diphenhydramine (150 micrograms/ml) attenuated the PAM-derived TNF activity but also decreased viability of PAM, indicating a toxic effect of this agent on PAM.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8093999&dopt=Abstract ibuprofen Motrin



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Metabolic inversion of (R)-ibuprofen. Formation of ibuprofenyl-coenzyme A.

Tracy TS, Wirthwein DP, Hall SD.

Department of Medicine, Indiana University School of Medicine, Wishard Memorial Hospital.

Ibuprofen [(racemic)2-(4-isobutylphenyl)propionic acid] undergoes metabolic inversion via formation, epimerization, and hydrolysis of the coenzyme A (CoA) thioester, ibuprofenyl-CoA. In this study, (R)-ibuprofen was incubated with either rat whole liver homogenate, human whole liver homogenate, rat liver mitochondria, or rat liver microsomes, and the formation of ibuprofenyl-CoA measured. Rat whole liver homogenate (Vmax/KM = 0.022 +/- 0.005 ml/min/mg protein) was approximately 4-fold more efficient at forming ibuprofenyl-CoA than human whole liver homogenate (Vmax/KM, = 0.005 +/- 0.004 ml/min/mg protein). Rat liver microsomes (Vmax/KM = 0.047 +/- 0.019 ml/min/mg protein) were approximately 2-fold more efficient than rat whole liver homogenate at forming ibuprofenyl-CoA, whereas rat liver mitochondria (Vmax/KM = 0.027 +/- 0.017 ml/min/mg protein) did not differ from whole liver homogenate. Palmitic (Ki = 0.005 mM) and octanoic acids (Ki = 0.19 mM) were capable of inhibiting ibuprofenyl-CoA formation, whereas propionic acid had no effect, suggesting the possible involvement of both long- and medium-chain fatty acyl-CoA synthetases. Of the xenobiotics tested, only bezafibrate (Ki = 0.85 mM) and (S)-ibuprofen (Ki = 0.095 mM in rats, 0.32 mM in human tissue) were capable of substantially inhibiting ibuprofenyl-CoA formation. Thus, it appears that the metabolic inversion of ibuprofen involves lipid-metabolizing pathways and may be affected by fatty acids or xenobiotics.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8095203&dopt=Abstract ibuprofen Motrin



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Stereochemical aspects of the molecular pharmaceutics of ibuprofen.

Romero AJ, Rhodes CT.

University of Rhode Island, Department of Pharmaceutics, Kingston 02881.

Thermal analysis, thermodynamics of solution and molecular modelling of (+)-ibuprofen and (+/-)-ibuprofen gave information on how heterochiral or homochiral interactions would affect the processing of ibuprofen. The study confirmed that (+/-)-ibuprofen exists as a true racemate with a 10% eutectic pure enantiomer composition. Both the racemate and the (+)-isomer crystal unit cells include four molecules and crystallize in the P2(1/c) and P2(1) space groups, respectively. Thus the intermolecular forces were different in each crystal. As a consequence the (+)-enantiomer lattice was more fragile but only slightly more soluble than the racemate in aqueous media. The solid-state structure contributions to solubility were different for the two crystals (delta H (+) = 51.1 and delta H(+/-) = 32.2 kJ mol-1) but the standard free energies of the solutions were comparable for both compounds.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8098364&dopt=Abstract ibuprofen Motrin