Predicting passive and active tissue:plasma partition coefficients: interindividual and interspecies variability.
A mechanistic tissue composition model incorporating passive and active transport for the prediction of steady-state tissue:plasma partition coefficients (K(t:pl)) of chemicals in multiple mammalian species was used to assess interindividual and interspecies variability. This approach predicts K(t:pl) using chemical lipophilicity, pKa, phospholipid membrane binding, and the unbound plasma fraction, together with tissue fractions of water, neutral lipids, neutral and acidic phospholipids, proteins, and pH. Active transport K(t:pl) is predicted using Michaelis-Menten transport parameters. Species-specific biological properties were identified from 126 peer reviewed journal articles, listed in the Supporting Information, for mouse, rat, guinea pig, rabbit, beagle dog, pig, monkey, and human species. Means and coefficients of variation for biological properties were used in a Monte Carlo analysis to assess variability. The results show K(t:pl) interspecies variability for the brain, fat, heart, kidney, liver, lung, muscle, red blood cell, skin, and spleen, but uncertainty in the estimates obscured some differences. Compounds undergoing active transport are shown to have concentration-dependent K(t:pl). This tissue composition-based mechanistic model can be used to predict K(t:pl) for organic chemicals across eight species and 10 tissues, and can be an important component in drug development when scaling K(t:pl) from animal models to humans.
HJF, Molecular Bioeffects Branch, Bioeffects Division, Human Effectiveness Directorate, Air Force Research Laboratory, Wright-Patterson AFB, Dayton, Ohio 45433; Department of Biomedical Sciences, Wright State University, Dayton, Ohio 45435.
Christopher D
CD
Ruark
HJF, Molecular Bioeffects Branch, Bioeffects Division, Human Effectiveness Directorate, Air Force Research Laboratory, Wright-Patterson AFB, Dayton, Ohio 45433.
C Eric
CE
Hack
HJF, Molecular Bioeffects Branch, Bioeffects Division, Human Effectiveness Directorate, Air Force Research Laboratory, Wright-Patterson AFB, Dayton, Ohio 45433.
Peter J
PJ
Robinson
USAF, Molecular Bioeffects Branch, Bioeffects Division, Human Effectiveness Directorate, Air Force Research Laboratory, Wright-Patterson AFB, Dayton, Ohio 45433.
Deirdre A
DA
Mahle
HJF, Molecular Bioeffects Branch, Bioeffects Division, Human Effectiveness Directorate, Air Force Research Laboratory, Wright-Patterson AFB, Dayton, Ohio 45433; Department of Biomedical Sciences, Wright State University, Dayton, Ohio 45435. Electronic address: jeffery.gearhart.ctr@us.af.Mil.
Jeffery M
JM
Gearhart
D000818:Animals; D001693:Biological Transport, Active; D004285:Dogs; D005544:Forecasting; D006168:Guinea Pigs; D000882:Haplorhini; D051379:Mice; D008954:Models, Biological; D009010:Monte Carlo Method; D009928:Organ Specificity; D004364:Pharmaceutical Preparations / Q000097:blood* / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D013552:Swine; D014018:Tissue Distribution
D004364:Pharmaceutical Preparations
Monte Carlo; QSPR; active transport; computational ADME; computational biology; drug transport; in silico modeling; physicochemical properties; population pharmacokinetic/pharmacodynamic models; tissue partition