Alterations in Sulfobromophthalein Sodium-Removal Mechanisms From Blood During Normal Pregnancy*

Abstract

During the past few years, we have been impressed by the observation that our patients with pre-eclampsia and eclampsia usually demonstrate sulfobromophthalein sodium (BSP) retention in blood in the 45-minute BSP test. On the basis of these findings, we undertook a study of hepatic BSP-removal mechanisms during the course of normal pregnancy. Increased BSP retention in 45 minutes was not detected in normal pregnancy when compared to results obtained in a group of nonpregnant women of comparable age. When hepatic BSP-removal mechanisms were appraised quantitatively by a prolonged-infusion method (1, 2), however, significant changes in both hepatic uptake and excretion of BSP were observed. The following study presents in detail such data obtained from women in various stages of normal pregnancy and in the early postpartum period, and compares these findings with data obtained in a separate group of control nonpregnant women. METHODSThe method used in the present studies was devised by Wheeler and his associates (1,2) and is based on the observations that removal of BSP from plasma depends on the simultaneous operation of at least two separate hepatic mechanisms: 1) uptake of BSP into a hepatic * This work was supported by research grants from the U. S. Public Health Service (H-3439, A-6082), and frcm Parke, Davis & Co. Part of this work has appeared in abstract form (Clin. Res. 1962, 10, 189; 1963, 11, 58) and was presented at the Annual Meeting of the American Association for the Study of Liver Diseases, Chicago, Ill., November, 1962, and "storage compartment," and 2) active secretion into bile (1-8). The quantity of BSP taken up into the "storage compartment" appears to be directly proportional to plasma concentration (1). Thus, uptake into storage during a period of changing plasma concentration can be represented in symbols as S X AP/At, where the "relative storage capacity" S, a proportional factor, is defined as the number of milligrams of BSP stored in the liver per milligram per 100 ml of plasma concentration, and AP/At signifies the rate of change of plasma concentration in milligrams per 100 ml per minute. Secretion of BSP into bile is a rate-limited process characterized by a maximal excretory rate or Tm (1, 2, 8), defined in terms of milligrams per minute. The maximal rate of BSP secretion into bile is achieved when plasma BSP concentration is maintained in excess of 2 to 3 mg per 100 ml during prolonged infusions of BSP (1, 8). At these plasma concentrations, the general equation for the hepatic removal rate of BSP (1), RH, in milligrams per minute, is as follows: RH = S X (AP/At) + Tm.Values for RH and AP/At obtained during two or more different rates of BSP infusion are substituted in the formula, providing a set of simultaneous equations that can be solved for both S and Tm. In practice, values for RH and AP/At were obtained during three separate infusion rates of BSP, each given for an hour. As indicated by Wheeler, when the corresponding values for RH and AP/At are plotted on the ordinate an...

Estrogen Pharmacology. I. The Influence of Estradiol and Estriol on Hepatic Disposal of Sulfobromophthalein (BSP) in Man*

“…Although standard texts still suggest that pregnancy does not alter hepatic function in humans, elevation of serum levels of alkaline phosphatase is common during the last trimester (37)(38)(39)(40) (6). The results of the present study are consistent with this view and indicate that estrogens in particular may account wholly, or in part, for the maternal hepatic functional alterations described.…”

“…biological action of natural estrogens in man, further substantiate the role of the liver as a site of action of these hormones (5), and probably account, in part, for the impairment of BSP disposal that characterizes pregnancy (6) and the neonatal period (7)(8)(9)(10).…”

“…Determination of the hepatic secretory Tm and hepatic relative storage space for BSP according to the methods of Wheeler and associates coupled with chromatographic analysis of the amounts of free and conjugated dye in plasma provides a quantitative description of the hepatic processes concerned with BSP metabolism (2,3,6,10,(16)(17)(18)(19)(20)(21)(22). By inference, such data also provide information on the probable site of action of substances affecting disposition of this dye.…”

The effect of estrogen on bile formation in the rat

“…Sporadic occurrence of recurrent jaundice and/or pruritus in the last trimester of pregnancy (1)(2)(3), abnormal removal of sulfobromophthalein (BSP) during otherwise uncomplicated pregnancy (4,5), and the predisposition of multiparous women to form gallstones all point to a possible association between high levels of circulating estrogen and altered bile formation. Scattered reports (6)(7)(8)(9) of cholestasis following the use of oral contraceptives have heightened this suspicion as have recent suggestions (10)(11)(12), that impaired hepatic excretion in the newborn may reflect, at least in part, a deleterious effect of maternal estrogen on the fetus.…”

Metabolism of arterial plasma estrogens by the splanchnic organs of the dog in vivo

“…Splanchnic blood flow estimations usually depend on hepatic extraction of dyes such as sulfobromophthalein (BSP). There is good evidence that estrogens depress the hepatic Tm for BSP (28)(29)(30). Conversely it seemed likely that BSP administration would depress the hepatic extraction of estrogens.…”