Microsomal prediction of in vivo clearance and associated interindividual variability of six benzodiazepines in humans

The intrinsic clearances (CLint) of midazolam, triazolam, diazepam, nordiazepam, flunitrazepam and alprazolam were determined from two liver banks (n = 21) by formation kinetics of ten metabolites. A literature-collated database of in vivo CLint values (811 subjects) was used to assess predictions and variability. The in vivo clearance of six benzodiazepines was generally underpredicted by in vitro data and the degree of bias was in agreement with a database of structurally diverse compounds (n = 37). The variability observed for in vitro clearances (11–19-fold for midazolam, diazepam and nordiazepam in liver bank 1; 101–269-fold for triazolam, flunitrazepam and alprazolam in liver bank 2) exceeded the in vivo variability for the same compounds (4–59 and 10–29, respectively). This mismatch may contribute to the bias in microsomal predictions and it highlights the need for careful selection of representative livers for human liver banks.