A physicochemical basis for the extensive intestinal lymphatic transport of a poorly lipid soluble antimalarial, halofantrine hydrochloride, after postprandial administration to dogs

Khoo, Shui‐Mei; Prankerd, Richard J.; Edwards, Glenn A.; Porter, Christopher John; Charman, William N.

doi:10.1002/jps.10045

Cited by 40 publications

(32 citation statements)

References 21 publications

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“…The rate profiles for saquinavir mesilate and free base were also similar (data not shown). This suggests the partial conversion of the saquinavir mesilate to the saquinavir free base (pK a $ 7.1) following administration in the gastrointestinal tract, similar to the acid-base conversion that has previously been reported for halofantrine hydrochloride and free base (Khoo et al 2002).…”

Section: Intestinal Lymphatic Transport Of Saquinavir From Lipid-basesupporting

confidence: 80%

A comparison of intestinal lymphatic transport and systemic bioavailability of saquinavir from three lipid-based formulations in the anaesthetised rat model

Griffin

O’Driscoll

2006

Journal of Pharmacy and Pharmacology

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Saquinavir is a lipophilic, poorly water-soluble HIV protease inhibitor that undergoes extensive firstpass metabolism and exhibits poor oral bioavailability. Redirection of the absorption pathway of anti-HIV compounds from the portal blood to the HIV-rich intestinal lymphatics may enhance therapeutic efficacy and reduce the extent of the first-pass effect. This study investigates the potential of targeted intestinal lymphatic transport of saquinavir via a lipid formulation approach. Three formulations containing oleic acid were examined: cremophor-oleic acid mixed micelles, D-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS)-oleic acid mixed micelles and an oleic acid microemulsion. The mesenteric lymph duct cannulated anaesthetised rat model was employed. Plasma and lymph samples were analysed by HPLC. Lymph triglyceride was measured using an enzymatic colorimetric technique. The extent of lymphatic transport from the lipid vehicles was 0.025-0.05% of the dose administered. The microemulsion produced higher and more prolonged mesenteric lymph concentrations than the micellar formulations. A strong correlation existed between the concentration of saquinavir in intestinal lymph and lymph triglyceride levels. The systemic bioavailability was estimated to be 8.5% and 4.8% for the cremophor mixed micelle and the microemulsion, respectively. The cremophor mixed micelles produced higher bioavailability than TPGS mixed micelles, implying that the nature of the surfactant can influence the distribution of drug between lymph and plasma.

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Section: Intestinal Lymphatic Transport Of Saquinavir From Lipid-basesupporting

confidence: 80%

A comparison of intestinal lymphatic transport and systemic bioavailability of saquinavir from three lipid-based formulations in the anaesthetised rat model

Griffin

O’Driscoll

2006

Journal of Pharmacy and Pharmacology

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“…For example, Frey et al (1979) compared the relative bioavailabilities of orally administered T (in the form micronized T, crystalline TU, and TU in arachis oil) and reported an increase in systemic T exposure when TU was administered in conjunction with a high-fat meal. Although this result is consistent with enhanced lymphatic drug transport due to the simultaneous absorption of dietary lipids (Geurts and Coelingh Bennink, 2000;Khoo et al, 2001Khoo et al, , 2002Bagchus et al, 2003), the data are not conclusive nor quantitatively insightful. Similarly, Tauber et al (1986) reported that the mean absolute bioavailability of T after oral administration of TU to women was 6.83 Ϯ 3.32%, whereas the mean absolute bioavailability of orally administered T after oral T ad- jpet.aspetjournals.org Downloaded from ministration was 3.64 Ϯ 2.45%.…”

Section: Discussionmentioning

confidence: 79%

Contribution of Lymphatically Transported Testosterone Undecanoate to the Systemic Exposure of Testosterone after Oral Administration of Two Andriol Formulations in Conscious Lymph Duct-Cannulated Dogs

Shackleford¹,

Faassen²,

Houwing³

et al. 2003

J Pharmacol Exp Ther

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100

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Orally administered testosterone (T) is ineffective in the treatment of male androgen deficiency syndromes due to extensive presystemic first-pass metabolism. In contrast, the lipophilic long-chain ester testosterone undecanoate (TU) exhibits androgenic activity that has been attributed to formation of T via systemic hydrolysis of lymphatically transported TU. However, there are no definitive data regarding the oral bioavailability of TU or the extent to which lymphatically transported TU contributes to the systemic availability of T after oral TU administration. This report describes the application of stable isotope methodology in a thoracic lymph duct-cannulated dog model to study the oral bioavailability and lymphatic transport of TU after postprandial administration. When administered as either Andriol or Andriol Testocaps, the mean (ϮS.E., n ϭ 4) absolute bioavailability of TU was 3.25 Ϯ 0.48 and 2.88 Ϯ 0.88%, respectively, and lymphatically transported TU accounted for between 91.5 and 99.7% of the systemically available ester. Model-independent pharmacokinetic analysis indicated that 83.6 Ϯ 1.6 and 84.1 Ϯ 8.2% of the systemically available T, resulting from Andriol or Andriol Testocaps, respectively, was due to systemic hydrolysis of lymphatically transported TU. These data demonstrate that intestinal lymphatic transport of TU produces increased systemic exposure of T by avoiding the extensive first-pass effect responsible for the inactivation of T after oral administration.The oral administration of testosterone (T) is ineffective in the treatment of male androgen deficiency syndromes because T is subject to almost quantitative presystemic firstpass metabolism mediated by the gut wall and liver (Daggett et al., 1978). Conversely, the lipophilic ester prodrug testosterone undecanoate (TU) demonstrates androgenic activity after oral administration to rats and humans (Hirschhauser et al., 1975;Maisey et al., 1981;Skakkebaek et al., 1981). Because oral administration of TU results in the appearance of TU (and the metabolite 5␣-dihydrotestosterone undecanoate; DHTU) in lymph of thoracic duct-cannulated rats Noguchi et al., 1985) and humans (for whom a thoracic duct cannula was inserted after neck dissection surgery; Horst et al., 1976), the androgenic activity of orally administered TU is generally attributed to T (and 5␣-dihydrotestosterone; DHT) formed during the systemic metabolic elimination of TU, which escaped the presystemic first-pass effect due to intestinal lymphatic absorption and transport Horst et al., 1976).Although it is accepted that lymphatic absorption of TU likely contributes to systemic T exposure after oral TU administration, the extent of that contribution has not been quantitatively determined. Indirect evidence of lymph transport of TU in humans was reported where the systemic exposure of T increased after oral TU administration in the fed state, compared with administration in the fasted state (Frey et al., 1979;Bagchus et al., 2003). However, human studies cannot determine ...

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“…These data are consistent with the in vitro data, 2 and also with recent data from this laboratory, which has described similar biopharmaceutical exposure after post-prandial administration of either Hf base or Hf Á HCl formulations to greyhound dogs. 17 By way of explanation, these recent data indicate that the apparent pK a of Hf in the intestinal environment (i.e., in the presence of mixed bile salt/lecithin micelles and lipid) is approximately 6.9, 30 as opposed to the value of 8-9 that might be predicted for a tertiary amine and that which is observed in a pure aqueous milieu for Hf. 31 Therefore, it is likely that the higher solubility of Hf Á HCl in the micellar aqueous phase (when compared with Hf base) leads to drug transfer out of the digesting lipid into the mixed micelles, where equilibration to Hf base occurs.…”

Section: Lipid Suspension Formulations (Study 2)mentioning

confidence: 92%

Use of in vitro lipid digestion data to explain the in vivo performance of triglyceride-based oral lipid formulations of poorly water-soluble drugs: Studies with halofantrine

Porter

Kaukonen

Taillardat-Bertschinger

et al. 2004

Journal of Pharmaceutical Sciences

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203

139

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A physicochemical basis for the extensive intestinal lymphatic transport of a poorly lipid soluble antimalarial, halofantrine hydrochloride, after postprandial administration to dogs

Cited by 40 publications

References 21 publications

A comparison of intestinal lymphatic transport and systemic bioavailability of saquinavir from three lipid-based formulations in the anaesthetised rat model

A comparison of intestinal lymphatic transport and systemic bioavailability of saquinavir from three lipid-based formulations in the anaesthetised rat model

Contribution of Lymphatically Transported Testosterone Undecanoate to the Systemic Exposure of Testosterone after Oral Administration of Two Andriol Formulations in Conscious Lymph Duct-Cannulated Dogs

Use of in vitro lipid digestion data to explain the in vivo performance of triglyceride-based oral lipid formulations of poorly water-soluble drugs: Studies with halofantrine

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