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• W2037421803 abstract "The clearance (Cl) and volume of distribution (Vss) of a lipophilic, lymphatically transported drug, halofantrine (Hf) have been evaluated after intravenous delivery to the systemic circulation in ex vivo lymph and plasma, and compared with the data obtained after administration of a lipid-based emulsion and a lipid-free cosolvent formulation. Systemic Cl and Vss were significantly lower (approximately twofold) after delivery of Hf in lymph or the emulsion when compared with the administration in plasma or the cosolvent formulation. Preadministration of drug-free lymph, immediately before administration of drug in plasma, however, resulted in plasma profiles consistent with that obtained after administration of drug in lymph/emulsion. Where drug and lipid entered the systemic circulation coincidentally, systemic Cl of Hf, therefore, appeared to be relatively unaffected by the route of entry to the systemic circulation (i.e. via the lymph or the blood), but more significantly altered by total plasma lipid levels. Because temporal changes to plasma lipid levels occur as a result of the absorption of formulation or food-derived lipids and the infusion of intravenous lipid emulsions, the current data suggest that a mismatch in plasma lipid levels after intravenous and oral administrations may lead to differences in drug Cl and errors in bioavailability assessment. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association The clearance (Cl) and volume of distribution (Vss) of a lipophilic, lymphatically transported drug, halofantrine (Hf) have been evaluated after intravenous delivery to the systemic circulation in ex vivo lymph and plasma, and compared with the data obtained after administration of a lipid-based emulsion and a lipid-free cosolvent formulation. Systemic Cl and Vss were significantly lower (approximately twofold) after delivery of Hf in lymph or the emulsion when compared with the administration in plasma or the cosolvent formulation. Preadministration of drug-free lymph, immediately before administration of drug in plasma, however, resulted in plasma profiles consistent with that obtained after administration of drug in lymph/emulsion. Where drug and lipid entered the systemic circulation coincidentally, systemic Cl of Hf, therefore, appeared to be relatively unaffected by the route of entry to the systemic circulation (i.e. via the lymph or the blood), but more significantly altered by total plasma lipid levels. Because temporal changes to plasma lipid levels occur as a result of the absorption of formulation or food-derived lipids and the infusion of intravenous lipid emulsions, the current data suggest that a mismatch in plasma lipid levels after intravenous and oral administrations may lead to differences in drug Cl and errors in bioavailability assessment. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association INTRODUCTIONFor some lipophilic, poorly water-soluble drugs, the intestinal lymphatic system can be an important route of transport from the intestine to the systemic circulation following oral administration.1.Trevaskis N.L. Charman W.N. Porter CJH. Lipid-based delivery systems and intestinal lymphatic drug transport: A mechanistic update.Adv Drug Deliv Rev. 2008; 60: 702-716Crossref PubMed Scopus (327) Google Scholar,2.Porter C.J.H. Trevaskis N.L. Charman WN. Lipids and lipid-based formulations: Optimizing the oral delivery of lipophilic drugs.Nat Rev Drug Discov. 2007; 6: 231-248Crossref PubMed Scopus (1397) Google Scholar Lymphatic transport is typically a significant contribution to exposure for drugs where lipophilicity is high (log Ds > 5; long chain lipid solubilities >50 mg/g),3.Charman W.N. Noguchi T. Stella VJ. An experimental system designed to study the in situ intestinal lymphatic transport of lipophilic drugs in anaesthetised rats.Int J Pharm. 1986; 33: 155-164Crossref Scopus (44) Google Scholar although recent studies provide some examples where this physicochemical requirement has been less stringent.4.Gershkovich P. Hoffman A. Uptake of lipophilic drugs by plasma derived isolated chylomicrons: Linear correlation with intestinal lymphatic bioavailability.Eur J Pharm Sci. 2005; 26: 394-404Crossref PubMed Scopus (113) Google Scholar, 5.Trevaskis N.L. McEvoy C.L. McIntosh M.P. Edwards G.A. Shanker R.M. Charman W.N. Porter CJH. The role of the intestinal lymphatics in the absorption of two highly lipophilic cholesterol ester transfer protein inhibitors (CP524,515 and CP532,623).Pharm Res. 2010; 27: 878-893Crossref PubMed Scopus (35) Google Scholar, 6.Trevaskis N.L. Shanker R.M. Charman W.N. Porter CJH. The mechanism of lymphatic access of two cholesteryl ester transfer protein inhibitors (CP524,515 and CP532,623) and evaluation of their impact on lymph lipoprotein profiles.Pharm Res. 2010; 27: 1949-1964Crossref PubMed Scopus (34) Google Scholar Importantly, unlike absorption and transport to the systemic circulation via the portal vein, intestinal lymphatic transport results in drug delivery to the systemic blood in association with triglyceride (TG)-rich lipoproteins (TRL) produced by the intestine such as chylomicrons and very low-density lipoprotein (VLDL).7.Sieber S.M. Cohn V.H. Wynn WT. The entry of foreign compounds into the thoracic duct lymph of the rat.Xenobiotica. 1974; 4: 265-284Crossref PubMed Scopus (65) Google Scholar,8.Porter C.J.H. Charman S.A. Charman WN. Lymphatic transport of halofantrine in the triple-cannulated anesthetized rat model: Effect of lipid vehicle dispersion.J Pharm Sci. 1996; 85: 351-356Abstract Full Text PDF PubMed Scopus (119) Google ScholarSeveral authors have speculated that transport to the systemic circulation within lymph lipoproteins may subsequently lead to changes in drug clearance (Cl) and volume of distribution (Vss) because these parameters often differ in situations wherein systemic lipoprotein levels are changed.9.Porter CJH. Drug delivery to the lymphatic system.Crit Rev Ther Drug Carrier Syst. 1997; 14: 333-393PubMed Google Scholar, 10.Hauss D.J. Mehta S.C. Radebaugh GW. Targeted lymphatic transport and modified systemic distribution of CI-976, a lipophilic lipid regulator drug.Int J Pharm. 1994; 108: 85-93Crossref Scopus (70) Google Scholar, 11.Brocks D.R. Ala S. Aliabadi HM. The effects of increased lipoprotein levels on the pharmacokinetics of Cyclosporine A in the laboratory rat.Biopharm Drug Dispos. 2006; 27: 7-16Crossref PubMed Scopus (44) Google Scholar, 12.Wasan K.M. Brocks D.R. Lee S.D. Sachs-Barrable K. Thornton SJ. Impact of lipoproteins on the biological activity and disposition of hydrophobic drugs: Implications for drug discovery.Nat Rev Drug Discov. 2008; 7: 84-99Crossref PubMed Scopus (188) Google Scholar, 13.Gershkovich P. Hoffman A. Effect of a high-fat meal on absorption and disposition of lipophilic compounds: The importance of degree of association with triglyceride-rich lipoproteins.Eur J Pharm Sci. 2007; 32: 24-32Crossref PubMed Scopus (70) Google Scholar This contention is also supported by studies that report discrepancies in mass balance for lymphatically transported compounds when oral bioavailability is assessed in conventional bioavailability studies [i.e., by comparison of plasma exposure (area under the curve; AUC) after oral administration with an equivalent IV control group] and in studies where lymphatic transport is assessed directly via cannulation of the mesenteric lymph duct (and total drug availability estimated from the mass of lymphatically transported drug plus systemic plasma exposure).5.Trevaskis N.L. McEvoy C.L. McIntosh M.P. Edwards G.A. Shanker R.M. Charman W.N. Porter CJH. The role of the intestinal lymphatics in the absorption of two highly lipophilic cholesterol ester transfer protein inhibitors (CP524,515 and CP532,623).Pharm Res. 2010; 27: 878-893Crossref PubMed Scopus (35) Google Scholar,10.Hauss D.J. Mehta S.C. Radebaugh GW. Targeted lymphatic transport and modified systemic distribution of CI-976, a lipophilic lipid regulator drug.Int J Pharm. 1994; 108: 85-93Crossref Scopus (70) Google Scholar,14.Caliph S.M. Charman W.N. Porter CJH. Effect of short-, medium-, and long-chain fatty acid-based vehicles on the absolute oral bioavailability and intestinal lymphatic transport of halofantrine and assessment of mass balance in lymph-cannulated and non-cannulated rats.J Pharm Sci. 2000; 89: 1073-1084Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar,15.Holm R. Porter C.J.H. Mullertz A. Kristensen H.G. Charman WN. Structured triglyceride vehicles for oral delivery of halofantrine: Examination of intestinal lymphatic transport and bioavailability in conscious rats.Pharm Res. 2002; 19: 1354-1361Crossref PubMed Scopus (64) Google ScholarThe primary aim of the current study was to directly determine whether the systemic pharmacokinetics of a model lipophilic (and lymphatically transported) drug (halofantrine, Hf) are altered after delivery to the systemic circulation in intestinal lymph when compared with plasma. The data suggest that significant differences in Cl and Vss are apparent if Hf is administered in lymph or plasma separately. However, in more usual circumstances, where lipids and drug are simultaneously absorbed via both lymphatic and portal pathways (such as after oral administration of a lipid-based formulation, or after coadministration with food), equilibration of drug binding to plasma lipoproteins may occur rapidly, regardless of the route of entry to the plasma, and systemic Cl may be dictated by total plasma lipid levels. The implications of the current study are in the appropriate choice of intravenous vehicle when evaluating bioavailability under circumstances where plasma lipid levels may change, such as after administration of lipid vehicles or food. In this regard, cosolvent formulations appear to closely mimic the introduction of drug into plasma with low lipid levels (such as absorption from nonlipidic vehicles and in the fasted state), whereas intravenous emulsion formulations more closely approximate Cl patterns in the fed state, or after coadministration with (relatively large quantities of) lipid.MATERIALS AND METHODSChemicalsHalofantrine base and internal standard 2,4-dilchloro-6-trifluromethyl-9-1-2-(dibutylamino) ethylphenanthrenemethanol were obtained from GlaxoSmithKline (King of Prussia, PA). Acetonitrile, tert-butylmethylether, sodium dodecyl sulfate, and glacial acetic acid were high-performance liquid chromatography (HPLC) grade. Lecithin was purchased from Pharmacia (Uppsala, Sweden) and soybean oil (superfine), oleic acid (OA), and glyceryl monoolein (GMO) were from Sigma –Aldrich (Sydney, Australia). Purified water was obtained from a Milli-Q water purification system (Millipore, Milford, Massachusetts). All other chemicals were analytical reagent grade.Study DesignAll experimental procedures were approved and conducted in accordance with the Australian and New Zealand Council for the Care of Animals in Research and Teaching guidelines. The systemic disposition of Hf in male Sprague–Dawley rats (285–320 g) was compared after intravenous administration (5 min infusion) of 0.5 mg of Hf in 1 mL of: (1) rat lymph, (2) rat plasma, (3) a lymph-like lipid-based emulsion, or (4) a nonlipid-based cosolvent formulation. Furthermore, two groups were also examined where 0.5 mg of Hf was administered intravenously in 1 mL of: (5) rat plasma over 5 min immediately after intravenous administration of 1 mL of drug-free rat lymph as a bolus over 10 s, and (6) rat lymph administered intravenously over a longer (1 h) infusion period. The Hf concentration in all formulations was verified on the day of dosing by HPLC as below. Data are presented dose normalized to 1.7 mg/kg (∼0.5 mg Hf/300 g rat).Collection of Rat Lymph Containing HfRat lymph containing Hf was collected from donor rats after oral gavage of 20 mg Hf base dissolved in 0.2 g of peanut oil. After 1 h, the mesenteric lymph duct and duodenum were cannulated, and Hf containing lymph was continuously collected over 2–6 h as previously described.8.Porter C.J.H. Charman S.A. Charman WN. Lymphatic transport of halofantrine in the triple-cannulated anesthetized rat model: Effect of lipid vehicle dispersion.J Pharm Sci. 1996; 85: 351-356Abstract Full Text PDF PubMed Scopus (119) Google Scholar,13.Gershkovich P. Hoffman A. Effect of a high-fat meal on absorption and disposition of lipophilic compounds: The importance of degree of association with triglyceride-rich lipoproteins.Eur J Pharm Sci. 2007; 32: 24-32Crossref PubMed Scopus (70) Google Scholar Lymphatic transport of Hf was promoted throughout the lymph collection period by continuous intraduodenal infusion of a micellar formulation containing 1 mg Hf base, 25 μL of lipid [OA/GMO (2:1)] in 4% (w/v) Tween 80 in 1.5 mL normal saline. The formulation was infused continuously at a rate of 1.5 mL/h.16.Porter C.J.H. Charman S.A. Humberstone A.J. Charman WN. 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. 1996; 85: 357-361Abstract Full Text PDF PubMed Scopus (66) Google Scholar The collected lymph was stored overnight in a sealed sterile tube at 4°C before administration to recipient rats. A concentration of 0.5 mg/mL Hf in lymph was obtained by dilution with drug-free lymph collected under identical conditions as needed. The TG content of the dosing lymph was 3.8 g/dL in group 1, 4.6 g/dL in group 5, and 3.4 g/dL in group 6.Preparation of Rat Plasma Containing HfTen milligrams of crystalline Hf base was melted at 90°C for 1 h, cooled to ambient temperature, and mixed with 2 mL of donor rat plasma by vortexing for 2 min followed by constant mixing (230 strokes/min) and incubation at 37°C in a water bath for 10 h. The plasma was subsequently centrifuged at 700 g for 10 min to precipitate and remove any undissolved drug. A concentration of 0.5 mg/mL Hf in plasma was obtained by dilution with drug-free plasma as needed.Preparation of Lipid-Based Emulsion Containing HfThe lipid-based emulsion, in which Hf was incorporated, was similar to the proprietary product Intralipid® (Baxter Healthcare, Sydney, Australia). Briefly, Hf base was dissolved in soybean oil to a concentration of 50 mg/g, and 1 g soybean oil was emulsified in 10 mL of water for injection containing 1% (w/v) phospholipid (lecithin) and 2% (w/v) glycerol using a microfluidiser (Microfluidic Corporation, Newton, Massachusetts) to produce a final emulsion with a lipid content of 10% (w/v) and a droplet size of approximately 250 nm as described.17.Charman W.N. Porter C.J.H. Halofantrine free base for the treatment of malaria and compositions. United States Patent Documents. ed.United States; Bedford, United Kingdom: SmithKline Beecham p.I.c. 1999: 1-9Google Scholar 0.2 mL of this emulsion (5 mg/mL) was diluted 1:10 with normal saline immediately before intravenous administration to recipient rats (which received 0.5 mg of Hf in a 1 mL dose containing 2%, w/v soybean oil).Preparation of Cosolvent Formulation Containing HfThe cosolvent formulation vehicle comprised ethanol/propylene glycol/water for injection (10:40:50, v/v). Crystalline Hf base was first melted and mixed with ethanol/propylene glycol (1:4, v/v) at ambient temperature by vortexing for 2 min. Water was then added slowly while vortexing continuously for 5 min resulting in a clear homogenous drug solution that was inspected under polarized light.Administration of Hf to Recipient Animals and Sample CollectionThe jugular vein and carotid artery of recipient rats were cannulated as described previously,18.Edwards G.A. Porter C.J.H. Caliph S.M. Khoo S.M. Charman WN. Animal models for the study of intestinal lymphatic drug transport.Adv Drug Deliv Rev. 2001; 50: 45-60Crossref PubMed Scopus (89) Google Scholar and animals were allowed to recover unrestrained for 20 h before dosing. Food was withheld during the recovery and for 10 h postdosing but water was available ad libitum. In groups 1–4, Hf in lymph, plasma, lipid emulsion, or cosolvent was administered by intravenous infusion over 5 min via the jugular cannula. In group 5, Hf in rat plasma was administered intravenously immediately after 1 mL of drug-free rat lymph was administered by intravenous bolus (over 10 s). In group 6, Hf in rat lymph was infused over a longer timescale (1 h). Systemic blood (250 μL) was sampled from the carotid artery cannula at −5 min, 5 min, 10 min, 20 min, 30 min, 1 h, 2 h, 4 h, 7 h, 10 h, and 24 h after initiation of intravenous infusions and plasma (100 μL) separated by centrifugation. In group 6, where Hf was infused in lymph over 1 h, the sampling protocol was the same except that the 5 min plasma sample was not taken. Hf and TG concentrations in plasma, lymph, and the intravenous formulations were measured using HPLC and colorimetric kits as previously described.13.Gershkovich P. Hoffman A. Effect of a high-fat meal on absorption and disposition of lipophilic compounds: The importance of degree of association with triglyceride-rich lipoproteins.Eur J Pharm Sci. 2007; 32: 24-32Crossref PubMed Scopus (70) Google Scholar,19.Humberstone A.J. Currie G.J. Porter C.J.H. Scanlon M.J. Charman WN. A simplified liquid chromatography assay for the quantitation of halofantrine and desbutylhalofantrine in plasma and identification of a degradation product of desbutylhalofantrine formed under alkaline conditions.J Pharm Biomed Anal. 1995; 13: 265-272Crossref PubMed Scopus (48) Google ScholarPharmacokinetic and Statistical AnalysisApparent elimination half-life (t1/2) and the elimination rate constants (k) for the terminal elimination phase were calculated from the slope of the log plasma concentration versus time curves. The area under the plasma concentration versus time curves from time 0 to 24 h (AUC0–24) were calculated using the linear trapezoidal rule from time 0 to 24 h. AUC0–∞ was calculated via addition of AUC0–24 to the extrapolated tail area calculated by dividing the 24 h plasma concentration by the terminal elimination rate constant, k. The Cl and Vss were calculated using standard noncompartmental methods. Statistically significant differences were calculated by one way analysis of variance followed by the Student—Newman–Keuls test for multiple comparisons using Sigma Plot for Windows Version 11 (SPSS Inc.,Chicago, IL).RESULTS AND DISCUSSIONPlasma concentrations of Hf were significantly higher (p < 0.05) at each time point following intravenous administration of Hf in ex vivo lymph when compared with ex vivo plasma (Figure 1a). The plasma AUC0–24 and AUC0–∞ were therefore higher, and a significant (p < 0.05) reduction in systemic Cl and Vss was apparent (Table 1). t1/2 was unchanged in both groups. Preinfusion of drug-free lymph, immediately before administration of Hf in ex vivo plasma, however, resulted in plasma Hf profiles that were similar to that obtained after administration of drug in lymph and significantly higher than that observed after administration of Hf in plasma alone (Figure 1b). These data suggest rapid equilibration of drug binding across different plasma lipoproteins after entry into the systemic circulation in either lymph or plasma.Table 1Pharmacokinetic Parameters of Halofantrine (Hf) in Rats After Intravenous Administration of 1.7 mg/kg Hf in Lymph, Plasma, a Lipid-Based Emulsion or a Lipid-Free Cosolvent Formulation (Mean ± SEM; n = 4)Lymph 5 min InfusionPlasma 5 min InfusionPlasma 5 min Infusion Following LymphaRats predosed with a bolus of 1mL blank lymph immediately before infusion of Hf in plasma.Lymph 60 min InfusionLipid emulsion 5 min InfusionCosolvent 5 min InfusionAUC0–24 (ng h/mL)4295 ± 541817 ± 307*Significantly different (p < 0.05) when compared with other groups.5067 ± 10743331 ± 2424454 ± 2752372 ± 548*Significantly different (p < 0.05) when compared with other groups.AUC0–∞ (ng h/mL)5971 ± 2672835 ± 384*Significantly different (p < 0.05) when compared with other groups.8647 ± 4504990 ± 3265516 ± 3993922 ± 615*Significantly different (p < 0.05) when compared with other groups.Cl [mL/(h kg)]280 ± 13622 ± 85*Significantly different (p < 0.05) when compared with other groups.195 ± 10279 ± 66307 ± 20514 ± 84*Significantly different (p < 0.05) when compared with other groups.Vss (L/kg)4.5 ± 0.210.6 ± 1.3*Significantly different (p < 0.05) when compared with other groups.5.4 ± 1.16.7 ± 1.34.0 ± 0.611.9 ± 2.1*Significantly different (p < 0.05) when compared with other groups.t1/2 (h)14.7 ± 0.616.6 ± 2.420.3 ± 2.213.6 ± 3.413.7 ± 1.514.4 ± 4.1* Significantly different (p < 0.05) when compared with other groups.a Rats predosed with a bolus of 1 mL blank lymph immediately before infusion of Hf in plasma. Open table in a new tab Drug entry into the systemic circulation after oral administration is, however, expected to occur more slowly than the 5 min intravenous infusion time employed here. A separate group of animals was therefore administered Hf in ex vivo lymph over a 1 h infusion time to provide a preliminary indication of whether the changes in drug pharmacokinetics that result from lipid transport into the plasma are dependent on the rate of lipid entry. In this case, the slower infusion rate resulted in lower drug concentrations at early time points when compared with infusion in lymph over 5 min, but somewhat higher concentrations from 30 min to 1 h post injection (Figure 1c). The plasma concentrations were similar from 2 h to 24 h post injection. Cl was therefore relatively insensitive to the rate of lymph infusion, and remained significantly lower than that after drug administration in plasma.The reductions in Cl and Vss seen under conditions where drug and lymph lipoproteins enter the plasma simultaneously, are likely to reflect, at least in part, differences in the free fraction in plasma because Hf is primarily eliminated by hepatic metabolism and is a low extraction efficiency compound,20.Baune B. Flinois J.P. Furlan V. Gimenez F. Taburet A.M. Becquemont L. Farinotti R. Halofantrine metabolism in microsomes in man: Major role of CYP 3A4 and CYP 3A5.J Pharm Pharmacol. 1999; 51: 419-426Crossref PubMed Scopus (26) Google Scholar, 21.Khoo S.M. Porter C.J.H. Edwards G.A. Charman WN. Metabolism of halofantrine to its equipotent metabolite, desbutylhalofantrine, is decreased when orally administered with ketoconazole.J Pharm Sci. 1998; 87: 1538-1541Abstract Full Text PDF PubMed Scopus (22) Google Scholar, 22.Gharavi N. Sattari S. Shayeganpour A. El-Kadi A.O.S. Brocks DR. The stereoselective metabolism of halofantrine to desbutylhalofantrine in the rat: Evidence of tissue-specific enantioselectivity in microsomal metabolism.Chirality. 2007; 19: 22-33Crossref PubMed Scopus (9) Google Scholar and is therefore expected to show binding-dependent Cl. This is consistent with previous studies that have shown significant increases in Hf and amiodarone plasma AUC after intravenous administration to fed and hyperlipidemic animals (where plasma lipoprotein levels are higher than fasted or normolipidemic animals), and corresponding decreases in Cl and Vss that are correlated with decreases in unbound fraction. 23.Brocks D.R. Wasan KM. The influence of lipids on stereoselective pharmacokinetics of halofantrine: Important implications in food-effect studies involving drugs that bind to lipoproteins.J Pharm Sci. 2002; 91: 1817-1826Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 24.Humberstone A.J. Porter C.J.H. Edwards G.A. Charman WN. Association of halofantrine with postprandially derived plasma lipoproteins decreases its clearance relative to administration in the fasted state.J Pharm Sci. 1998; 87: 936-942Abstract Full Text PDF PubMed Scopus (56) Google Scholar, 25.Patel J.P. Fleischer J.G. Wasan K.M. Brocks DR. The effect of experimental hyperlipidemia on the stereoselective tissue distribution, lipoprotein association and microsomal metabolism of (+/−)-halofantrine.J Pharm Sci. 2009; 98: 2516-2528Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 26.Shayeganpour A. Korashy H. Patel J.P. El-Kadi A.O. Brocks DR. The impact of experimental hyperlipidemia on the distribution and metabolism of amiodarone in rat.Int J Pharm. 2008; 361: 78-86Crossref PubMed Scopus (45) Google Scholar In lymph, Hf is almost exclusively present in the apolar lipid core of TRL, but is less highly lipoprotein bound in plasma. For example, after intraduodenal administration to rats in 50 μL of a mixture of OA/GMO, Hf in lymph was approximately 60%–80% bound to chylomicrons, 15%–36% to VLDL, and only 2%–4% was present in the remaining lipoprotein and protein-bound fractions and lymph fluid.8.Porter C.J.H. Charman S.A. Charman WN. Lymphatic transport of halofantrine in the triple-cannulated anesthetized rat model: Effect of lipid vehicle dispersion.J Pharm Sci. 1996; 85: 351-356Abstract Full Text PDF PubMed Scopus (119) Google Scholar By contrast, after in vitro incubation with fasted and fed human and beagle plasma, Hf is associated with smaller and more dense low-density lipoproteins and high-density lipoproteins (rather than TRL), and a much larger proportion of the mass of Hf (28%–45%) is recovered in the lipoprotein-free fraction.27.McIntosh M.P. Porter C.J.H. Wasan K.M. Ramaswamy M. Charman WN. Differences in the lipoprotein binding profile of halofantrine in fed and fasted human or beagle plasma are dictated by the respective masses of core apolar lipoprotein lipid.J Pharm Sci. 1999; 88: 378-384Abstract Full Text PDF PubMed Scopus (20) Google Scholar Patterns of Hf binding in lymph and plasma therefore differ markedly, however, the data in Figure 1b suggest that re-equilibration of Hf binding occurs rapidly (probably in conjunction with rapid catabolism of chylomicrons and VLDL) after entry into the plasma and that the route of Hf entry into the systemic circulation does not, per se, influence Cl kinetics. This suggestion is supported by the data in Figure 2 that show an increase in plasma TG concentrations after administration of lymph and a corresponding increase in plasma Hf concentration in samples with the highest plasma TG levels. These data are consistent with previous data for Hf, dichlorodiphenyltrichloroethane, and amiodarone, in pre- and post-prandial states and in hypertriglyceridemic models where plasma drug concentrations changed with triglyceride levels.13.Gershkovich P. Hoffman A. Effect of a high-fat meal on absorption and disposition of lipophilic compounds: The importance of degree of association with triglyceride-rich lipoproteins.Eur J Pharm Sci. 2007; 32: 24-32Crossref PubMed Scopus (70) Google Scholar,24.Humberstone A.J. Porter C.J.H. Edwards G.A. Charman WN. Association of halofantrine with postprandially derived plasma lipoproteins decreases its clearance relative to administration in the fasted state.J Pharm Sci. 1998; 87: 936-942Abstract Full Text PDF PubMed Scopus (56) Google Scholar,26.Shayeganpour A. Korashy H. Patel J.P. El-Kadi A.O. Brocks DR. The impact of experimental hyperlipidemia on the distribution and metabolism of amiodarone in rat.Int J Pharm. 2008; 361: 78-86Crossref PubMed Scopus (45) Google Scholar As Hf appears to rapidly re-equilibrate with plasma lipoproteins, the Cl patterns are likely determined by total plasma lipid and lipoprotein profiles rather than entry into the plasma in association with a particular lipoprotein class, for example, lymph TRL. The data also suggest that differences in the extent of lipid input (absorption) into the systemic circulation may lead to temporal changes to drug Cl, presumably reflecting temporal changes to plasma lipid levels.Figure 2(a) Systemic plasma triglyceride (TG) concentration versus time profiles (mean ± SEM; n = 4) for the first 1 h post injection of 1.7 mg/kg Hf base in 1 mL ex vivo rat lymph over 5 min (▴); 1 mL ex vivo rat plasma over 5 min (○); 1 mL ex vivo rat lymph over 60 min (▿) or 1 mL ex vivo rat plasma over 5 min immediately after a bolus dose of 1 mL of blank rat lymph (♦). (b) Correlation between plasma Hf concentrations and plasma TG concentrations. Symbols reflect data obtained at the different time points described in (a) (mean ± SEM; n = 4).View Large Image Figure ViewerDownload (PPT)The potential for acute changes to plasma lipid levels to lead to changes to drug Cl led us to subsequently explore the potential for lipid-based and nonlipid-based intravenous formulations to mimic the Cl patterns seen under conditions of differing plasma levels. Previous studies have demonstrated that intravenous lipid emulsions acquire apoproteins after delivery into the systemic circulation and may be cleared in an analogous manner to TRL.28.Ferezou J. Bach AC. Structure and metabolic fate of triacylglycerol- and phospholipid-rich particles of commercial parenteral fat emulsions.Nutrition. 1999; 15: 44-50Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 29.Robinson S.F. Quarfordt SH. Apoproteins in association with Intralipid incubations in rat and human plasma.Lipids. 1979; 14: 343-349Crossref PubMed Scopus (38) Google Scholar, 30.Weinberg R.B. Scanu AM. In vitro reciprocal exchange of apoproteins and nonpolar lipids between human high density lipoproteins and an artificial triglyceride-phospholipid emulsion (Intralipid).Atherosclerosis. 1982; 44: 141-152Abstract Full Text PDF PubMed Scopus (38) Google Scholar The plasma concentration versus time profiles of Hf were therefore compared after delivery into the systemic circulation in lymph and a ``lymph-like” lipid-based emulsion (Figure 3a). The Cl and Vss were similar (Table 1) and consistently lower than the data obtained after administ" @default.
• W2037421803 created "2016-06-24" @default.
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• W2037421803 date "2012-09-01" @default.
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• W2037421803 title "Intravenous Dosing Conditions May Affect Systemic Clearance for Highly Lipophilic Drugs: Implications for Lymphatic Transport and Absolute Bioavailability Studies" @default.
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