Pharmacokinetic analysis of factors determining elimination pathways for sulfate and glucuronide metabolites of xenobiotics II: Studies with isolated perfused rat liver

Abstract

1. To elucidate the determining factors for elimination pathways of sulfate and glucuronide metabolites of xenobiotics, a single-pass perfusion of 4-methylumbelliferone (4MU) or p-nitrophenol (pNP) was performed with an isolated rat liver preparation. 2. Without bovine serum albumin in the perfusion system, clearance calculated based on the unbound concentration in the liver clearly showed that the net efflux clearances (CLeff) of sulfates from the sinusoidal membrane were much higher than those of glucuronides and that the biliary excretion clearances (CLb) of glucuronides were approximately two times larger than those of sulfates. 3. The ratios of CLeff to CLb were much higher for sulfates than those for glucuronides. The bile-oriented elimination of glucuronides or sinusoidal efflux-oriented elimination of sulfates was observed even using the perfusate including 3% bovine serum albumin, but the sinusoidal efflux of sulfates was extensively enhanced by bovine serum albumin in the perfusate. The mechanisms behind this stimulatory effect remain to be elucidated. 4. For both compounds, CLb of glucuronide was comparable with CLb of sulfate, meaning that CLb is not responsible for the biliary excretion of glucuronides at extensively higher rate than sulfates. 5. Higher concentration of glucuronides in the liver, partly caused by much lower CLeff of glucuronides than that of sulfates, is likely responsible for the bile-oriented excretion of glucuronides. The extensive sinusoidal efflux of sulfates, leading to the urine-oriented excretion, is attributed to the substantially higher CLeff than CLb. 6. In conclusion, the sinusoidal efflux is an important factor for determining elimination pathways of both sulfates and glucuronides, although further studies are needed to clarify the mechanisms of the sinusoidal efflux.

Pharmacokinetic analysis of factors determining elimination pathways for sulfate and glucuronide metabolites of xenobiotics. iii: mechanisms for sinusoidal efflux of 4-methylumbelliferone sulfate

“…Furthermore, the higher hepatic concentration of 4MUG than 4MUS was generated by much lower CL eff of 4MUG than that of 4MUS (Higaki et al 2003) as well as a higher capacity for glucuronidation than that of sulfation (Benet et al 1995), whereas CL b is comparable between 4MUG and 4MUS (Higaki et al 2003). These results obviously reveal that the sinusoidal efflux must be one of the most important factors for determining the elimination pathways of both conjugates.…”

“…The reason why CL eff of 4MUS increased might be the non-linearity of the efflux of 4MUS, that is to say, the sinusoidal efflux of 4MUS would already be saturated under normal condition because the hepatic concentration of 4MUS is much higher than that in the presence of NaN 3 . Our previous study also showed that CL eff of 4MUS decreased with the increase in hepatic concentration of 4MUS (Higaki et al 2003). f T for both conjugates also decreased due to very low hepatic concentrations of both conjugates.…”

“…The urinary excretion of 4MUS can be ascribed to the extensive sinusoidal efflux, and the bile-oriented excretion of 4MUG can be explained by its high concentration in the liver, but not by the CL b as reported by Higaki et al (2003). Furthermore, the higher hepatic concentration of 4MUG than 4MUS was generated by much lower CL eff of 4MUG than that of 4MUS (Higaki et al 2003) as well as a higher capacity for glucuronidation than that of sulfation (Benet et al 1995), whereas CL b is comparable between 4MUG and 4MUS (Higaki et al 2003).…”

“…It was also found that the biliary excretion clearance (CL b ) and renal clearance do not necessarily reflect the actual excretion rate of conjugates, and that sulfates generated in the liver are subject to an extensive sinusoidal efflux. Furthermore, the biliary excretion and net sinusoidal efflux of conjugates of 4MU and pNP were examined by using an isolated liver perfusion technique (Higaki et al 2003). It has been reported that the biliary excretion of their glucuronides can be ascribed not to their CL b values based on the unbound concentration in the liver, but to their high concentration in the liver.…”

Improvement of Oral Bioavailability of N-251, a Novel Antimalarial Drug, by Increasing Lymphatic Transport with Long-Chain Fatty Acid-Based Self-Nanoemulsifying Drug Delivery System

“…The liver single-pass perfusion study was performed following the methods reported by Mortimore with some modifications (21). Briefly, the bile duct and portal vein were cannulated with polyethylene tubes, SP10: i.d.…”