Abstract
Purpose. To examine whether the small quantities of lipid present in unit-dose microemulsion formulations comprising medium- (C8-10) or long-chain (C18) glyceride lipids can stimulate the intestinal lymphatic transport of halofantrine (Hf), a model lymphatically transported drug.
Methods. Hf (50 mg) was administered to thoracic lymph duct- and cephalic vein-cannulated fasted greyhound dogs. Drug was formulated as a single soft gelatin capsule containing approximately 1 g of a microemulsion preconcentrate based on either medium- or long-chain glycerides. Thoracic lymph was collected, and systemic plasma samples taken over 10 h postdose.
Results. The extent of lymphatic transport of Hf after administration of the long-chain lipid formulation was high (28.3% of dose), and significantly higher than that seen after administration of the medium-chain formulation (5.0% of dose). Plasma levels of Hf were not significantly different across the two formulations when assessed by AUC0-10h.
Conclusions. This is the first study to demonstrate that the small amounts of lipid present within a single lipid-based dose form can support substantial intestinal lymphatic transport in the fasted state. Furthermore, microemulsions based on long-chain glycerides appear to be more effective with respect to lymphatic transport than the equivalent medium-chain formulation.
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References
C. J. H. Porter and W. N. Charman. Uptake of drugs into the intestinal lymphatics after oral administration. Adv. Drug Deliv. Rev. 25:71–89 (1997).
C. J. H. Porter. Drug delivery to the lymphatic system. Crit. Rev. Ther. Drug Carrier Syst. 14:333–393 (1997).
W. N. Charman and V. J. Stella. Estimating the maximal potential for intestinal lymphatic transport of lipophilic drug molecules. Int. J. Pharm. 34:175–178 (1986).
C. J. H. Porter and W. N. Charman. Model systems for intestinal lymphatic transport studies. In R. T. Borchardt, P. L. Smith, and G. Wilson (eds.), Models for Assessing Drug Absorption and Metabolism, Plenum Press, New York, pp. 85–102 (1996).
G. A. Edwards, C. J. H. Porter, S. M. Caliph, S.–M. Khoo, and W. N. Charman. Animal models for the study of intestinal lymphatic drug transport. Adv. Drug Deliv. Rev. 50:45–60 (2001).
S.–M. Khoo, G. A. Edwards, C. J. H. Porter, and W. N. Charman. A conscious dog model for assessing the absorption, enterocyte–based metabolism, and intestinal lymphatic transport of halofantrine. J. Pharm. Sci. 90:1599–1607 (2001).
W. N. Charman, C. J. H. Porter, S. Mithani, and J. B. Dressman. Physicochemical and physiological mechanisms for the effects of food on drug absorption: The effect of lipids pH. J. Pharm. Sci. 86:269–282 (1997).
C. J. H. Porter, S. A. Charman, A. J. Humberstone, and W. N. Charman. Lymphatic transport of halofantrine in the conscious rat when administered as either the free base or the hydrochloride salt: effect of lipid class and lipid vehicle dispersion. J. Pharm. Sci. 85:357–361 (1996).
S.–M Khoo, A. J. Humberstone, C. J. H. Porter, G. A. Edwards, and W. N. Charman. Formulation design and bioavailability assessment of lipidic self–emulsifying formulations of halofantrine. Int. J. Pharm. 167:155–164 (1998).
A. J. Humberstone, G. J. Currie, C. J. H. Porter, M. J. Scanlon, and W. N. Charman. A simplified liquid chromatography assay for the quantitation of halofantrine and desbutylhalofantrine in plasma identification of a degradation product of desbutylhalofantrine formed under alkaline conditions. J. Pharm. Biomed. Anal. 13:265–272 (1995).
Y.–F. Shiau, D. A. Popper, M. Reed, C. Umstetter, D. Capuzzi, and G. M. Levine. Intestinal triglycerides are derived from both endogenous and exogenous sources. Am. J. Physiol. 248:G164–G169 (1985).
R. K. Ockner, F. B. Hughes, and K. J. Isselbacher. Very low density lipoproteins in intestinal lymph: role in triglyceride and cholesterol transport during fat absorption. J. Clin. Invest. 48:2367–2373 (1969).
R. K. Ockner, F. B. Hughes, and K. J. Isselbacher. Very low density lipoproteins in intestinal lymph: Origin, composition, and role in lipid transport in the fasting state. J. Clin. Invest. 48:2079–2088 (1969).
C. M. Mansbach, A. Arnold, and M. A. Cox. Factors influencing triacylglycerol delivery into mesenteric lymph. Am J. Physiol. 249:G642–G648 (1985).
M. P. McIntosh, A. J. Batey, C. J. H. Porter, W. N. Charman, and S. J. Coker. Desbutylhalofantrine: Evaluation of QT prolongation and other cardiovascular effects after intravenous administration in vivo. J. Cardiovasc. Pharmacol. 41:406–413 (2003).
S.–M. Khoo, R. J. Prankerd, G. A. Edwards, C. J. H. Porter, and W. N. Charman. A physicochemical basis for the extensive intestinal lymphatic transport of a poorly lipid soluble antimalarial, halofantrine hydrochloride, after postprial administration to dogs. J. Pharm. Sci. 91:647–659 (2002).
D. J. Hauss, S. Mehta, and G. W. Radebaugh. Targeted lymphatic transport and modified systemic distribution of CI–976, a lipophilic lipid–regulator drug via a formulation approach. Int. J. Pharm. 108:85–93 (1994).
S. M. Caliph, W. N. Charman, and C. J. H. Porter. Effect of short–, medium–, long–chain fatty acid–based vehicles on the absolute oral bioavailability and intestinal lymphatic transport of halofantrine assessment of mass balance in lymph–cannulated non–cannulated rats. J. Pharm. Sci. 89:1073–1086 (2000).
S. M. Khoo, C. J. H. Porter, and W. N. Charman. The formulation of halofantrine as either non–solubilising PEG 6000 or solubilising lipid–based solid dispersions: physical stability and absolute bioavailability assessment. Int. J. Pharm. 205:65–78 (2000).
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Khoo, SM., Shackleford, D.M., Porter, C.J.H. et al. Intestinal Lymphatic Transport of Halofantrine Occurs After Oral Administration of a Unit-Dose Lipid-Based Formulation to Fasted Dogs. Pharm Res 20, 1460–1465 (2003). https://doi.org/10.1023/A:1025718513246
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DOI: https://doi.org/10.1023/A:1025718513246