An Examination of the Interplay Between Enterocyte-Based Metabolism and Lymphatic Drug Transport in the Rat

Trevaskis, Natalie L.; Porter, Christopher John; Charman, William Neil

doi:10.1124/dmd.105.008102

Cited by 34 publications

(30 citation statements)

References 13 publications

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“…This has been reported in both dogs and rats, where postprandial administration of halofantrine resulted in a decreased metabolite-to-parent ratio (Porter et al, 1996;Khoo et al, 2001). In addition, it has also been suggested that enteric metabolism may be reduced by lymphatic transport (Trevaskis et al, 2006). It is unlikely, however, for navitoclax or ABT-199 that avoidance of enteric metabolism/hepatic first-pass lymphatic transport is playing a role in increasing systemic oral exposure of either navitoclax or as 14 C preclinical data suggest that the fraction absorbed is limiting F rather than CL (data not shown).…”

Section: Discussionmentioning

confidence: 90%

The Role of Lymphatic Transport on the Systemic Bioavailability of the Bcl-2 Protein Family Inhibitors Navitoclax (ABT-263) and ABT-199

Choo

Boggs

Zhu

et al. 2014

Drug Metabolism and Disposition

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Navitoclax (ABT-263), a Bcl-2 family inhibitor and ABT-199, a Bcl-2 selective inhibitor, are high molecular weight, high logP molecules that show low solubility in aqueous media. While these properties are associated with low oral bioavailability (F), both navitoclax and ABT-199 showed moderate F in preclinical species. The objective of the described study was to determine if lymphatic transport contributes to the systemic availability of navitoclax and ABT-199 in dogs. The intravenous pharmacokinetics of navitoclax and ABT-199 were determined in intact (noncannulated) dogs. In oral studies, tablets (100 mg) of navitoclax and ABT-199 were administered to both intact and thoracic lymph duct-cannulated (TDC) dogs. The clearance of navitoclax and ABT-199 was low; 0.673 and 0.779 ml/min per kilogram, respectively. The volume of distribution of both compounds was low (0.5-0.7 l/kg). The half-lives of navitoclax and ABT-199 were 22.2 and 12.9 hours, respectively. The F of navitoclax and ABT-199 were 56.5 and 38.8%, respectively, in fed intact dogs. In fed TDC dogs, 13.5 and 4.67% of the total navitoclax and ABT-199 doses were observed in lymph with the % F of navitoclax and ABT-199 of 21.7 and 20.2%, respectively. The lower lymphatic transport of ABT-199 corresponds to the lower overall % F of ABT-199 versus navitoclax despite similar systemic availability via the portal vein (similar % F in TDC animals). This is consistent with the higher long chain triglyceride solubility of navitoclax (9.2 mg/ml) versus ABT-199 (2.2 mg/ml). In fasted TDC animals, lymph transport of navitoclax and ABT-199 decreased by 1.8-fold and 10-fold, respectively.

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Section: Discussionmentioning

confidence: 90%

The Role of Lymphatic Transport on the Systemic Bioavailability of the Bcl-2 Protein Family Inhibitors Navitoclax (ABT-263) and ABT-199

Choo

Boggs

Zhu

et al. 2014

Drug Metabolism and Disposition

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“…17,22 Indeed, KTZ, which is itself chiral, has been presumed to be a selective inhibitor of CYP3A4 in human microsomes. 34,35 However, KTZ is not a wholly specific inhibitor of CYP3A isoenzymes in rat, as has been demonstrated by other studies.…”

Section: Discussionmentioning

confidence: 99%

“…15,16 Rat has been used as a model for study of HF lymphatic transport and for the effect of hyperlipidemia on its pharmacokinetics. 15,17 With respect to the metabolism of HF, although it is known that (À)-HF is preferentially metabolized by rat liver homogenates, 18 to date, little is known of the enzymes involved in the formation of equipotent DHF in the rat. It is known that in humans, CYP3A4, CYP2D6, and CYP3A5 are the major enzymes involved in the metabolism of HF.…”

Section: Introductionmentioning

confidence: 99%

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The stereoselective metabolism of halofantrine to desbutylhalofantrine in the rat: Evidence of tissue‐specific enantioselectivity in microsomal metabolism

et al. 2006

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The pharmacokinetics of the antimalarial drug (+/-)-halofantrine are stereoselective in humans and rats. To better understand the stereoselective metabolism of the drug to its primary metabolite, desbutylhalofantrine (DHF), a series of in vitro and in vivo experiments were undertaken in the rat. Formation of (-)-DHF exceeded that of (+)-DHF in liver microsomes [(-):(+) ratio of intrinsic formation clearances = 1.4]. In contrast, in intestinal microsomes no significant stereoselectivity was noted in the formation of the DHF enantiomers. Intestinal microsomes were also less efficient at producing the DHF enantiomers than were liver microsomes. Based on kinetic analysis of the DHF formation, there appeared to be more than one enzyme involved in the biotransformation. (+/-)-Ketoconazole (KTZ) effectively inhibited the formation of both DHF enantiomers by both liver and intestinal microsomes, although the reduction was more marked in liver microsomes. Through a combination of the use of CYP antibodies and recombinant CYP isoenzymes, the involvement of CYP 2B1/2, 3A1, 3A2, 1A1, 2C11, 2C6, 2D1, and 2D2 were implicated in the metabolism of halofantrine to DHF. Of these, CYP3A1/2 and CYP2C11 appeared to be the primary isoenzymes involved, although CYP2C11 showed greater (+)-DHF than (-)-DHF formation, whereas for CYP3A1 it was similar to the isolated rat liver microsomes. In vivo, oral (+/-)-KTZ caused significant increases in plasma halofantrine and decreases in DHF enantiomer plasma concentrations.

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“…Previous studies have suggested that increasing the mass of lipid within the enterocyte may reduce drug exposure to enterocyte-based metabolic enzymes (Van Veld et al, 1987;Trevaskis et al, 2006) and that inhibition of enterocytebased cytochrome P450 metabolism and intestinal P-glycoprotein efflux may significantly enhance the extent of lymphatic transport of metabolically labile drugs (Griffin and O'Driscoll, 2008). Therefore, in light of the significant extent of enterocyte-based conversion of MU to M, the differences in the lipid dependence of lymphatic transport of MU and halo- jpet.aspetjournals.org fantrine may reflect the requirement for a larger intracellular lipid pool to protect the more metabolically labile MU from conversion to M before substantial lymphatic transport can occur.…”

Section: Discussionmentioning

confidence: 99%

Lymphatic Transport of Methylnortestosterone Undecanoate (MU) and the Bioavailability of Methylnortestosterone Are Highly Sensitive to the Mass of Coadministered Lipid after Oral Administration of MU

White¹,

Nguyen²,

Charman³

et al. 2009

The Journal of Pharmacology and Experimental Therapeutics

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The contribution of lymphatic transport to the oral bioavailability of methylnortestosterone (M) after oral administration of the lipophilic prodrug methylnortestosterone undecanoate (MU) has been evaluated, and the sensitivity of lymphatic MU transport to lymphatic lipid transport has been investigated. M and MU were administered intravenously and orally to greyhound dogs to determine absolute bioavailability after oral dosing of MU. MU was also administered orally with differing quantities of food (lipid) to lymph duct-cannulated greyhound dogs to investigate the relative roles of lymph versus blood transport on M bioavailability and the effect of lipid load on systemic exposure. The relationship between lymphatic lipid and MU transport was further investigated in anesthetized rats. The oral bioavailability of M after administration of MU was found to be highly dependent on coadministration of food, and the bioavailability of M increased approximately 700% in fed versus fasted animals. In both cases, lymph diversion resulted in negligible systemic exposure of M, indicating almost complete dependence on lymphatic transport of MU for systemic exposure of M. Lymphatic transport of MU was even more highly dependent on the quantity of coadministered lipid and increased more than 50-fold with increasing lipid load. Therefore, increasing the quantity of food or lipid coadministered with MU stimulated a significant increase in the lymphatic transport of MU and systemic exposure of M. The lipid sensitivity of lymphatic transport of MU is significantly higher than previously observed for more metabolically stable compounds, suggesting a role for coadministered lipid in promoting avoidance of enterocyte-based cleavage of MU.

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An Examination of the Interplay Between Enterocyte-Based Metabolism and Lymphatic Drug Transport in the Rat

Cited by 34 publications

References 13 publications

The Role of Lymphatic Transport on the Systemic Bioavailability of the Bcl-2 Protein Family Inhibitors Navitoclax (ABT-263) and ABT-199

The Role of Lymphatic Transport on the Systemic Bioavailability of the Bcl-2 Protein Family Inhibitors Navitoclax (ABT-263) and ABT-199

The stereoselective metabolism of halofantrine to desbutylhalofantrine in the rat: Evidence of tissue‐specific enantioselectivity in microsomal metabolism

Lymphatic Transport of Methylnortestosterone Undecanoate (MU) and the Bioavailability of Methylnortestosterone Are Highly Sensitive to the Mass of Coadministered Lipid after Oral Administration of MU

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