Abstract
The futile cycling of estrone sulfate (E1S) and estrone (E1) was investigated in the recirculating, perfused, rat liver preparation. Although E1S was not distributed into bovine erythrocytes, the compound was highly bound to albumin [4% bovine serum albumin (BSA), unbound fraction of 0.03 ± 0.01]. By contrast, E1 was bound and metabolized to estradiol (E2) by bovine erythrocytes, with metabolic clearances of 0.061 to 0.069 ml/min when normalized to the hematocrit. Due to strong binding of E1 to albumin, BSA (4%) greatly reduced the red cell clearance to a minimum (0.0024 to 0.0031 ml/min/unit of hematocrit). Despite the low unbound fractions of E1S (0.027 ± 0.004) and E1 (0.036 ± 0.006), clearances of the simultaneously delivered tracers [3H]E1S and [14C]E1in perfusate (4% BSA and 20% erythrocytes) by the recirculating, perfused rat liver (flow rate of 0.91 ± 0.1 ml/min/g of liver) were high (0.53 ± 0.08 and 0.85 ± 0.2 ml/min/g of liver, respectively). Although low levels of [3H]E1were observed following the tracer [3H]E1S, both parent and metabolite species displayed similar decay half-lives that were characteristic of compounds undergoing futile cycling. The same decay profile was observed for [14C]E1S but the half-life of administered [14C]E1 was shorter in comparison. A series-compartment liver model that incorporated previously noted heterogeneity in estrone sulfation and glucuronidation activities among periportal and perivenous hepatocytes, and homogeneity in sinusoidal transport and desulfation was used to explain the discrepant half-lives. The model described a high partitioning of E1 in the endoplasmic reticulum and the segregation of estrone sulfation activities in the cytosolic space from the desulfation and glucuronidation activities in the endoplasmic reticulum space.
Footnotes
-
Send reprint requests to: Dr. K. Sandy Pang, Faculty of Pharmacy, University of Toronto, 19 Russell St., Toronto, ON M5S 2S2 Canada. E-mail: ks.pang{at}utoronto.ca
-
This work was supported by the Medical Research Council of Canada (MT-15657). Eugene Tan was a recipient of graduate scholarships from the Natural Sciences and Engineering Research Council and Medical Research Council of Canada.
- Abbreviations:
- 4-MU
- 4-methylumbelliferone
- 4-MUS
- 4-MU sulfate
- E1
- estrone
- E1S
- E1sulfate
- E1G
- E1 glucuronide
- E2
- estradiol
- UGT
- UDP-glucuronosyltransferase
- RBC
- red blood cell
- HPLC
- high performance liquid chromatography
- TLC
- thin layer chromatography
- BSA
- bovine serum albumin
- HCT
- hematocrit
- MSC
- model selection criterion
- AUC
- area under the concentration time profile
- ANOVA
- analysis of variance
- CL
- clearance
- Received October 19, 2000.
- Accepted January 4, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|