Fig. 3.

Disposition of prodrugs pafuramidine (A) and CPD-0868 (B), and corresponding metabolites over 120 min in rat isolated perfused livers. Prodrug (10 μM) was administered as a bolus to the perfusion reservoir, which contained 80 ml of 20% (v/v) rat blood. ♦, prodrug; □, M1; ○, M3; ▴, active metabolite. Symbols and error bars for perfusate concentrations denote means and SDs, respectively, of n = 5 livers. Symbols and error bars for liver mass denote means and SDs, respectively, of n = 5 livers, using a destructive sampling strategy. Solid lines represent perfusate concentration-time profile of prodrug and derived metabolites. Dashed lines represent liver amount-time profile of active metabolite. Solid and dashed lines represent the computer-generated best fit of the pharmacokinetic scheme depicted in Fig. 2 (model 1) to the data. Note: pafuramidine contained 5 to 10% impurities, largely as M3; M1 from pafuramidine is not included in A because of low recovery in perfusate, as described under Results.