Abstract
Substitution of the steroid epitiostanol (EP) at position 17 with methoxycyclopentane yields the extremely lipophilic mepitiostane (MP) with preferential partitioning into the lymph. Most of the MP in the lymph was associated with the core lipids of chylomicrons and very low-density lipoproteins (VLDL), as was also the case for EP. However, the dialysis velocity of EP and MP from lymph to plasma differed greatly; EP, but not MP, was transferred from the lymph to the plasma. This difference was attributed to differences in their unbound fraction in the lymph. Lymphatic transfer and the logP value of several tested steroids correlated well. Therefore, the oral EP prodrug, MP, partitioned into the lymph because of its superlipophilicity and resultant retention in the core lipids of chylomicrons and VLDL.
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REFERENCES
B. Bloom, I. L. Chaikoff, and W. O. Reinhardt. Intestinal lymph as pathway for transport of absorbed fatty acids of different chain lengths. Am. J. Physiol. 166:451–455 (1951).
C. E. Rubin. Electron microscopic studies of triglyceride absorption in man. Gastroenterology 50:65–77 (1966).
L. Hellman, E. L. Frazell, and R. S. Rosenfeld. Direct measurement of cholesterol absorption via the thoracic duct in man. J. Clin. Invest. 39:1288–1294 (1960).
C. R. Treadwell and G. V. Vahouny. Alimentary canal. 3. Intestinal absorption. In C. F. Code (ed.), Handbook of Physiology, Section 6, American Physiology Society, 1968, pp. 1407–1438.
B. Bloom, I. L. Chaikoff, W. O. Reinhardt, C. Entenman, and W. G. Dauben. The quantitative significance of the lymphatic pathway in transport of absorbed fatty acids. J. Biol. Chem. 184:1–8 (1950).
R. Blomstrand. The intestinal absorption of linolic-l-14C acid. Acta Physiol. Scand. 32:99–105 (1954).
R. Blomstrand and L. Forsgren. Intestinal absorption and esterification of vitamin D3-1,2-3H in man. Acta Chem. Scand. 21:1662–1663 (1967).
R. Blomstrand and L. Forsgren. Vitamin K1-3H in man. Its intestinal absorption and transport in the thoracic duct lymph. Int. Z. Vit. Forsch. 38:45–64 (1968).
S. M. Sieber, V. H. Cohn, and W. T. Wynn. The entry of foreign compounds into the thoracic duct lymph of the rat. Xenobiotica 4:265–284 (1974).
D. M.-E. Pocock and A. Vost. DDT absorption and chylomicron transport in rat. Lipids 9:374–381 (1974).
T. Noguchi, Y. Jinguji, T. Kimura, S. Muranishi, and H. Sezaki. Mechanism of the intestinal absorption of drugs from oil-in-water emulsions. VII. Role of bile in the lymphatic transport of lipid-soluble compounds from triolein emulsions. Chem. Pharm. Bull. 23:782–786 (1975).
R. C. Grimus and I. Schuster. The role of the lymphatic transport in the enteral absorption of naftifine by the rat. Xenobiotica 14:287–294 (1984).
T. Ichihashi, H. Kinoshita, and H. Yamada. Absorption and disposition of epithiosteroids in rats [2]: Avoidance of first-pass metabolism of mepitiostane by lymphatic absorption. Xenobiotica 21:873–880 (1991).
L. S. Schanker, P. A. Shore, B. B. Brodie, and C. A. M. Hogben. Absorption of drugs from the stomach I. The rat. J. Pharmacol. Exp. Ther. 120:528–539 (1957).
C. A. M. Hogben, D. J. Tocco, B. B. Brodie, and L. S. Schanker. On the mechanism of intestinal absorption of drugs. J. Pharmacol. Exp. Ther. 125:275–282 (1959).
J. B. Houston and S. G. Wood. Gastrointestinal absorption of drugs and other xenobiotics. In J. W. Bridges and L. F. Chasseaud (eds.), Progress in Drug Metabolism, Vol. 4, John Wiley & Sons, New York, 1980, pp. 57–129.
T. Ichihashi, H. Kinoshita, Y. Takagishi, and H. Yamada. Intrinsic lymphatic partition rate of mepitiostane, epitiostanol and oleic acid absorbed from rat intestine. Pharm. Res. 8:1302–1306 (1991).
J. L. Bollman, J. C. Cain, and J. H. Grindlay. Techniques for the collection of lymph from liver, small intestine or thoracic duct of the rat. J. Lab. Clin. Med. 33:1349–1352 (1948).
G. Hübscher, G. R. West, and D. N. Brindley. Studies on the fractionation of mucosal homogenates from the small intestine. Biochem. J. 97:629–642 (1965).
F. T. Hatch and R. S. Lees. Practical methods for plasma lipoprotein analysis. In Advances in Lipid Research, Academic Press, New York, 1968, Vol. 6, pp. 1–68.
D. B. Zilversmit. The surface coat of chylomicrons: Lipid chemistry. J. Lipid Res. 9:180–186 (1968).
C. Hansch and A. J. Leo. Substituent Constants for Correlation Analysis in Chemistry and Biology, Wiley, New York, 1979.
S. L. Palay and L. J. Karlin. An electron microscopic study of the intestinal villus. II. The pathway of fat absorption. J. Biophys. Biochem. Cytol. 5:373–384 (1959).
R. R. Cardell, Jr., S. Badenhausen, and K. P. Porter. Intestinal triglyceride absorption in the rat. An electron microscopical study. J. Cell Biol. 34:123–155 (1967).
F. C. Courtice. Lymph and plasma proteins: Barriers to their movement throughout the extracellular fluid. Lymphology 4:9–17 (1971).
T. Ichihashi, H. Kinoshita, Y. Takagishi, and H. Yamada. Effect of bile on absorption of mepitiostane by the lymphatic system in rats. J. Pharm. Pharmacol. 44:565–569 (1992).
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Ichihashi, T., Takagishi, Y. & Yamada, H. Factors Determining the Intrinsic Lymphatic Partition Rate of Epitiostanol and Mepitiostane. Pharm Res 9, 1617–1621 (1992). https://doi.org/10.1023/A:1015824710957
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DOI: https://doi.org/10.1023/A:1015824710957