Plasma disappearance and biliary excretion of sulfobromophthalein and phenol-3,6-dibromphthalein disulfonate after microsomal enzyme induction☆
Abstract
The ability of various microsomal drug metabolizing enzyme inducers to enhance the plasma disappearance and biliary excretion of sulfobromophthalein (BSP) and phenol-3,6-dibromphthalein disulfonate (DBSP) was compared to the ability of these agents to increase biliary flow. Phenobarbital (PB) treatment produced the greatest increase in biliary flow and also had the greatest effect in enhancing the plasma disappearance and excretion of BSP and DBSP into the bile. With chlordane, phenylbutazone, nikethamide and chlorcyclizine treatment, no statistically significant changes in biliary flow were produced prior to dye administration. These agents produced a significant decrease in the plasma concentration of BSP or DBSP only at the 30-min sample and produced a slight increase in the excretion of these 2 dyes into the bile. With 3-methylcholanthrene and 3,4-benzpyrene, there was no apparent increase in biliary flow, plasma disappearance of the dyes, or excretion rate into the bile. Therefore, there appears to be no direct correlation between the ability of these agents to induce rates of drug metabolism and the ability to enhance the disappearance of these dyes. However, there generally appears to be a good correlation in the ability of these agents to increase biliary flow in rats and their ability to increase the plasma disappearance and biliary excretion of BSP and DBSP.
References (20)
- R.J. Roberts et al.
Biochem. Pharmac.
(1967) - M.J. Kreek et al.
Lancet
(1968) - H.M. Maurer et al.
Lancet
(1968) - D. Trolle
Lancet
(1968) - J.M. Fujimoto et al.
Biochem. Pharmac.
(1965) - E.R.L. O'Maille et al.
J. Physiol., Land.
(1966) - E.W. Callahan et al.
Gastroenterology
(1969) - C.A. Goresky et al.
Gastroenterology
(1969) - C. Catz et al.
Pediat. Res.
(1968) - S.J. Jaffe et al.
New Engl. J. Med.
(1966)
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Role of rat multidrug resistance protein 2 in plasma and biliary disposition of dibromosulfophthalein after microsomal enzyme induction
2002, Toxicology and Applied PharmacologyWe have previously demonstrated that microsomal enzyme inducers phenobarbital (PB) and pregnenolone-16α-carbonitrile (PCN), but not 3-methylcholanthrene (3-MC) and benzo(a)pyrene (BaP), increase expression and function of rat Multidrug Resistance Protein 2 (Mrp2), a canalicular organic anion transporter. Thus, the purpose of this study was to determine whether Mrp2 protein induction alters the biliary and plasma dispositions of dibromosulfophthalein (DBSP). After four daily ip injections of PB, PCN, 3-MC, BaP, or vehicle, DBSP (100 mg/kg) was injected iv and was measured in blood and bile over a 40-min period. PB and PCN significantly enhanced plasma disappearance and biliary excretion of DBSP, whereas 3-MC and BaP did not. To determine whether the enhanced plasma disappearance and biliary excretion was entirely due an increase in Mrp2, PCN was also administered ip daily for 4 days to Mrp2-null Eisai hyperbilirubinemic (EHBR) rats and then injected iv with DBSP. PCN significantly increased plasma DBSP disappearance in EHBR rats during early time intervals (2–20 min), but not at later time intervals (25–40 min). PCN did not increase DBSP biliary excretion in EHBR rats, but actually decreased it at later time intervals. In summary, the increase in Mrp2 protein after microsomal enzyme induction is responsible for increased biliary DBSP excretion. Furthermore, the increase in Mrp2 protein after microsomal enzyme induction is not responsible for the enhanced plasma DBSP disappearance at early time points, yet may influence plasma DBSP disappearance at later time points. This study also demonstrates the importance of compensatory hepatic transporters in eliminating DBSP by alternative pathways other than Mrp2.
Differential effects of microsomal enzyme-inducing chemicals on the hepatic expression of rat organic anion transporters, Oatp1 and Oatp2
2001, HepatologyThe organic anion transporting polypeptides, Oatp1 (Slc21a1) and Oatp2 (Slc21a5), mediate hepatic uptake of cardiac glycosides. Previously, we demonstrated that chemicals that increase cytochrome P450s differentially affect hepatic uptake of cardiac glycosides. We postulated that increased uptake of cardiac glycosides observed after pretreatment of animals with phenobarbital (PB) and pregnenolone-16α-carbonitrile (PCN) occurs via increased hepatic expression of Oatp1 and/or Oatp2. Male Sprague-Dawley rats were injected with PB, PCN, 3-methylcholanthrene (3-MC), or vehicle for 4 days. Branched-DNA (bDNA) signal amplification and Western blot analyses were used to assess hepatic Oatp1 and Oatp2 mRNA and protein, respectively. The expression of Oatp1 was not increased by any chemical treatment. Increases in Oatp2 expression were observed from livers of rats treated with PB and PCN, in which PCN caused a robust elevation of Oatp2 mRNA and protein. Oatp2 expression was suppressed in response to 3-MC. To determine the temporal effects of PCN treatment on the expression of Oatp2, rats were administered PCN, livers were extracted at various times, and Oatp2 expression was analyzed. Maximal expression of Oatp2 mRNA was observed at 24 hours and remained elevated, whereas the amount of Oatp2 protein increased throughout the 96-hour interval. The finding that Oatp2 expression increases in response to PB and PCN is consistent with our previous findings that PB and PCN enhance hepatic uptake of cardiac glycosides. These results suggest that Oatp2, but not Oatp1, is inducible by PB and PCN, which imparts the increased capacity of the liver to extract cardiac glycosides from the plasma. (HEPATOLOGY 2001;33:1469-1478.)
Glutathione conjugation of bromosulfophthalein in relation to hepatic glutathione content in the rat in vivo and in the perfused rat liver
1995, HepatologyThe relation between the rate of glutathione (GSH) conjugation and hepatic GSH content was studied in the rat in vivo and the in situ single-pass-perfused rat liver preparation with bromosulfophthalein (BSP) as the model substrate. The biliary excretion of the BSP-GSH conjugate and the hepatic GSH content were monitored simultaneously during intravenous infusions with BSP in the rat in vivo, and during liver perfusions with BSPcontaining perfusion medium. Rats were pretreated with single or multiple doses of buthionine sulfoximine, an inhibitor of the de novo synthesis of GSH. Surprisingly, the excretion of the BSP-GSH conjugate was sustained at a high rate, despite a virtually complete depletion of hepatic GSH, both in the rat in vivo as well as in the perfused rat liver. The results indicate that GSH was still available for conjugation with BSP after apparent depletion of the hepatic GSH pool, presumably because of a residual de novo synthesis of GSH in the liver. Despite the multiple pretreatment with buthionine sulfoximine, the de novo GSH synthesis was sufficient to sustain a high rate of GSH conjugation of BSP. The cosubstrateKm for GSH conjugation of BSP in the liver was estimated to be very small (approximately 0.3 μmol/g): the excretion rate of the BSP-GSH conjugate was only impaired at minimal hepatic GSH levels.
Antiarrhythmic drugs impair hepatic uptake and secretory function by different mechanisms in the isolated perfused rat liver
1991, BBA - General SubjectsIn the present study the effect of various antiarrhythmic drugs on hepatic perfusi organic anions and biliary secretion using the isolated perfused rat liver was examined. Infusion of verapamil (VP), diltiazem, N-propyl-ajmaline (NPAB), and quinidine at pharmacological doses induced consistently a 1.4–1.6-fold increase in portal pressure accompanied by a ∼60% decrease in bile flow and a ∼65% inhibition of biliary taurocholate (TC) excretion. Furthermore, hepatic uptake of oxygen, bromosulphthalein (BSP), and TC was significantly reduced. All these effects were dose-dependent and reversible upon withdrawal of the drugs. Studies of the hepatic circulation using a Trypan blue staining technique demonstrated a patchy perfusion pattern during infusion of the antiarrhythmic drugs as compared to the homogenously stained control organ. The hemodynamic alterations and the impairment of the hepatic initial uptake function could be entirely prevented by concomitant administration of the vasodilator papaverine. Bile flow and biliary TC excretion, however, were still inhibited under these conditions. The present results indicate that antiarrhythmic drugs produce cholestasis in the isolated perfused rat liver independently of their adverse effect on hepatic hemodynamics.
Bile pigment metabolism
1989, Bailliere's Clinical Gastroenterology
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This work was supported by funds from the Public Health Service Grant GM 15956.