Assuntos
Ciclofosfamida/toxicidade , Células-Tronco Hematopoéticas/efeitos dos fármacos , Imunossupressores/toxicidade , Modelos Biológicos , Modelos de Riscos Proporcionais , Animais , Ciclofosfamida/farmacocinética , Granulócitos/citologia , Granulócitos/efeitos dos fármacos , Doenças Hematológicas/induzido quimicamente , Hematopoese/efeitos dos fármacos , Células-Tronco Hematopoéticas/citologia , Humanos , Imunossupressores/farmacocinética , Camundongos , Reprodutibilidade dos TestesRESUMO
Physiologically based pharmacokinetic (PBPK) models are useful in describing the distribution, metabolism, and fate of xenobiotics across multiple species. The eventual goal of the present research is to create PBPK models for all 209 polychlorinated biphenyls (PCBs). Key parameters in any PBPK model are the metabolic rates. Data on metabolic rates of PCBs were derived from in vitro experiments and from fitting of PBPK models to in vivo data. The rate of metabolism was assumed to be a linear function of PCB concentration. Structural descriptors suggested by the literature were used in a stepwise regression to find an expression for the metabolic rate of PCBs as a function of five structural descriptors related to the degree and pattern of chlorine substitution. R2 for the fit of the model to the data is 0.9606.
Assuntos
Modelos Biológicos , Bifenilos Policlorados/farmacocinética , Animais , Técnicas In Vitro , Masculino , Taxa de Depuração Metabólica , Bifenilos Policlorados/química , Ratos , Análise de Regressão , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
Physiologically based pharmacokinetic (PBPK) models are useful in describing the distribution, metabolism, and fate of xenobiotics across multiple species. The eventual goal of the present research is to create PBPK models for all 209 polychlorinated biphenyls (PCBs). Key parameters in any PBPK model are the tissue-to-blood partition coefficients. Tissue:blood partition coefficients relate the compound's concentration in a target tissue to its concentration in blood under equilibrium conditions. Data on the adipose:plasma partition coefficients of 24 PCBs were used in a regression analysis to find an expression for the adipose:plasma partition coefficient as a function of molecular structure. Using stepwise regression, it was found that three simple structural descriptors were sufficient to predict adipose:plasma partition coefficients for all 209 PCB congeners. Data on the distribution of PCBs among blood components were used to derive the adipose:blood partition coefficient from the adipose:plasma partition coefficient. The lipid contents of liver, muscle, and skin were used to derive the tissue:blood partition coefficient for those tissues from the adipose:blood partition coefficient. These results allow for the calculation of tissue:blood partition coefficients for liver, skin, muscles, and fat for all 209 PCB congeners.
