Stereoselective Pharmacokinetics of Mefloquine in Healthy Caucasians after Multiple Doses

Gimenez, François; Pennie, Ross A.; Koren, Gideon; Crevoisier, C; Wainer, Irving W.; Farinotti, Robert

doi:10.1002/jps.2600830613

Cited by 49 publications

(25 citation statements)

References 20 publications

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“…The ratio of the AUC of the metabolite to the AUC of the parent drug (the metabolic ratio) was about 2 for both patients, a value which is within the range (1.3 to 4.2) observed in healthy volunteers (5,18). The ratio of the concentration of mefloquine on day 49 to its concentration on day 7 (the accumulation ratio) for patient 1 was 4.2, a value which is identical to that observed previously in healthy volunteers (6). For patient 2, the accumulation ratio could not be calculated exactly, because no predose sample was taken on day 7 and steady-state conditions were not sufficiently defined.…”

supporting

confidence: 80%

Influence of hemodialysis on plasma concentration-time profiles of mefloquine in two patients with end-stage renal disease: a prophylactic drug monitoring study

Crevoisier

Joseph

Fischer

et al. 1995

Antimicrob Agents Chemother

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Prophylactic drug monitoring of mefloquine and its carboxylic acid metabolite were studied in two patients with end-stage renal disease undergoing long-term hemodialysis treatment. The patients, short-term travellers to areas where malaria is endemic, took 250 mg of mefloquine (Lariam) once weekly for 2 weeks before and during their 3-week stay abroad and for one week after their return. Pre-and postdialysis blood samples were drawn before their departure and after their return. The concentration-time profiles of mefloquine and its metabolite in plasma samples taken before and after the 3-to 4-h dialysis sessions were similar. Mefloquine and its metabolite could not be detected in the dialysate. These findings show that mefloquine and its metabolite are not, or are very poorly, removed by hemodialysis. Concentrations in plasma and accumulation kinetics were similar to those reported for healthy volunteers and were associated with high prophylactic efficacy against malaria. No special dosage adjustments have to be made in patients undergoing hemodialysis treatment to achieve concentrations in plasma similar to those in healthy volunteers. The prophylactic dose of mefloquine could be given before, during, or after the hemodialysis session.

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supporting

confidence: 80%

Influence of hemodialysis on plasma concentration-time profiles of mefloquine in two patients with end-stage renal disease: a prophylactic drug monitoring study

Crevoisier

Joseph

Fischer

et al. 1995

Antimicrob Agents Chemother

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“…Mefloquine is a 4-quinolinemethanol available commercially as the racemic 50:jo mixture pharmacokinetics are highly stereo-selective with a significantly longer mean terminal half-life for the SR enantiomer (430 hours) compared to the RS (172 hours). During 250 mg weekly chemoprophylaxis the mean steady-state SR concentration in plasma was 6.6 times higher than that of the RS (Gimenez et al 1994). Furthermore, the SR enantiomer is a more potent acetylcholinesterase inhibitor (Ngiam & Go 1987).…”

Section: Introductionmentioning

confidence: 81%

Mefloquine tolerability during chemoprophylaxis: focus on adverse event assessments, stereochemistry and compliance

Schlagenhauf

Steffen

Lobel

et al. 1996

Tropical Med Int Health

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SummaryThis longitudinal study of travellers to Africa taking mefloquine ( M Q ) chemoprophylaxis aimed to quantify and assess non-serious adverse events (AE) occurring during short-term prophylaxis and relate these to concentrations of racemic MQ, its enantiomers and metabolite. A total of 420 volunteers ( 5 2 % F) participated. AEs with some impact on activities were reported by I I .2% of participants including 7.9 % of neurological/psychiatric symptoms. Women were more likely to report AEs (P=0.02). The standardized questionnaires used showed more pathological indicators in travellers who reported subjective AE with significantly more dizziness, distress, sleep disturbances and a high total mood disturbance (TMD) in the AE group. There was, however, no significant performance deficit in computerized psychomotor tests in those experiencing AE. Furthermore, no significant differences were observed in enantiomer ratios, metabolite concentrations, or racemic M Q levels in participants with or without AEs suggesting that these factors are not the main predictors of mefloquine intolerability. keywords mefloquine, adverse event correspondence

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“…Stereoselectivity plays a role in human mefloquine pharmacokinetics. (Ϫ)-Mefloquine has consistently shown significantly higher peak concentrations and areas under the curve as well as longer plasma half-lives than (ϩ)-mefloquine (2,3,8,9,24). Taggart et al (23) reported that quinine produces higher plasma concentrations than quinidine.…”

Section: Discussionmentioning

confidence: 99%

Crystal Structure of (−)-Mefloquine Hydrochloride Reveals Consistency of Configuration with Biological Activity

Karle

2002

Antimicrob Agents Chemother

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The absolute configuration of (؊)-mefloquine has been established as 11R,12S by X-ray crystallography of the hydrochloride salt, thus allowing comparison of the configuration of mefloquine's optical isomers to those of quinine and quinidine. (؊)-Mefloquine has the same stereochemistry as quinine, and (؉)-mefloquine has the same stereochemistry as quinidine. Since (؉)-mefloquine is more potent than (؊)-mefloquine in vitro against the D6 and W2 strains of Plasmodium falciparum and quinidine is more potent than quinine, a common stereochemical component for antimalarial activity is implicated. The crystal of (؊)-mefloquine hydrochloride contained four different conformations which mainly differ in a small rotation of the piperidine ring. These conformations are essentially the same as the crystalline conformations of racemic mefloquine methylsulfonate monohydrate, mefloquine hydrochloride, and mefloquine free base. Quinine and quinidine (Fig. 1), antimalarial agents isolated from the bark of the Cinchona tree, are diastereomers, but they mirror each other at carbons C-8 and C-9. In vitro quinidine is more potent than quinine against many strains of Plasmodium falciparum. Specifically, quinidine is 2.3 and 2.8 times more potent than quinine against the chloroquine-sensitive Sierra Leone D-6 clone and the chloroquine-resistant Indochina W-2 clone, respectively (15). Quinidine is 2.5 times more potent than quinine and cinchonine (the demethoxy analog of quinidine) is 2.8 times more potent than cinchonidine (the demethoxy analog of quinine) in vitro against Papua New Guinea FCQ-27/PNG P. falciparum (25). Similarly, quinidine was 2.2 and 3.2 times more potent than quinine against Cameroon chloroquine-resistant FCM 29 and Ivory Coast chloroquine-sensitive L-3 strains, respectively (1). Against clinical isolates from Liberia, quinidine was on average 3 times more potent than quinine (4). Clinical differences in the antimalarial activities of quinine and quinidine have also been reported. Compared to quinine, quinidine was twice as effective against induced McClendon P. falciparum infections (23) and more potent clinically against Thai P. falciparum (18,26).Mefloquine, a synthetic analog of quinine and quinidine, is marketed in racemic form under the trade name Lariam. Mefloquine is basically a structurally simpler form of quinine and quinidine. Mefloquine differs from the cinchona alkaloids in that it has a different substitution on the quinoline ring, a piperidine ring rather than the bicyclo quinuclidine ring, and no vinyl group (see Fig. 1). However, the C-8 and C-9 chiral centers of the cinchona alkaloids are preserved in the mefloquine molecule (numbered C-12 and C-11, respectively). Thus, one enantiomer of mefloquine will share the same stereochemistry as quinine and the other enantiomer of mefloquine will share the same stereochemistry as quinidine at the equivalent chiral centers.Since quinine and quinidine possess different antimalarial activities, the (ϩ) and (Ϫ) isomers of mefloquine were tested against P. falc...

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Stereoselective Pharmacokinetics of Mefloquine in Healthy Caucasians after Multiple Doses

Cited by 49 publications

References 20 publications

Influence of hemodialysis on plasma concentration-time profiles of mefloquine in two patients with end-stage renal disease: a prophylactic drug monitoring study

Influence of hemodialysis on plasma concentration-time profiles of mefloquine in two patients with end-stage renal disease: a prophylactic drug monitoring study

Mefloquine tolerability during chemoprophylaxis: focus on adverse event assessments, stereochemistry and compliance

Crystal Structure of (−)-Mefloquine Hydrochloride Reveals Consistency of Configuration with Biological Activity

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