Tacrolimus Population Pharmacokinetic-Pharmacogenetic Analysis and Bayesian Estimation in Renal Transplant Recipients

Objectives: The aims of this study were (i) to investigate the population pharmacokinetics of tacrolimus in renal transplant recipients, including the influence of biological and pharmacogenetic covariates; and (ii) to develop a Bayesian estimator able to reliably estimate the individual pharmacokinetic parameters and inter-dose area under the blood concentration-time curve (AUC) from 0 to 12 hours (AUC12) in renal transplant patients. Methods: Full pharmacokinetic profiles were obtained from 32 renal transplant patients at weeks 1 and 2, and at months 1, 3 and 6 post-transplantation. The population pharmacokinetic analysis was performed using the nonlinear mixed-effect modelling software NONMEM® version VI. Patients’ genotypes were characterized by allelic discrimination for PXR −25385C>T genes. Results: Tacrolimus pharmacokinetics were well described by a two-compartment model combined with an Erlang distribution to describe the absorption phase, with low additive and proportional residual errors of 1.6 ng/mL and 9%, respectively. Both the haematocrit and PXR −25385C>T single nucleotide polymorphism (SNP) were identified as significant covariates for apparent oral clearance (CL/F) of tacrolimus, which allowed improvement of prediction accuracy. Specifically, CL/F decreased gradually with the number of mutated alleles for the PXR −25385C>T SNP and was inversely proportional to the haematocrit value. However, clinical criteria of relevance, mainly the decrease in interindividual variability and residual error, led us to retain only the haematocrit in the final model. Maximum a posteriori Bayesian forecasting allowed accurate prediction of the tacrolimus AUC12 using only three sampling times (at 0 hour [predose] and at 1 and 3 hours postdose) in addition to the haematocrit value, with a nonsignificant mean AUC bias of 2% and good precision (relative mean square error = 11%). Conclusion: Population pharmacokinetic analysis of tacrolimus in renal transplant recipients showed a significant influence of the haematocrit on its CL/F and led to the development of a Bayesian estimator compatible with clinical practice and able to accurately predict tacrolimus individual pharmacokinetic parameters and the AUC12

Genetic diversity analysis of common beans based on molecular markers

A core collection of the common bean (Phaseolus vulgaris L.), representing genetic diversity in the entire Mexican holding, is kept at the INIFAP (Instituto Nacional de Investigaciones Forestales, Agricolas y Pecuarias, Mexico) Germplasm Bank. After evaluation, the genetic structure of this collection (200 accessions) was compared with that of landraces from the states of Oaxaca, Chiapas and Veracruz (10 genotypes from each), as well as a further 10 cultivars, by means of four amplified fragment length polymorphisms (AFLP) +3/+3 primer combinations and seven simple sequence repeats (SSR) loci, in order to define genetic diversity, variability and mutual relationships. Data underwent cluster (UPGMA) and molecular variance (AMOVA) analyses. AFLP analysis produced 530 bands (88.5% polymorphic) while SSR primers amplified 174 alleles, all polymorphic (8.2 alleles per locus). AFLP indicated that the highest genetic diversity was to be found in ten commercial-seed classes from two major groups of accessions from Central Mexico and Chiapas, which seems to be an important center of diversity in the south. A third group included genotypes from Nueva Granada, Mesoamerica, Jalisco and Durango races. Here, SSR analysis indicated a reduced number of shared haplotypes among accessions, whereas the highest genetic components of AMOVA variation were found within accessions. Genetic diversity observed in the common-bean core collection represents an important sample of the total Phaseolus genetic variability at the main Germplasm Bank of INIFAP. Molecular marker strategies could contribute to a better understanding of the genetic structure of the core collection as well as to its improvement and validation

Campagne de mesure de l'ozone sur le site de Creteil (mai 1979 - avril 1981)

Comite: Milieux physiques: AirSIGLEAvailable from Centre de Documentation Scientifique et Technique, CNRS, 26 rue Boyer, 75971 Paris Cedex 20 (France) / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Tests of some reduction hypotheses made in photochemical mechanisms, Atmos

Abstraet--The purpose of this paper is to evaluate the errors induced by different hypotheses used to elaborate reduced kinetic mechanisms of tropospheric chemistry. To do that, a reference chemical kinetic scheme was developed: it includes a limited number of representative primary species (6 alkanes, 4 alkenes, 2 aromatics) for which up to date kinetic constants and mechanisms were used. This chemical scheme constitutes a reference against which the various reduction methods were tested. The tests were performed for three different scenarios characterised by various VOC/NO x ratios (5,10, 20). These scenarios are assumed to correspond to the chemical state of the atmosphere in urban areas and in rural situations. In a first step, the high NO x approximation (i.e. a chemical scheme without treatment of peroxy + HO = and peroxy + peroxy reactions) was tested. The results show that this scheme does not produce significant error on the simulated concentrations for NO concentrations above 2 ppb. In a second step, three successive reduction methods were applied to the reference mechanism: (1) use of the chemical operator concept to treat the organic peroxy chemistry, (2) loss of information on the organic peroxy class, (3) lumping of secondary organic species into surrogate species. The use of chemical operators provides a satisfactory representation of the organic peroxy chemistry for NO concentration down to 100 ppt. The scheme obtained after the loss of information on the organic peroxy class increases only slightly the error