Reduced extraction of I-propranolol by perfused rat liver in the presence of uremic blood.

Previous in vivo studies have shown that the presystemic clearance of p.o.-administered levo-isomer of propranolol is inhibited in rats with uranyl nitrate-induced acute renal failure. A series of steady-state single-pass rat liver perfusion studies were performed to explore the probable mechanism of the observed metabolic inhibition. When livers from normal rats were perfused with blood perfusate prepared from normal donor animals, a high extraction ratio (Eh) of 0.974 +/- 0.005 (mean +/- S.D.) was observed at an influent I-propranolol concentration of 400 ng/ml, i.e., only 2.6% of drug entering the liver escaped single-pass extraction. The extraction of I-propranolol was significantly lower (i.e., Eh = 0.906 +/- 0.017) when livers isolated from uranyl nitrate-induced renal failure rats were perfused with uremic blood; such that there was an approximate 3-fold increase in the amount of drug escaping single-pass extraction (i.e., from 2.6 to 9.4%). This difference in hepatic extraction is quantitatively consistent with the increase in p.o. systemic availability of I-propranolol observed in our previous in vivo study with the uranyl nitrate-induced renal failure rat model. When livers from normal rats were cross-perfused with uremic blood, extraction of I-propranolol was depressed to almost the same level (i.e., Eh = 0.927 +/- 0.009) as when livers from renal failure animals were perfused with uremic blood. In contrast, livers from renal failure rats cross-perfused with normal blood exhibited comparable extraction for I-propranolol (Eh = 0.970 +/- 0.010) as normal livers perfused with normal blood.(ABSTRACT TRUNCATED AT 250 WORDS)