Whole blood concentrations of mefloquine enantiomers in healthy Thai volunteers

Martin, C. A. E.; Gimenez, François; Bangchang, Kesara Na; Karbwang, Juntra; Wainer, Irving W.; Farinotti, Robert

doi:10.1007/bf00193485

Cited by 19 publications

(8 citation statements)

References 14 publications

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“…Similar findings have been reported in Thai volunteers given a Mefloquine (MQ), a quinoline methanol chemically related to quinine, is an important drug for malaria prophylaxis and single dose of 750 mg MQ [7]. The aims of the present study were to investigate the treatment of multi-drug resistant P. falciparum malaria.…”

supporting

confidence: 67%

Enantioselective pharmacokinetics of mefloquine during long‐term intake of the prophylactic dose

Hellgren

Berggren-Palme

Bergqvist³

et al. 1997

Brit J Clinical Pharma

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Aims To investigate the kinetics of the (+)RS-and (−)SR-enantiomers and the carboxylic acid metabolite (MMQ) of the antimalarial drug mefloquine (MQ) in healthy volunteers. Methods Ten subjects of which three were poor metabolizers of debrisoquine received racemic MQ 250 mg once weekly for 16 weeks. The kinetics were followed in plasma and urine and evaluated by individual kinetic modelling as well as by a nonparametric population kinetic method. Results A two-compartment model adequately described the disposition of (+)RS-MQ. CL/F was 6.5±1.8 l h The aims of the present study were to investigate the treatment of multi-drug resistant P. falciparum malaria. The available preparation is a racemate of the (+)RS-MQ and enantioselective kinetics of MQ during long-term prophylaxis including the early phase after drug intake, the renal (−)SR-MQ enantiomers. Both enantiomers are active against P. falciparum in vitro [1] although a slightly higher excretion of the enantiomers and to define any difference between poor and extensive metabolizers of debrisoquine in activity for (+)RS-MQ has been reported [2]. A major problem with MQ is the occurrence of neuropsychiatric the elimination of the MQ enantiomers. For determination of the typical kinetic characteristics for (+)RS-MQ and adverse reactions, in particular after therapeutic doses [3]. It has not been clarified whether the potential to cause adverse (−)SR-MQ in this population, we performed a population analysis using the nonparametric NPEM method [8]. reactions differs between the enantiomers. MQ is a local irritant that cannot be given intravenously. Hence, absoluteCompared with the standard two-stage method, more accurate estimates of the distribution of kinetic parameters bioavailability and systemic clearance are not known. The metabolism of MQ is not well characterised. At steady-state, in a population can be obtained with the population methodology as it takes into account the quality of the data an average of 9% of the dose is excreted unchanged in urine and 4% as the carboxylic acid metabolite (MMQ) [4]. MMQ from each subject and the covariance between the parameters. is regarded as the main metabolite in man but it has no significant antimalarial effect in vitro [5]. Methods A recent pharmacokinetic study during prophylactic intake of MQ (250 mg once weekly) demonstrated a Subjects significantly longer mean half-life of (−)SR-MQ compared Ten healthy adult Caucasian volunteers (mean age 42 years, range 29-50 years, six females and four males) participated

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supporting

confidence: 67%

Enantioselective pharmacokinetics of mefloquine during long‐term intake of the prophylactic dose

Hellgren

Berggren-Palme

Bergqvist³

et al. 1997

Brit J Clinical Pharma

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“…The higher AUC value in whole blood for (À)mefloquine was also observed in plasma samples after oral administration in adult Caucasian healthy subjects , adult Thai healthy subjects (Martin et al, 1994) and Thai malaria children (Bourahla et al, 1996). In contrast, after repeated oral administration of the racemic mixture in rats, plasma concentrations of ( þ )mefloquine were higher than those of its antipode (Baudry et al, 1997), opposite to those obtained after oral administration in humans and intraperitoneal injection in mice.…”

Section: Stereoselectivity In Blood Pharmacokineticsmentioning

confidence: 90%

Cerebral uptake of mefloquine enantiomers with and without the P‐gp inhibitor elacridar (GF1210918) in mice

Lagerie

Comets

Gautrand

et al. 2004

British J Pharmacology

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1 Mefloquine is a chiral neurotoxic antimalarial agent showing stereoselective brain uptake in humans and rats. It is a substrate and an inhibitor of the efflux protein P-glycoprotein. 2 We investigated the stereoselective uptake and efflux of mefloquine in mice, and the consequences of the combination with an efflux protein inhibitor, elacridar (GF120918) on its brain transport. 3 Racemic mefloquine (25 mg kg À1 ) was administered intraperitoneally with or without elacridar (10 mg kg À1 ). Six to seven mice were killed at each of 11 time-points between 30 min and 168 h after administration. Blood and brain concentrations of mefloquine enantiomers were determined using liquid chromatography. 4 A three-compartment model with zero-order absorption from the injection site was found to best represent the pharmacokinetics of both enantiomers in blood and brain. (À)Mefloquine had a lower blood and brain apparent volume of distribution and a lower efflux clearance from the brain, resulting in a larger brain/blood ratio compared to ( þ )mefloquine. Elacridar did not modify blood concentrations or the elimination rate from blood for either enantiomers. However, cerebral AUC inf of both enantiomers were increased, with a stronger effect on ( þ )mefloquine. The efflux clearance from the brain decreased for both enantiomers, with a larger decrease for ( þ )mefloquine. 5 After administration of racemic mefloquine in mice, blood and brain pharmacokinetics are stereoselective, ( þ )mefloquine being excreted from brain more rapidly than its antipode, showing that mefloquine is a substrate of efflux proteins and that mefloquine enantiomers undergo efflux in a stereoselective manner. Moreover, pretreatment with elacridar reduced the brain efflux clearances with a more pronounced effect on ( þ )mefloquine.

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“…Our data showed that, in BALB/c mice, the t 1/2 for the threo compounds was half that of the erythro compounds, which could explain, at least in part, our findings. It should be noted, however, that pharmacokinetic studies in healthy humans have shown that the halflife of (Ϫ)-erythro-mefloquine is significantly longer than that of (ϩ)-erythro-mefloquine; no stereoselectivity was seen for values of time to maximum concentration of drug in serum (T max ) (18). Similar results were observed in adults with uncomplicated multidrugresistant falciparum malaria, where the mean ratio between the concentrations of the (Ϫ)-and (ϩ)-enantiomers of erythro-mefloquine was 3.37 (12).…”

Section: What Could Explain the Different Activities Among The Enantimentioning

confidence: 99%

Identification of (+)-Erythro-Mefloquine as an Active Enantiomer with Greater Efficacy than Mefloquine against Mycobacterium avium Infection in Mice

Bermudez

Inderlied

Kolonoski³

et al. 2012

Antimicrob Agents Chemother

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Whole blood concentrations of mefloquine enantiomers in healthy Thai volunteers

Cited by 19 publications

References 14 publications

Enantioselective pharmacokinetics of mefloquine during long‐term intake of the prophylactic dose

Enantioselective pharmacokinetics of mefloquine during long‐term intake of the prophylactic dose

Cerebral uptake of mefloquine enantiomers with and without the P‐gp inhibitor elacridar (GF1210918) in mice

Identification of (+)-Erythro-Mefloquine as an Active Enantiomer with Greater Efficacy than Mefloquine against Mycobacterium avium Infection in Mice

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