Development of a whole body physiologically based model to characterise the pharmacokinetics of benzodiazepines. 1: Estimation of rat tissue-plasma partition ratios

Three methods for estimation of the equilibrium tissue-to-plasma partition ratios (Kp values) in the presence of tissue concentration time data have been investigated. These are the area method, the open loop (tissue specific) method and the whole body model(closed loop) method, each with different model assumptions. Additionally, multiple imputations, a technique for dealing with deficiencies in data sets (i.e., missing tissues) is used. The estimated Kp values by the three methods have been compared and the limitations and advantages of each approach drawn. The area method, which is essentially model free, gives only a crude estimate of Kp without making any statement of its uncertainty; whereas both the open and closed loop methods provide an estimate of this. The closed loop method, where the most assumptions are made, is the approach that gives the best overall estimates of Kp, which was confirmed by comparing the predicted concentration-time profiles with experimental data. Although the estimates from the closed loop method, as well as the other two methods, are conditioned on the data, they are the most reliable for both propagating parameter variability and uncertainty through a whole body physiologically based model, as well as for extrapolation to human. A series of benzodiazepines, namely alprazolam, chlordiazepoxide, clobazam, diazepam, flunitrazepam, midazolam and triazolam in rat is used as a case study in the current investigation.