Stereoselective halofantrine and desbutylhalofantrine disposition in the rat: cardiac and plasma concentrations and plasma protein binding

Brocks, Dion R.

doi:10.1002/bdd.286

Cited by 17 publications

(14 citation statements)

References 16 publications

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“…These findings likely reflect a gradual change to the proportion of the (+) enantiomer present in systemic blood. Previous data have shown that systemic levels of the (+)-Hf enantiomer in both human and rat are approximately 1.5 times higher than its antipode [1][2][3][4][5][6][7], and preliminary plasma assays performed in our laboratory have indicated that the same trend is followed in the dog (data not shown). At later time periods, when intestinal lymphatic transport has slowed, an increasing proportion of the Hf in thoracic lymph is present as a result of equilibration of Hf across lymphatic and blood capillaries.…”

Section: Resultssupporting

confidence: 64%

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Does stereoselective lymphatic absorption contribute to the enantioselective pharmacokinetics of halofantrine In Vivo?

Shackleford

Porter

Charman

2003

Biopharm & Drug Disp

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Halofantrine (Hf) is a chiral, lipophilic phenanthrene methanol antimalarial which exhibits both enantioselective plasma pharmacokinetics and extensive lymphatic absorption when administered postprandially. In order to determine whether enantioselective lymphatic absorption contributes to the previously reported enantioselective pharmacokinetics of Hf, lymph samples collected from thoracic duct-cannulated dogs dosed with racemic Hf (100 mg, administered postprandially) were assayed with a chiral HPLC method capable of quantifying the relative amounts of (+)- and (-)-Hf. During the period when the majority (>95%) of Hf transport into lymph occurred (0-5 h post dose), essentially equal amounts of the two enantiomers were present in the intestinal lymph. At later times (e.g. 5-12 h post dose), there was a steady increase in the fraction of (+)-Hf present in lymph. The trends evident at later time points most likely reflect an increase in the proportion of (+)-Hf present in systemic blood, (resulting from enantioselective systemic metabolism) and a corresponding increase in (+)-Hf in the thoracic lymph by equilibration of drug across blood and lymphatic capillaries, as opposed to enantioselective lymphatic transport per se. This study was the first to examine the possibility of stereoselectivity in lymphatic transport, however, the data suggest that drug absorption (at least in the case of halofantrine) via the intestinal lymphatics is not enantioselective.

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Section: Resultssupporting

confidence: 64%

“…relative enrichment of the (+)-enantiomer (data not shown) [1][2][3][4][5][6][7]. transport of the drug-lipoprotein complex via the intestinal lymphatic to the thoracic lymph.…”

Section: Resultsmentioning

confidence: 93%

Does stereoselective lymphatic absorption contribute to the enantioselective pharmacokinetics of halofantrine In Vivo?

Shackleford

Porter

Charman

2003

Biopharm & Drug Disp

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“…9 As such, stereoselectivity in the CL of HF enantiomers is highly dependent on CLint and the degree of plasma protein binding, which is reportedly high. 14,15 Because in rat the plasma unbound fraction is the same for both HF enantiomers, 14 stereoselectivity in CLint of plasma unbound drug is expected to be a major contributor to stereoselectivity in CL of HF. Indeed, all metabolic assessments involving harvested hepatic microsomes, and the predominant metabolizing recombinant CYP3A2, in which (À)-DHF was preferentially formed, were in line with this belief.…”

Section: Discussionmentioning

confidence: 99%

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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“…This study was the to provide information regarding LDL chiral selectivity. In another study, halofantrine enantiomers showed some stereoselectivity for lipoprotein binding in vitro , but they did not show stereoselectivity for plasma protein binding 115 .…”

Section: Stereoselectivity Of Plasma Protein Binding To Chiral Drugsmentioning

confidence: 93%

Stereoselective binding of chiral drugs to plasma proteins

et al. 2013

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Chiral drugs show distinct biochemical and pharmacological behaviors in the human body. The binding of chiral drugs to plasma proteins usually exhibits stereoselectivity, which has a far-reaching influence on their pharmacological activities and pharmacokinetic profiles. In this review, the stereoselective binding of chiral drugs to human serum albumin (HSA), α1-acid glycoprotein (AGP) and lipoprotein, three most important proteins in human plasma, are detailed. Furthermore, the application of AGP variants and recombinant fragments of HSA for studying enantiomer binding properties is also discussed. Apart from the stereoselectivity of enantiomer-protein binding, enantiomer-enantiomer interactions that may induce allosteric effects are also described. Additionally, the techniques and methods used to determine drug-protein binding parameters are briefly reviewed.

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Stereoselective halofantrine and desbutylhalofantrine disposition in the rat: cardiac and plasma concentrations and plasma protein binding

Cited by 17 publications

References 16 publications

Does stereoselective lymphatic absorption contribute to the enantioselective pharmacokinetics of halofantrine In Vivo?

Does stereoselective lymphatic absorption contribute to the enantioselective pharmacokinetics of halofantrine In Vivo?

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

Stereoselective binding of chiral drugs to plasma proteins

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