Motrin
Metabolic inversion of (R)-ibuprofen. Epimerization and hydrolysis of ibuprofenyl-coenzyme A.

Tracy TS, Hall SD.

Department of Medicine, Indiana University School of Medicine, Wishard Memorial Hospital, Indianapolis 46202-2879.

Ibuprofen [(racemic)2-(4-isobutylphenyl)propionic acid] has been proposed but not directly demonstrated to undergo unidirectional inversion from the (R)- to the (S)-configuration via a coenzyme A (CoA) thioester intermediate. Chemically synthesized (R)- and (S)-ibuprofenyl-CoA, and rat and human liver homogenates were used to investigate the relative rates of ibuprofenyl-CoA epimerization and hydrolysis. Rat whole liver homogenate completely epimerized (R)- or (S)-ibuprofenyl-CoA, whereas hydrolysis of this intermediate occurred at a much slower rate. Rat liver mitochondria was the most efficient at both epimerizing and hydrolyzing ibuprofenyl-CoA, whereas rat liver microsomes hydrolyzed ibuprofenyl-CoA at a rate similar to whole liver homogenate but had very little epimerization activity. Rat liver cytosol was the poorest at hydrolyzing ibuprofenyl-CoA but had substantial epimerization capability. Whole liver homogenate from human tissue was less efficient at epimerizing but as efficient at hydrolyzing ibuprofenyl-CoA as rat whole liver homogenate. No stereoselectivity of either epimerization or hydrolysis was noted for any of the enzyme preparations studied. This study demonstrates that the inversion of (R)-ibuprofen occurs, at least in part, via the epimerization of the metabolic intermediate, ibuprofenyl-CoA, in both rat and human liver tissues.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1352228&dopt=Abstract ibuprofen Motrin



Motrin
Use of lipases in the resolution of racemic ibuprofen.

Mustranta A.

VTT, Biotechnical Laboratory, Espoo, Finland.

Resolution of (R,S)-ibuprofen enantiomers by esterification in different organic solvents was studied using Candida cylindracea lipase. This enzyme preparation had high enantiospecificity for S(+)-ibuprofen in the esterification reaction of a racemic ibuprofen with primary alcohols. The esterification yields of secondary alcohols were much lower than those of primary alcohols. Esterification with tertiary alcohols was not observed. The synthesis of esters was profoundly affected by the amount of water in the reaction mixture. C. cylindracea lipase was active only in very hydrophobic solvents. The esterification activity of the lipase was reduced significantly by addition of water. The R- and S-enantiomers of ibuprofen were determined without derivatization by HPLC using a chiral column.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1369010&dopt=Abstract ibuprofen Motrin



Motrin
Ibuprofen restores cellular immunity and decreases susceptibility to sepsis following hemorrhage.

Ertel W, Morrison MH, Meldrum DR, Ayala A, Chaudry IH.

Department of Surgery, Michigan State University, East Lansing 48824.

Although hemorrhage depresses splenocyte (SPL) functions and increases susceptibility to sepsis, it is not known whether increased tumor necrosis factor (TNF) or prostaglandin (PG) production are responsible for it. To study this, mice (C3H/HeN) were bled to a mean blood pressure of 35 mm Hg, maintained at that pressure for 60 min, resuscitated, and treated with ibuprofen (1.0 mg/kg body weight) or vehicle (saline). Hemorrhage reduced (P less than 0.05) SPL proliferation by 60%, SPL release of interleukin-2 (IL-2) by 47%, interferon-gamma (IFN-gamma) by 67%, TNF by 54%, and interleukin-6 (IL-6) by 46% compared to sham. In addition, splenic macrophage (sM phi) release of interleukin-1 (IL-1) and TNF was decreased by 58 and 67% (P less than 0.05), respectively. However, ibuprofen treatment increased (P less than 0.05) SPL proliferation, lymphokine (IL-2, IFN-gamma, and IL-6) synthesis, and IL-1 release by sM phi compared to hemorrhage alone. Furthermore, ibuprofen enhanced the release of TNF by SPL (+175%, P less than 0.05) and sM phi (+68%) compared to the vehicle group. Ibuprofen also decreased (P = 0.011) the susceptibility to sepsis following hemorrhage. These results indicate that PGs are involved in hemorrhage-induced suppression of cellular immunity and in the increased mortality of such animals following a septic challenge.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1405592&dopt=Abstract ibuprofen Motrin



Motrin
Anti-arthritic medication usage: United States, 1991.

[No authors listed]

In 1991, about 70.3 million prescriptions for nonsteroidal anti-inflammatory drugs (NSAIDs) were filled across the United States to treat arthritis and related musculoskeletal problems. The retail costs exceeded $2.2 billion in 1991 and were 6 percent higher than the costs in 1990 despite a 2.2 percent decrease in volume of prescriptions written. Per capita consumption averaged 278.6 prescriptions per 1,000 population with substantial variation by state. Kentucky led with 380.9 per 1,000 population and the District of Columbia had the lowest rate, 177.0. Ibuprofens were the most frequently prescribed class of NSAIDs, with Motrin capturing 20 percent of this generic class. Naproxen (Naprosyn) was the second most frequently prescribed class accounting for 19 percent of the NSAIDs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1411912&dopt=Abstract ibuprofen Motrin



Motrin
Ibuprofen abolishes the increase in leucocyte chemiluminescence observed during ischemic myocardial failure, but fails to improve hemodynamic function.

Ytrehus K, Semb AG, Myhre ES.

Institute of Medical Biology, University of Tromso, Norway.

The aim of the study was to evaluate 1) whether the ability of leucocytes to produce oxygen radicals was increased by ischemia and 2) if ibuprofen pretreatment could influence leucocyte oxygen radical production, hemodynamic function, and myocardial oxygen consumption during acute ischemic myocardial failure. We studied two groups of anesthetized dogs (control and ibuprofen-treated), both subjected to coronary embolization with polystyrene microspheres (diameter 50 microns). The embolization procedure was ended when left-ventricular end-diastolic pressure in both groups exceeded 20 mm Hg. Before and after induction of ischemia leucocytes were isolated and stimulated with opsonized zymosan, and oxygen radical production was measured using the luminol-dependent chemiluminescence technique. Significant increase occurred in oxygen radical production (from 10.9 +/- 2.2 to 16.3 +/- 2.3 x 10(5) counts x 10(6) cells-1 x 60 min-1) 90 min after failure in the control group, whereas in ibuprofen-pretreated dogs oxygen radical production was unchanged. Hemodynamic registrations and myocardial oxygen consumption 90 min after failure were, however, not significantly different in control dogs and dogs pretreated with ibuprofen. Thus, in the present study, within the first 90 min of acute ischemic failure, a decrease in the ability of leucocytes to produce oxygen radicals was not related to significant changes in myocardial function.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1417707&dopt=Abstract ibuprofen Motrin



Motrin
The effects of ibuprofen enantiomers on hepatocyte intermediary metabolism and mitochondrial respiration.

Knights KM, Drew R.

Dept of Clinical Pharmacology, School of Medicine, Flinders University of South Australia, Bedford Park.

In vivo and in vitro (-)R-ibuprofen is inverted to the (+)S antipode via stereoselective formation of an R-ibuprofenyl-CoA intermediate. In this study the effects of (-)R- and (+)S-ibuprofen on metabolism and respiration were studied using isolated rat hepatocytes and mitochondria. R-Ibuprofen significantly increased the lactate to pyruvate ratio, perturbed mitochondrial ketogenesis as evidenced by alterations in the beta-hydroxybutyrate to acetoacetate ratio and uncoupled mitochondrial oxidative phosphorylation. In addition, substantial dose- and time-dependent sequestration of reduced CoA (CoASH) occurred in the presence of the R enantiomer. Similarly, S-ibuprofen altered both the cytosolic and mitochondrial redox states although the magnitude of the effect was substantially less than that observed with the R enantiomer. In contrast to R-ibuprofen, S-ibuprofen did not uncouple oxidative phosphorylation or sequester hepatocyte CoASH. It is proposed that the perturbations observed in hepatocyte intermediary metabolism and mitochondrial function are attributable to a combination of the direct effects of R-ibuprofen per se and the sequestration of CoASH as R-ibuprofenyl-CoA during the process of chiral inversion. On the basis of these results, R-ibuprofen should be considered more in terms of metabolism to a reactive acyl-CoA intermediate rather than as a pro-drug for the pharmacologically active S-enantiomer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1417953&dopt=Abstract ibuprofen Motrin



Motrin
Influence of palmitate and benzoate on the unidirectional chiral inversion of ibuprofen in isolated rat hepatocytes.

Muller S, Mayer JM, Etter JC, Testa B.

Ecole de Pharmacie, Universite de Lausanne, Switzerland.

The influence of benzoic acid, a typical substrate of medium-chain acyl-CoA synthetase, and of palmitic acid, a substrate of long-chain acyl-CoA synthetase, on the metabolic chiral inversion of ibuprofen was investigated in freshly isolated hepatocytes. It was shown that the conjugation of benzoid to hippuric acid does not influence the chiral inversion of ibuprofen. In contrast, palmitic acid inhibited markedly the R-to-S inversion of ibuprofen. It was concluded that this inhibition is due to competition between (R)-ibuprofen and palmitic acid for long-chain acyl-CoA synthetases.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1417968&dopt=Abstract ibuprofen Motrin



Motrin
Effect of acetylsalicylic acid, ascorbate and ibuprofen on the macrophage system.

Hockertz S, Schettler T, Rogalla K.

Fraunhofer Institute of Toxicology, Hannover, Fed. Rep. of Germany.

The influence of ascorbic acid (CAS 50-81-7), acetylsalicylic acid (CAS 50-78-2) and ibuprofen (CAS 15687-27-1) on macrophages of C57BL/6 mice was investigated in vitro. It has been shown that ascorbic acid or acetylsalicylic acid alone did not stimulate or inhibit the production of interleukin-6, whereas a combination of both substances caused a significant stimulation. The viral replication in L929 fibroblasts was not affected by ascorbate and/or acetylsalicylic acid. In addition, the tumor-necrosis factor (TNF) synthesis of peritoneal macrophages was neither stimulated nor inhibited by both substances, alone or in combination. The oxygen radical production, however, was definitely inhibited by ascorbic acid, the effect of acetylsalicylic acid was far less marked, but at the high concentrations the inhibition was clearly discernible. Ibuprofen, a propionic acid derivate, was able to reduce the replication of vesicular stomatitis virus in L929 fibroblast cells. At the highest concentration of ibuprofen, 100 micrograms/ml, 34% of the fibroblast were able to survive. This protective effect declined as the ibuprofen concentration decreased. Ibuprofen could not stimulate peritoneal macrophages to secrete TNF, whereas the oxygen radical production was significantly reduced. In addition, ibuprofen activated mouse macrophages to produce interleukin-6 in a dose dependent way. The results of the in vitro experiments presented clearly show that ascorbic acid, acetylsalicylic acid in ibuprofen influenced the unspecific immune system.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1418082&dopt=Abstract ibuprofen Motrin