A Conscious Dog Model for Assessing the Absorption, Enterocyte‐Based Metabolism, and Intestinal Lymphatic Transport of Halofantrine

doi:10.1002/jps.1110

Journal of Pharmaceutical Sciences

Volume 90, Issue 10, October 2001, Pages 1599-1607

https://doi.org/10.1002/jps.1110 Get rights and content

ABSTRACT

Postprandial administration of halofantrine (Hf), an important antimalarial, leads to 3‐ and 12‐fold increases in oral bioavailability in humans and beagles, respectively, and corresponding 2.4‐fold and 6.8‐fold decreases in metabolic conversion to desbutylhalofantrine (Hfm). Factors contributing to the decreased postprandial metabolism of Hf could include inhibition of presystemic CYP3A metabolism by food components and/or recruitment of the intestinal lymphatics as an absorption pathway. Although previous rat studies confirmed Hf base is a substrate for lymphatic transport, it is difficult to extrapolate such data to higher species, as the largely constant bile flow in a rat precludes attainment of representative pre‐ and postprandial states, and formulations administered to rats are often not relevant to higher species. These limitations have now been addressed by development of a conscious dog model that allows simultaneous study of intestinal lymphatic and nonlymphatic drug absorption and aspects of enterocyte‐based drug metabolism. After oral administration of 100 mg Hf base, the mean fasted and postprandial lymphatic transport was 1.3% and 54% of the administered dose, respectively. Comparison of portal and systemic plasma Hfm concentration profiles suggested enterocyte‐based conversion of Hf to Hfm; however, the proportion of Hf metabolized to Hfm was similar after fasted or postprandial administration. Hence, it appears that the previously observed decrease in the postprandial metabolism of Hf is largely a consequence of significant postprandial intestinal lymphatic transport (which bypasses first pass hepatic metabolism). This new dog model will facilitate identification of the key factors that impact bioavailability, lymphatic transport, and metabolic profiles of highly lipophilic drugs. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1599–1607, 2001

Section snippets

INTRODUCTION

Halofantrine (Hf) is an important antimalarial drug effective in the treatment of multidrug resistant Plasmodium falciparum. Absorption of Hf after fasted oral administration of the commercially available Hf·HCl tablet is low and highly variable, which gives rise to concerns of treatment failure and selection of drug‐resistant strains.¹ Postprandial administration increases Hf oral bioavailability 3‐fold in humans and 12‐fold in beagles,²^,³ due at least in part to enhanced dissolution and drug

Chemicals, Reagents, and Hf Formulation

Hf base was supplied by SmithKline Beecham Pharmaceuticals (Mysore, India), and PEG 600 (poly ethylene glycol 6000) was from Ajax Chemicals (Australia). Acetylpromazine maleate (Delvet Pty. Ltd., Australia), propofol (Schering‐Plough, Australia), cephazolin (Sigma Pharmaceuticals, Australia), carprofen (Pfizer, Australia), Iohexol (Nycomed, Australia), and polydioxinone sutures (Ethicon, USA) were used as received. Normal saline (0.9%) and Lactated Ringer's Solution (an isotonic solution

RESULTS AND DISCUSSION

Rats are often employed to investigate intestinal lymphatic transport of lipophilic drugs and for examining the effects of prototype lipidic formulations on lymphatic transport and bioavailability. However, extrapolation of rat data to higher species is difficult, as bile flow in the rat is essentially continuous and independent of food intake. To address these limitations, we have developed a new conscious dog model that enables collection of thoracic lymph and sampling of portal and systemic

ACKNOWLEDGEMENTS

This work was supported, in part, by SmithKline Beecham Pharmaceuticals (UK). We thank Dr. Michelle McIntosh for assistance with lymph lipoprotein fractionation, and S.M.K. gratefully acknowledges scholarship support provided by an Australian Postgraduate Award.

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Mechanistic Oral Absorption Modeling of Halofantrine: Exploring the Role of Intestinal Lymphatic Transport
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Citation Excerpt :
In contrast, only a 2-fold increase in the AUC of the primary metabolite, desbutylhalofantrine was observed in the fed state, suggesting bypass of first-pass hepatic metabolism.7 Later canine studies including cannulation of the thoracic lymph duct identified that >50% of the halofantrine dose was absorbed via lymphatic transport in the fed state, compared to 1.3% in the fasted state.6 While the intrinsic solubility of halofantrine is extremely low (≤5 ng/mL), solubility is improved around 150,000-fold in fed simulated intestinal fluid (FeSSIF–V2) and a further 68-fold in triglycerides (~50 mg/mL),4,10,11 consistent with other highly lipid soluble compounds that are known to be transported in intestinal lymph.1
Absorption via the intestinal lymphatic system is known to be important for some highly lipophilic compounds, and can be associated with unique pharmacokinetic properties due to evasion of hepatic first-pass metabolism. This work aimed to develop a physiologically-based pharmacokinetic model incorporating the role of lymphatic transport in a physiologically-based, mechanistic oral absorption model, using halofantrine as a model compound. Simcyp V19 was used for model development; oral absorption was characterized using the multi-layer gut wall (M-ADAM) model, and the model was constructed and verified using parameters derived from in vitro experiments and clinical PK data. The final model appeared to adequately capture halofantrine pharmacokinetics in the fasted state and the magnitude of the effect of food on halofantrine total exposure; the effect of food on peak exposure was slightly underpredicted, which may be due to transient post-prandial changes in protein binding. The model simulated halofantrine fraction absorbed (f_a) via the lymph in the fed state was 0.26, representing 62% of the increase in f_a in the fed state over fasting. This work demonstrates that a PBPK modeling approach can be used to mechanistically describe oral absorption incorporating intestinal lymphatic transport.

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Research ArticlesA Conscious Dog Model for Assessing the Absorption, Enterocyte‐Based Metabolism, and Intestinal Lymphatic Transport of Halofantrine

ABSTRACT

Section snippets

INTRODUCTION

Chemicals, Reagents, and Hf Formulation

RESULTS AND DISCUSSION

ACKNOWLEDGEMENTS

J Pharm Sci

J Pharm Sci

Adv Drug Del Rev

Int J Pharm

J Pharm Sci

J Pharm Sci

Int J Pharm

J Surg Res

J Pharm Biomed Anal

Int J Pharm

Trans R Soc Trop Med Hyg

Research Articles
A Conscious Dog Model for Assessing the Absorption, Enterocyte‐Based Metabolism, and Intestinal Lymphatic Transport of Halofantrine