The importance of acinar heterogeneity in ursodeoxycholic acid (UDCA)-induced bile flow was assessed in isolated rat livers that underwent restricted acinar damage by antegrade (A; 50 nmol) or retrograde (R; 500 nmol) digitonin infusion, as confirmed by histological evaluation. Stability of reduced (-40%) bile flow and perfusion flow (-25%) at constant pressure and potassium and lactate dehydrogenase release indicated similar viability of A and R preparations. They also showed similar abilities to secrete increasing doses of taurocholate (TC, maximal secretion rate approximately 105 nmol.min-1.g liver-1). TC-induced bile flow was not reduced by digitonin. In contrast, UDCA-induced choleresis was sensitive to zonal injury. Moreover, increases in bile flow and bicarbonate secretion observed under UDCA infusion (1.5 mumol/min) were lower in R than in A (-33 and -51%, respectively). No significant difference was observed in UDCA amidation or glucuronation between A and R preparations. With the use of single-pass perfusion on intact isolated livers that received 1 or 10 mumol UDCA, an early peak in bile acid output was observed to occur before the appearance of the major secretory peak. This was not found when 1 mumol of chenodeoxycholic acid bolus or trace amounts of [14C]TC were given. High-performance liquid chromatographic analysis of the early peak revealed it to be mainly due to unconjugated UDCA. This suggests the existence of a diffusional pathway for protonated bile acids and hence that the exist of lipophilic UDCA from bile during its way through the intra-acinar canaliculi across this pathway is also possible.(ABSTRACT TRUNCATED AT 250 WORDS)