Previous estimates of the peritoneal solvent drag reflection coefficient (sigma) are widely disparate; some are outside the range expected for a semipermeable membrane (i.e., between 0 and 1). We have evaluated a novel method for determining sigma in a rabbit model of peritoneal dialysis. Test solute was infused intravenously, and sequential 2-hour isotonic and hypertonic exchanges (40 ml/kg) were performed in random order. Test solute was also added to the instilled hypertonic dialysis solution to inhibit transperitoneal solute diffusion during this exchange. Eight experiments were performed with creatinine as test solute and glucose as osmotic solute, and six experiments were performed with glucose as test solute and mannitol as osmotic solute. When using isotonic dialysis solution, the dialysate/plasma concentration ratio (D/P) for both test solutes increased throughout the exchange (p < 0.001). When using hypertonic dialysis solution, D/P creatinine was initially near 1 and decreased during the 1st hour of the exchange (p < 0.05); D/P glucose (as test solute) was initially 0.82 +/- (SEM) 0.07 and did not change during the exchange. The peritoneal diffusive permeability-area product (PA) was determined by fitting a mathematical model to the time dependence of the dialysate test solute concentration during the isotonic exchange using PA as an adjustable parameter, and sigma was determined in like manner during the hypertonic exchange using sigma as an adjustable parameter (and assuming a PA value equal to that during the isotonic exchange). The creatinine PA (1.37 +/- 0.28 ml/min) was higher than that for glucose (0.62 +/- 0.07 ml/min) as expected based on their solution diffusion coefficients. Creatinine and glucose sigma values were 0.38 +/- 0.06 and 0.43 +/- 0.05, respectively. We conclude that peritoneal sigma values for creatinine and glucose are within the physiological range.