Quantitative structure-pharmacokinetics relationships: II. A mechanistically based model to evaluate the relationship between tissue distribution parameters and compound lipophilicity.

摘要: The tissue-to-unbound plasma distribution coefficients (Kpus) of 14 rat tissues after iv administration nine 5-n-alkyl-5-ethyl barbituric acids, determined in a previous study, were used to identify model the relationship between tissue and lipophilicity homologs, expressed terms their octanol water partition ratio, P. Based on mechanistic considerations assumptions, parameter was asKpuτ= fW,τ[l + aτ(nPl,τ)Pbτ], where fW,τis content, (nPl,τ) is binding capacity tissue, n number sites, aτand bτare parameters Kaτ = aτPbτ Kaτis association constant each tissue. linearized fitted predetermined Kpu values, yielding correlation ranging .940 .997. predictive performance evaluated using leave-one-out procedure with subsequent computation mean prediction error (ME measurement bias) square root squared (RMSE accuracy). ME varied −22.48 61.14%, indicating slight tendency for overpredicting. RMSE 24.73 102% individual across different homologs; 28.33 85.2% homologs tissues. apparently high errors, when translated through low sensitivity barbiturate whole-body physiologically based pharmacokinetic model, established previously, leads predicted concentration–time profiles within 5 20% original ones. Therefore, it concluded, that identified mechanistically good predictor Kpus