Clofibric acid increases the undirectional chiral inversion of ibuprofen in rat liver preparations.

1. The formation of (S)-ibuprofen from (R)-ibuprofen was monitored in perfused rat livers and in rat hepatocytes and the rate constants calculated. 2. Pre-treatment of animals for three days with clofibric acid markedly increased the (R)-to-(S) inversion of ibuprofen in both preparations. In contrast, clofibric acid did not elicit such a reaction with flurbiprofen, an analogue that does not undergo inversion under control conditions. 3. An increase in the chiral inversion was also seen when clofibric acid was added to the perfusion medium or to hepatocyte suspensions. In the latter system this increase was shown to be concentration dependent. 4. Pre-treatment of rat combined with addition of clofibric acid to the perfusion medium produced a cumulative stimulation of (R)-to-(S) inversion of ibuprofen. 5. Clofibric acid added to hepatocyte suspensions transiently increased intracellular concentrations of coenzyme A whereas (R)-ibuprofen transiently decreased CoA concentrations. The two effects cancelled each other upon co-incubation of the two compounds. 6. It is postulated that the metabolic interaction observed between clofibric acid and (R)-ibuprofen may be due to changes in intracellular concentrations of CoA.

Interactions of anti-inflammatory 2-arylpropionates (profens) with the metabolism of fatty acids: in vitro studies.

This review shows conclusively that profens can enter physiological pathways of lipid biochemistry. The first step in this interaction is the formation of an acyl-CoA thioester. These conjugates can lead to the incorporation of the xenobiotic acid into lipids. The resulting hybrid triglycerides have the potential to form long-lasting residues in adipose tissues and to be incorporated into membranes. Furthermore, the acyl-CoA conjugate may also alter lipid biochemistry by inhibiting lipid beta-oxidation either by interfering with the acyl-CoA synthetases or by modifying CoA levels. Thus, the acyl-CoA conjugates of profens intermediates in the inversion of inactive (R)-profens to active (S)-profens can be viewed as pivotal to bioactivation and to pathways of potential toxicity.

Development of an ocular irritation test in the mouse: image analysis of corneal lesions.

An ocular irritation test in the mouse has been developed, in which corneal lesions consecutive to instillation of ophthalmic preparations are assessed by digital image processing. The high sensitivity of this method makes it possible to test very low (i.e. therapeutic) concentrations, which do not produce macroscopic damage to the eye. The relatively low variability of the results allows the determination of irritation potential with a small number of animals. The test permits the establishment of the relationship between instilled concentrations and corneal lesions. The rapidity and simplicity of this approach make the proposed test suitable for the screening of ophthalmic preparations.

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

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.

[The adverse effects of local anesthetics on the eye in the development of ocular irritation test]. / De l'agressivité des anesthésiques locaux envers l'oeil au développement d'un test d'irritation oculaire.

Referring to the ocular damage produced by local anaesthetics applied to the eye, the authors suggest the use of a test, to reveal the danger that some ophthalmic preparations may represent for patients. They review the studies devoted to the evaluation of ocular damage, particularly those which resulted into tests based on the methodology of Draize. A test scaled down to the mouse eye is described, in which the subjective appreciation is completed by an objective measurement. The test is based on the increased permeability of injured cornea for fluorescein. The fluorescence emitted by this tracer depends on the extent of the micro-lesions and is measured with an optical electronic device. The possibilities and limitations of this test are determined by the relationship between dose and extent of ocular damage. Such a relationship has been established for oxybuprocain. An appropriate concentration of this local anaesthetic allows to investigate the influence of adjuvants, preservatives and viscosifiers on the effect of oxybuprocain on the cornea. The authors conclude that it is possible to apply this test to the development of well-tolerated ophthalmic preparations.

Metabolic chiral inversion of ibuprofen in isolated rat hepatocytes.

Ibuprofen was used to demonstrate that isolated rat hepatocytes offer a suitable in vitro model to investigate the metabolic chiral inversion of anti-inflammatory 2-arylpropionic acids (profens). The inversion of the pharmacologically inactive (-)-(R)-ibuprofen to the active (+)-(S)-ibuprofen was shown to obey apparent first-order kinetics during 5 h and to increase linearly with increasing hepatocyte concentration up to 4 x 10(5) cells/ml. No elimination of (R)-ibuprofen by routes other than inversion was seen, whereas the elimination of (S)-ibuprofen appeared to be saturable.

[Biopharmaceutics of ophthalmic drugs]. / Biopharmacie des préparations ophtalmiques.

The importance of biopharmaceutics in the development of ophthalmic drugs is pointed out. Ophthalmic drugs have to be stable, sterile, well tolerated and effective. The constraints resulting from these requirements limit the number of pharmaceutical presentations. The development of pilocarpine eye drops is taken as an example to illustrate how difficult it is to satisfy Goldmann's criteria of stability, sterility, tolerance, and efficacy simultaneously. A rapid and sensitive ocular tolerance test for the selection of the most favorable formulations is proposed as a means of counteracting the present shortage of screening tests. Additionally, the physiological, physicochemical, and pharmaceutical factors are discussed which can influence the drugs' passage through the cornea and consequently increase or decrease their efficacy. Two examples, taken respectively from the aqueous solutions and lipophilic gels, demonstrate the importance of pharmaceutical and biological availability as well as the present tendency toward optimization in the development of ophthalmic preparations.

Biopharmaceutical test of ocular irritation in the mouse.

A simple and accurate test for ocular irritation in mice has been developed in which the subjective evaluation of intolerance is supplemented by an objective measurement, based on the change in corneal permeability following ocular damage. An episcopic microscope is used to detect, under blue light, the amount of fluorescein that diffuses across the inflamed or damaged cornea. The fluorescence emitted by this fluorochrome is quantified by a photomultiplier. The degree of ocular damage is expressed as a fluorescence index which can be subjected to statistical analysis. In a first stage of this study a series of surfactants has been examined and classified on the basis of their fluorescence index. The classification thus obtained is in agreement with those previously reported in the literature for assessment of ocular irritation by other methods.

Aryl ether O-dealkylase activity in the skin of untreated mice in vitro.

1. O-Dealkylation of p-nitroanisole and p-nitrophenetole in 10 000 g supernatant preparations of mouse skin is detectable and quantifiable. The reaction is NADPH-dependent and is mediated by cytochrome P-450. 2. The rate of p-nitroanisole O-demethylation in mouse skin preparations is 2% of that in mouse liver preparations on a mg protein basis, but only 0.23% on a g of tissue basis. 3. For p-nitrophenetole O-deethylation, the cutaneous Vmax is 3.8% of the hepatic Vmax on a mg protein basis. The Km values for the reaction in these two tissues are in a 3:1 ratio, suggesting that there are no marked qualitative differences between cutaneous and hepatic cytochrome P-450.