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Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Halofantrine is an antimalarial drug used in the treatment of chloroquine-resistant strains of P. falciparum. Halofantrine is chiral and is administered as a racemate. The pharmacokinetics of halofantrine are stereoselective in humans, with the (+)-enantiomer attaining higher plasma concentrations than antipode (Karbwang and Na Bangchang 1994; Warhurst 1987). The t1/2β of halofantrine is 2–5 days in patients with malaria. Halofantrine biotransforms in the liver to its major metabolite, N-desbutylhalofantrine (Figure 3.89), which is the major circulating metabolite and is equipotent to halofantrine in antimalarial activity (Karbwang and Na Bangchang 1994). Recombinant CYP3A4 and 2D6 convert halofantrine to its N-debutylated metabolite, but the metabolism of halofantrine to its N-desbutyl metabolite in human liver microsomes shows no correlation with CYP2D6 genotypic or phenotypic status and there is no consistent inhibition by quinidine (Halliday et al. 1995). However, halofantrine causes a dose-dependent increase in prolongation of the electrocardiac QT interval and, in some susceptible patients, torsade de pointes, a potentially fatal cardiac arrhythmia (Nosten et al. 1993; Traebert and Dumotier 2005; Wesche et al. 2000; White 2007).
Treatment and prevention of malaria
Published in David A Warrell, Herbert M Gilles, Essential Malariology, 2017
David A Warrell, William M Watkins, Peter A Winstanley
Quinine has a narrow therapeutic range, and doses should always be adjusted for body weight (see Table 12.3); even unconscious patients should be weighed wherever possible. A loading dose should be given to achieve therapeutic concentrations more rapidly. There is some evidence from clinical trials of the clinical benefit of a loading dose, but the practice is based largely upon sound pharmacokinetic data and empirical medical practice. Contraindications to the use of a loading dose are: treatment with quinine or quinidine in the previous 24 hourstreatment with halofantrine in the previous 24 hours.
Halofantrine
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Ric N. Price, Julie A. Simpson, James S. McCarthy
Halofantrine is an arylaminoalcohol anti-malarial drug that was first identified as a potential anti-malarial agent by the World War II Chemotherapy program and subsequently developed by the Walter Reed Army Institute of Research (Schuster and Canfield, 1989). It was first marketed in 1984 as Halfan by Smith Kline and French. The chemical structure of halofantrine is [R,S]-1,3-dichloro-α-[2-{dibutylamino} ethyl]-6-fluoromethyl 1-9-phenanthrenemethanol hydrochloride, its molecular formula is C26H30O2F3NO, and its molecular weight is 500.4 g/mol. Halofantrine is a racemate with two enantiomers, forming a molecular structure similar to that of the other class II schizonticidal drugs (quinine, mefloquine, and lumefantrine). The chemical structure is shown in Figure 179.1. The drug was marketed for use as a treatment for acute malaria until it was recognized that its variable pharmacokinetic profile, particularly its pronounced food effect, resulted in some individuals developing a life-threatening prolongation of the QT interval, leading to torsades de pointes and sudden cardiac death. As a consequence, the drug was withdrawn from the market. Halofantrine was available for oral administration in tablet form (250 mg), capsules, and flavored suspension, and in an intravenous preparation.
Enhanced dissolution and bioavailability of revaprazan using self-nanoemulsifying drug delivery system
Published in Pharmaceutical Development and Technology, 2022
Yoon Tae Goo, Cheol-Ki Sa, Min Song Kim, Gi Hyeong Sin, Chang Hyun Kim, Hyeon Kyun Kim, Myung Joo Kang, Sangkil Lee, Young Wook Choi
The self-nanoemulsifying drug delivery system (SNEDDS) is an isotropic mixture of oils, surfactants, and cosurfactants (Wu et al. 2006). This mixture spontaneously aggregates and forms nanosized oil-in-water emulsions when diluted with aqueous media such as GI fluids under gentle agitation (Wu et al. 2006). Spontaneous formation of a nanoemulsion incorporates the drugs in the mixture, thereby enhancing their solubilization (Jin et al. 2011). Small size droplets have some advantages such as rapid dissolution and enhanced permeation owing to their large surface area (Yao et al. 2008; Zhang et al. 2019). Furthermore, SNEDDSs are well known as digestible lipidic carriers having an oil component which encourages lymphatic absorption (Singh et al. 2009). Following oral administration of halofantrine-loaded SNEDDS, approximately 30% of halofantrine was detected in thoracic lymph in a fasted dog model (Khoo et al. 2003).