Mechanism-based inhibition of CYP2C8 by gemfibrozil in humans : characterisation of time and dose relationships

Drug-drug interactions may cause serious, even fatal clinical consequences. Therefore, it is important to examine the interaction potential of new chemical entities early in drug development. Mechanism-based inhibition is a pharmacokinetic interaction type, which causes irreversible loss of enzyme activity and can therefore lead to unusually profound and long-lasting consequences. The in vitro in vivo extrapolation (IVIVE) of drug-drug interactions caused by mechanism-based inhibition is challenging. Consequently, many of these interactions have remained unrecognised for many years. The concomitant use of the fibrate-class lipid-lowering agent gemfibrozil increases the concentrations of some drugs and their effects markedly. Even fatal cases of rhabdomyolysis occurred in patients administering gemfibrozil and cerivastatin concomitantly. One of the main mechanisms behind this effect is the mechanism-based inhibition of the cytochrome P450 (CYP) 2C8 enzyme by a glucuronide metabolite of gemfibrozil leading to increased cerivastatin concentrations. Although the clinical use of gemfibrozil has clearly decreased during recent years, gemfibrozil is still needed in some special cases. To enable safe use of gemfibrozil concomitantly with other drugs, information concerning the time and dose relationships of CYP2C8 inhibition by gemfibrozil should be known. This work was carried out as four in vivo clinical drug-drug interaction studies to examine the time and dose relationships of the mechanism-based inhibitory effect of gemfibrozil on CYP2C8. The oral antidiabetic drug repaglinide was used as a probe drug for measuring CYP2C8 activity in healthy volunteers. In this work, mechanism-based inhibition of the CYP2C8 enzyme by gemfibrozil was found to occur rapidly in humans. The inhibitory effect developed to its maximum already when repaglinide was given 1-3 h after gemfibrozil intake. In addition, the inhibition was shown to abate slowly. A full recovery of CYP2C8 activity, as measured by repaglinide metabolism, was achieved 96 h after cessation of gemfibrozil treatment. The dose-dependency of the mechanism-based inhibition of CYP2C8 by gemfibrozil was shown for the first time in this work. CYP2C8 activity was halved by a single 30 mg dose of gemfibrozil or by twice daily administration of less than 30 mg of gemfibrozil. Furthermore, CYP2C8 activity was decreased over 90% by a single dose of 900 mg gemfibrozil or twice daily dosing of approximately 100 mg gemfibrozil. In addition, with the application of physiological models to the data obtained in the dose-dependency studies, the major role of mechanism-based inhibition of CYP2C8 in the interaction between gemfibrozil and repaglinide was confirmed. The results of this work enhance the proper use of gemfibrozil and the safety of patients. The information related to time-dependency of CYP2C8 inhibition by gemfibrozil may also give new insights in order to improve the IVIVE of the drug-drug interactions of new chemical entities. The information obtained by this work may be utilised also in the design of clinical drug-drug interaction studies in the future.

Mechanical Properties And Constitutive Relationships Of 30Crmnsia Steel Heated At High Rate

In this paper, the mechanical behavior of 30CrMnSiA steel after heating at a high rate are investigated experimentally and theoretically, including a detailed discussion of the effects of strain rate and temperature. Two constitutive models are presented to describe the mechanical response of this material after heating at a high rate, and verified by experimental results. (C) 2007 Elsevier B.V. All rights reserved.

Mechanical properties and constitutive relationships of 30CrMnSiA steel heated at high rate

In this paper, the mechanical behavior of 30CrMnSiA steel after heating at a high rate are investigated experimentally and theoretically, including a detailed discussion of the effects of strain rate and temperature. Two constitutive models are presented to describe the mechanical response of this material after heating at a high rate, and verified by experimental results. (C) 2007 Elsevier B.V. All rights reserved.

Species and size relationships within schools of yellowfin and skipjack tuna as indicated by catches in the Eastern Tropical Pacific Ocean

ENGLISH: Yellowfin tuna, Neothunnus macropterus, and skipjack tuna, Katsuwonus pelamis, are fished intensively off the west coast of the Americas in an area from about the California-Mexico border in the north to the Peru-Chile border in the south. The historical development of this fishery, and its expansion by the long-range California fleets of bait and purse-seine vessels, are well documented by Godsil (1938), Scofield (1951) and Shimada and Sehaefer (1956). The quarterly distribution of the tuna catches within this area has been reported for some recent years by Alverson (1959). SPANISH: Los atunes aleta amarilla, Neothunnus macropterus, y barrilete, Katsuwonus pelamis, son pescados con intensidad frente a la costa occidental del continente americano, en un área comprendida más o menos entre la frontera California-México en el norte y el límite Perú-Chile en el sur. El desarrollo histórico de esta pesquería y la expansión que le han dado las flotas californianas de largo radio de acción, formadas por los barcos de carnada y rederos, están bien documentados por Godsil (1938), Scofield (1951) y Shimada y Schaefer (1956). La distribución trimestral de las pescas de atún dentro de esta área ha sido tratada por Alverson (1959) con referencia a años recientes.

Spatial and seasonal relationships between Pacific harbor seals (Phoca vitulina richardii) and their prey, at multiple scales

Knowing where pinnipeds forage is vital to managing and protecting their populations, and for assessing potential interactions with fisheries. We assessed the spatial relationship between the seasonal distribution of Pacific harbor seals (Phoca vitulina richardii) outfitted with satellite transmitters and the seasonal distributions of potential harbor seal prey species in San Francisco Bay, California. Pearson’s correlation coefficients were calculated between the number of harbor seal locations in an area of the San Francisco Bay and the abundance of specific prey species in the same area. The influence of scale on the analyses was assessed by varying the scale of analysis from 1 to 10 km. There was consistency in the prey species targeted by harbor seals year-round, although there were seasonal differences between the most important prey species. The highest correlations between harbor seals and their prey were found for seasonally abundant benthic species, located within about 10 km of the primary haul-out site. Probable foraging habitat for harbor seals was identified, based on areas with high abundances of prey species that were strongly correlated with harbor seal distribution. With comparable local data inputs, this approach has potential application to pinniped management in other areas, and to decisions about the location of marine reserves designed to protect these species.

Diets of and trophic relationships among dominant marine nekton within the northern California Current ecosystem

In this study we analyzed the diets of 26 nekton species collected from two years (2000 and 2002) off Oregon and northern California to describe dominant nekton trophic groups of the northern California Current (NCC) pelagic ecosystem. We also examined interannual variation in the diets of three nekton species. Cluster analysis of predator diets resulted in nekton trophic groups based on the consumption of copepods, euphausiids, brachyuran larvae, larval juvenile fishes, and adult nekton. However, many fish within trophic groups consumed prey from multiple trophic levels—euphausiids being the most widely consumed. Comparison of diets between years showed that most variation occurred with changes in the contribution of euphausiids and brachyuran larvae to nekton diets. The importance of euphausiids and other crustacean prey to nekton indicates that omnivory is an important characteristic of the NCC food web; however it may change during periods of lower or higher upwelling and ecosystem production.