PubMed Health⌕ Search

Biomedical subjects

D J Back

Publications and source records attributed to D J Back.

At least 73 records · Page 4Linked to original sources
PubMed1997

Effects of drugs on 2',3'-dideoxy-2',3'-didehydrothymidine phosphorylation in vitro.

Drugs commonly administered to patients infected with the human immunodeficiency virus (HIV) have been studied for their propensity to alter the intracellular phosphorylation of the anti-HIV nucleoside analog stavudine (2',3'-dideoxy-2',3'-didehydrothymidine; d4T) in peripheral blood mononuclear cells (PBMCs) and U937 cells in vitro. PBMCs isolated from the blood of healthy volunteers were stimulated by the mitogen phytohemagglutinin (10 microg/ml) for 72 h. Stimulated PBMCs (3 x 10(6) cells/plate) were then incubated with [3H]d4T (0.65 microCi; 3 microM) and either acyclovir, dapsone, ddC, ddI, fluconazole, foscarnet, ganciclovir, itraconazole, lobucavir, ranitidine, ribavirin, rifampin, sorivudine, sulfamethoxazole, trimethoprim, lamivudine (3TC), zidovudine, or thymidine (30 and 300 microM) for 24 h. Doxorubicin and drugs showing some evidence of inhibition were also studied at 0.3 and 3 microM. Cells were extracted overnight with 60% methanol prior to analysis by radiometric high-performance liquid chromatography. Additional data for nine of the drugs were obtained by incubation with [3H]d4T in U937 cells for 24 h. The effect of d4T (0.2 to 20 microM) on zidovudine (0.65 microCi; 0.018 microCi) phosphorylation was also studied. Zidovudine significantly reduced d4T total phosphates in PBMCs and U937 cells (in PBMCs to 33% [P < 0.001] and 17% [P < 0.001] of that in control cells at 3 and 30 microM, respectively). A small reduction in zidovudine phosphorylation was seen with d4T but only at d4T:zidovudine ratios of 100 and 1,000. Of the other compounds screened, only thymidine, ribavirin, and doxorubicin produced inhibition of d4T phosphorylation in both PBMCs and U937 cells. However, doxorubicin was cytotoxic at 3 microM. The decrease in d4T phosphorylation in the presence of ribavirin is consistent with previous findings with zidovudine. Although ddC significantly inhibited the phosphorylation of d4T in PBMCs, this was not seen in U937 cells, and it is probable that the findings in PBMCs are related to mitochondrial toxicity [based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide cytotoxicity assay]. The only drugs screened which may interfere with d4T phosphorylation at clinically relevant concentrations were zidovudine, ribavirin, and doxorubicin.

Anti-HIV Agents↗
PubMed1996

The effect of zidovudine dose on the formation of intracellular phosphorylated metabolites.

OBJECTIVES: Zidovudine (ZDV) requires intracellular phosphorylation to ZDV triphosphate (ZDV-TP) prior to the inhibition of HIV replication. The effect of ZDV dose on the formation of intracellular phosphorylated metabolites may help define the optimum daily dose of ZDV, which is still unknown. DESIGN AND METHODS: The plasma and intracellular phosphorylated metabolite concentrations of ZDV were determined over a 12 h period following oral administration of 100 and 300 mg ZDV to 10 HIV-seropositive patients at steady state during two dosing regimens (i.e., 100 mg three times daily and 300 mg twice daily). The intracellular ZDV phosphates, ZDV monophosphate (ZDV-MP), ZDV diphosphate (ZDV-DP) and ZDV-TP were measured in peripheral blood mononuclear cells using a combination of high-performance liquid chromatography and radioimmunoassay. RESULTS: There was a greater than threefold increase in maximum plasma concentration (Cmax) following 300 mg ZDV when compared with 100 mg ZDV (mean +/- SD, 2.59 +/- 0.52 versus 0.70 +/- 0.14 mumol/l). The area under the concentration time curve (AUC0-12 h) was also significantly increased (4.59 +/- 0.79 versus 1.42 +/- 0.51 mumol/l x h) following 300 mg ZDV dose. For total intracellular ZDV phosphate metabolites the AUC0-12 h was doubled (7.64 +/- 3.67 versus 3.71 +/- 1.83 pmol/10(6) cells x h) in patients taking 300 mg ZDV compared with 100 mg. The AUC0-12 h for ZDV-MP was significantly increased at the higher dose (6.47 +/- 3.14 versus 2.77 +/- 1.70 pmol/10(6) cells x h), whereas the active moiety ZDV-TP was variable and not significantly different (0.42 +/- 0.42 versus 0.61 +/- 0.81 pmol/10(6) cells x h) following 100 and 300 mg ZDV. CONCLUSIONS: Administration of 100 mg ZDV orally produces significantly less of the potentially toxic metabolite, ZDV-MP, and comparative, although variable, concentrations of the active metabolite ZDV-TP when compared with 300 mg ZDV orally. This finding supports clinical data indicating the efficacy of low-dose (300 mg daily) ZDV. The measurement of intracellular phosphorylated metabolites advances our understanding of the clinical pharmacology of ZDV.

Adult↗
PubMed1996

Dexamethasone metabolism by human liver in vitro. Metabolite identification and inhibition of 6-hydroxylation.

The metabolism of the synthetic glucocorticoid dexamethasone in human liver microsomal incubations has been studied. Metabolites were analyzed by radiometric high-performance liquid chromatography and were identified by liquid-chromatography-mass spectrometry; in addition, the major metabolite 6beta-hydroxydexamethasone was identified by cochromatography with a chemically synthesized standard. A total of 17 human livers were used in this study and the following metabolites were identified: 6beta-hydroxydexamethasone, 6 alpha-hydroxydexamethasone, 6-hydroxy-9 alpha-fluoro-androsta-1,4-diene-11 beta-hydroxy-16 alpha-methyl-3,17-dione (6-hydroxy-9 alpha-F-A) and 9 alpha-fluoro-androsta-1,4-diene-11 beta-hydroxy-16 alpha-methyl-3,17-dione (9 alpha-F-A). Dexamethasone underwent side-chain cleavage to form 9 alpha-F-A. This metabolite was then a substrate for 6-hydroxylation. There was considerable interindividual variability in metabolic profiles. Mean (+/-S.D.) K(m) values for 6 beta- and 6 alpha-hydroxydexamethasone formation were 23.2 +/- 3.8 and 25.6 +/- 1.6 microM (n = 4), respectively. The corresponding V max values were 14.3 +/- 9.9 and 4.6 +/- 3.1 pmol x min(-1) mg protein (-1). Ketoconazole (3 microM) completely inhibited 6 alpha- and 6 beta-hydroxylation, indicating that formation of both metabolites was catalyzed by CYP3A4. This was confirmed in studies of correlations between the rate of metabolite formation and the relative expression of CYP3A4: r = 0.74 for 6 beta-hydroxydexamethasone, P = .003; r = 0.70 for 6 alpha-hydroxydexamethasone, P = .006. In addition to ketoconazole, both ellipticine and gestodene caused marked inhibition of 6-hydroxylation. Ellipticine is clearly not a selective CYP1A inhibitor as has been stated previously. However, furafylline (CYP1A inhibitor), tolbutamide (CYP2C substrate), and sulfaphenazole (CYP2C inhibitor) were essentially noninhibitory. The relatively simple metabolic profile of dexamethasone compared to other steroids may point to this being a potentially useful in vivo probe for CYP3A4 in humans.

Cytochrome P-450 Enzyme System↗
PubMed1996

Theophylline metabolism in human liver microsomes: inhibition studies.

In this paper we describe the kinetics of formation of 1-methylxanthine (1-MX), 3-methylxanthine (3-MX) and 1,3-dimethyluric acid (1,3-DMU) from theophylline in human liver microsomal incubations and use the selective inhibitor approach to define the role of the individual cytochrome P450s (CYP) in each pathway. A biphasic model fitted the data best for the formation of each metabolite. The high-affinity site Km and Vmax values were: 1-MX, Km = 0.29 +/- 0.21 mM, Vmax = 5.92 +/- 3.74 pmol.mg(-1).min(-1) (mean +/- S.D.; n = 4); 3-MX, Km = 0.28 +/- 0.08 mM, Vmax = 3.32 +/- 2.19 pmol.mg(-1).min(-1); 1,3-DMU,Km = 0.31 +/- 0.14 mM, Vmax = 43.3 +/- 9.3 pmol.mg(-1).min(-1). The relative contribution of the high- and the low-affinity enzymes in 1,3-DMU formation was calculated based on the enzyme kinetic parameters. To characterize the high-affinity site, a range of CYP isozyme substrates and inhibitors were incubated with 100 microM theophylline. The CYP1A2 inhibitors furafylline, ellipticine and alpha-naphthoflavone were potent inhibitors of both 1-MX and 3-MX formation with more that 80% of N-demethylase activities inhibited below a concentration of 5 microM. These compounds also markedly inhibited 1,3-DMU formation. Enzyme kinetic and selective inhibition data indicated that about 80% of 1,3-DMU formation was catalyzed by the high-affinity isoform (CYP1A2) at a theophylline concentration of 100 microM. To investigate the role of other isoforms in 8-hydroxylation, experiments were performed involving incubation with a combination of inhibitors. It is evident that in addition to CYP1A2, CYP2E1 has a minor role om 8-hydroxylation. This based on the fact that 80% inhibition was seen on preincubation with furafylline and about 90% inhibition on preincubation with furafylline plus diethyldithiocarbamate. Low concentrations of ketoconazole (selective for CYP3A4) only produced marginal inhibition of 1,3-DMU and, therefore, CYP3A4 is only of minor significance in this reaction. Human B-lymphoblastoid cell lines expressing CYP1A2 catalyzed theophylline metabolism with formation of 1-MX, 3-MX and 1,3-MDU. CYP2E1 cells also catalyzed formation of 1,3-DMU. The CYP3A4 cell line did not catalyze theophylline metabolism.

Cells, Cultured↗
PubMed1995

Paracetamol disposition in Thai patients during and after treatment of falciparum malaria.

Investigations in animals have suggested that conjugation of paracetamol may be reduced in malaria. We have measured plasma concentrations and the urinary excretion of paracetamol and its phase II metabolites in eight Thai patients during uncomplicated falciparum malaria and in convalescence, following a 1000 mg single oral dose. The apparent oral clearance (Malaria, 3.6; Convalescence, 3.9; ml.min-1.kg-1), the elimination half-life (Malaria, 3.8; Convalescence, 3.7 h) and apparent volume of distribution (Malaria, 1.2; Convalescence, 1.2; l.kg-1) of paracetamol were similar during malaria and convalescence. In addition, the urinary excretion of paracetamol and its major phase II metabolites and their formation clearances from paracetamol were not significantly different between the two study phases. These data show that clinical malaria infection has no effect on the conjugation of paracetamol in man.

Acetaminophen↗
PubMed1995

Influence of high doses of vitamin C on the bioavailability and the serum protein binding of levonorgestrel in women using a combination oral contraceptive.

The absence of an effect of high oral doses of vitamin C on the systemic availability of ethinylestradiol in women using a levonorgestrel-containing combination oral contraceptive (0.15 mg levonorgestrel and 0.03 mg ethinylestradiol) was demonstrated in a recent study. However, it is conceivable that the oral administration of gram quantities of vitamin C could also interfere with the sulfation of levonorgestrel (LNG) metabolites during phase II biotransformation, because sulfates represent a major part of the conjugated metabolites of LNG in the serum. This possible interaction was investigated in the aforementioned study, comparing Cmax and AUC(0-12h) values of LNG on the first and 15th day of two successive treatment cycles with and without co-medication of vitamin C. In addition, the serum protein binding of LNG and the concentration of the binding proteins SHBG and CBG were compared between both treatments. Corresponding parameters obtained during treatment with the oral contraceptive alone and during co-administration of vitamin C were evaluated statistically for possible differences. No effect of vitamin C was observed for any of the parameters investigated. Thus, the repeated oral administration of gram quantities of vitamin C does not impair the sulfation of hydroxylated metabolites of LNG. There was also no observable effect on the serum protein binding of LNG and the concentrations of SHBG and CBG in the serum. The results obtained in this study population (American women) for LNG are in good agreement with those obtained from a previous study in European women, who had taken a combination oral contraceptive containing the same doses of LNG and ethinylestradiol.

Ascorbic Acid↗
PubMed1995

Metabolism of Zidovudine.

1. The anti-HIV drug zidovudine (3'-azido-2',3'-dideoxythymidine; ZDV) has three important pathways of metabolism. ZDV is a prodrug and must be phosphorylated in lymphocytes in order to exert its antiviral action. However, in quantitative terms this is a minor pathway probably accounting for less than 1% of the overall metabolic profile. The predominant pathway of metabolism is glucuronidation to GZDV and the metabolite is renally excreted. A further metabolite, derived by reduction of the azido moiety is 3'-amino-3'-deoxythymidine (AMT). 2. Zidovudine glucuronidation has been characterised in human liver microsomes. A number of drugs (e.g., naproxen, indomethacin and probenecid) have been shown to inhibit the in vitro conjugation of ZDV. Some of these drugs have also been co-administered with ZDV in HIV-positive patients. Significant pharmacokinetic interactions have been demonstrated with probenecid, naproxen and fluconazole. 3. 3'-amino-3'-deoxythymidine formation is probably mediated by both cytochrome P450 isozymes and NADPH-cytochrome P450 reductase. Peak plasma concentrations of AMT are approximately 10-15% of ZDV in patients. This is a potentially important metabolite because of its alleged cytotoxicity. 4. Measurement of intracellular ZDV phosphates in patients provides the key to our understanding of both the efficacy and toxicity of ZDV. Important recent work has demonstrated that as patients deteriorate (i.e., CD4 counts decrease below 100 x 10(6)/L), there is a corresponding increase in intracellular ZDV-monophosphate. This could have toxicological implications.

AIDS-Related Complex↗
PubMed1995

Drug interactions with zidovudine phosphorylation in vitro.

We have investigated the effect of a range of drugs (some commonly coadministered with zidovudine [ZDV] to human immunodeficiency virus-positive patients) on intracellular phosphorylation of ZDV by stimulated peripheral blood mononuclear cells, Molt 4 cells, and U937 cells in vitro. Of the drugs tested (azoles, antiviral agents, antibiotics, and anticancer agents), only doxorubicin and ribavirin caused inhibition of anabolite formation as measured by high-performance liquid chromatography. This in vitro approach may provide important leads to potential interactions at the phosphorylation level in patients with human immunodeficiency virus disease. It is reassuring that so many commonly administered drugs do not alter ZDV phosphorylation.

Anti-Bacterial Agents↗
PubMed1994

The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine.

The characterization of the enzymatic step(s) involved in the reduction of 3'-azido-3'-deoxythymidine (zidovudine)(ZDV) to 3'-amino-3'-deoxythymidine (AMT) was pursued. AMT formation by human liver microsomes was NADPH dependent, enhanced under anaerobic conditions, and increased by flavin adenine dinucleotide (FAD) and FMN. Carbon monoxide inhibited AMT formation by up to 80%. The effect of theophylline (CYP1A substrate), tolbutamide (CYP2C substrate), chlorzoxazone, thiobenzamide, p-nitrophenol, mercaptoethanol, isoniazid (CYP2E substrates), cortisol (CYP3A substrate), ketoconazole, itraconazole, fluconazole, cimetidine, micronazole (CYP inhibitors), methimazole (flavin-containing mono-oxygenase inhibitor), chloramphenicol (undergoes nitroreduction), allopurinol (xanthine oxidase inhibitor) and dicoumarol (DT-diaphorase inhibitor) on AMT formation were studied to see if the reduction reaction was mediated by a particular isozyme. The greatest inhibition was observed with ketoconazole (concentration producing 50% inhibition = 78.0 microM). At this concentration ketoconazole acted as a non-selective inhibitor of several CYP isozymes. Overall, these data suggested that ZDV reduction was probably mediated by both cytochrome P450 isozymes and NADPH-cytochrome P450 reductase. Formation of AMT, as measured by intrinsic clearance (Clint), was significantly increased in microsomes from rats pre-treated with phenobarbitone, dexamethasone and clofibrate (inducers of CYP2B, CYP3A and CYP4A, respectively). Pre-treatment of rats with beta-naphthoflavone and ethanol (CYP1A and CYP2E1 inducers, respectively) had no effect on AMT formation.

Animals↗
PubMed1994

Zidovudine pharmacokinetics in zidovudine-induced bone marrow toxicity.

1. The major adverse effect of zidovudine (ZDV) is haematological toxicity which results in anaemia and granulocytopenia. The aim of the present study was to investigate if HIV-positive patients developing erythroid aplasia/hypoplasia are exposed to higher plasma concentrations of ZDV owing to impaired hepatic metabolism to the major metabolite, 3'-azido-3'-deoxy-5'-beta-D-glucopyranuronosylthymidine (GZDV). 2. Twelve HIV-positive male patients were studied, six having developed bone marrow aplasia/hypoplasia within the first 6 months of ZDV therapy. Each of the patients exhibiting toxicity were matched for age, weight, risk factors for HIV infection and disease stage with patients who had no evidence of early bone marrow toxicity. 3. ZDV was administered orally in doses of 3-10 mg kg-1 and blood samples taken at intervals to 6 h. Urine was collected over the whole 6 h period. ZDV and GZDV were assayed by h.p.l.c. 4. There were no significant differences in the pharmacokinetic parameters between the two groups of patients. For patients with early bone marrow toxicity the elimination half-life of ZDV was 1.10 +/- 0.16 h with an oral clearance of 2752 +/- 1031 ml min-1 compared with values of 1.06 +/- 0.18 h and 2843 +/- 730 ml min-1 seen in the control group. Similarly there was no significant difference in the pharmacokinetics of GZDV or the urinary ratio of GZDV to ZDV. 5. Therefore, despite the fact that ZDV toxicity to haematopoietic progenitor cells has been previously shown to be dose related, there was no indication from this study that it is directly related to plasma concentrations of ZDV.

Administration, Oral↗
PubMed1994

Effects of dideoxyinosine and dideoxycytidine on the intracellular phosphorylation of zidovudine in human mononuclear cells.

1. Zidovudine (3'-azido-2',3'-dideoxythymidine; AZT; ZDV) is a dideoxynucleoside analogue active against human immunodeficiency virus (HIV). We are currently investigating the intracellular metabolism of ZDV to its putative active triphosphate form (ZDV triphosphate) in peripheral blood mononuclear cells and a lymphoblastoid cell line (h1A2v2). 2. Optimal conditions for intracellular phosphate formation in peripheral blood mononuclear cells occurred following a 72 h preincubation with the mitogen phytohaemagglutinin at a concentration of 10 micrograms ml-1. ZDV was metabolized predominantly to the monophosphate with smaller amounts of the di- and triphosphate anabolites. There was considerable inter- and intraindividual variability in phosphate formation in peripheral blood mononuclear cells. A similar pattern of phosphorylation was seen with the h1A2v2 lymphoblastoid cell line with ZDV monophosphate being the major metabolite. 3. With increasing interest in combination nucleoside analogue therapy in HIV-positive patients it is important to know if an interaction occurs at the level of phosphorylation. Neither dideoxyinosine (ddI) or dideoxycytidine (ddC) significantly reduced the intracellular phosphorylation of ZDV in either peripheral blood mononuclear cells or h1A2v2 cells. In contrast thymidine always gave marked inhibition (e.g. at 2.0 microM, 89% inhibition of total phosphate formation in peripheral blood mononuclear cells and 79% in h1A2v2 cells). It is, therefore, unlikely that in vivo either ddI or ddC will perturb ZDV phosphorylation.

Analysis of Variance↗
PubMed1994

Pharmacokinetics of zidovudine and dideoxyinosine alone and in combination in patients with the acquired immunodeficiency syndrome.

1. Zidovudine (ZDV) has proved unsuccessful in controlling disease progression over extended periods of time in patients with AIDS. Combination of ZDV with another reverse transcriptase inhibitor, dideoxyinosine (ddI) may improve the duration of effectiveness of antiretroviral therapy. The aim of this study was to investigate the possibility of a pharmacokinetic drug interaction between ZDV and ddI. 2. The pharmacokinetics of ZDV and ddI were determined in eight patients with AIDS who were randomised to receive ZDV 250 mg orally, ddI 250 mg orally or a combination of ZDV 250 mg plus ddI 250 mg orally on 3 study days separated by 1 week. 3. The administration of ZDV did not significantly alter ddI pharmacokinetics. The mean AUC was 6.8 +/- 2.0 s.d. and 7.6 +/- 2.5 s.d. mumol l-1 h and oral clearance was 2766 +/- 686 and 2660 +/- 1297 ml min-1 in the presence and absence of ZDV, respectively. 4. In the presence of ddI the elimination half-life of ZDV was increased significantly by 18% from 1.1 +/- 0.3 to 1.3 +/- 0.3 h (P < 0.05) and the mean AUC increased significantly by 35% from 4.8 +/- 1.5 to 6.5 +/- 1.5 mumol l-1 h (P < 0.05). The clearance was decreased by 29% from 3518 +/- 1123 to 2505 +/- 575 ml min-1, but this difference was not significant. The renal clearance of ZDV was not altered by ddI. 5. Administration of ddI also resulted in a significant 22% increase in the AUC of GZDV, from 28.5 +/- 15.7 to 34.9 +/- 12.8 mumol l-1 h (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed1994

Effect of malaria infection on the pharmacokinetics of paracetamol in rat.

1. Paracetamol (P; 50 and 300 mg/kg i.v.) was administered to the control and malaria-infected (MI) male Wistar rat in order to assess the effect of MI on the metabolism of paracetamol to its glucuronide (PG) and sulphate (PS) conjugates and their excretion in urine. 2. At a dose of 50 mg/kg, neither total clearance (ClT) (controls, 20.3 +/- 0.5; MI, 19.9 +/- 0.9, ml/min/kg; mean +/- SD, p > 0.05) nor the renal clearance of P (ClR) were affected by MI. Although the formation clearance of PG (Clf PG) was decreased by about 40% (controls, 6.6 +/- 1.1; MI, 3.9 +/- 0.9, ml/min/kg, p < 0.05), the formation clearance of PS (Clf PS) was increased by 30% in the MI rat (controls, 8.8 +/- 0.9; MI, 11.2 +/- 1.7, ml/min/kg, p < 0.05), and therefore Clm (controls, 19.7 +/- 0.5; MI, 19.2 +/- 0.8, ml/min/kg, p > 0.05) was unchanged by MI. 3. At a dose of 300 mg/kg, MI produced a significant decrease in the total clearance of P (ClT) (controls, 16.9 +/- 1.0; MI, 11.9 +/- 0.9, ml/min/kg, p < 0.05), metabolic clearance (Clm) (controls, 15.9 +/- 1.4; MI, 11.3 +/- 0.9, ml/min/kg, p < 0.05) and the formation clearance of PG (Clf PG) (controls, 7.9 +/- 1.3; MI, 4.7 +/- 1.5, ml/min/kg, p < 0.05) without affecting Clf PS and ClR of P. 4. These findings indicate that MI impairs the glucuronidation of paracetamol in rat in vivo at both the low and high doses of P. Increased sulphate formation appeared to compensate for decreased glucuronidation at the lower dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1994

Pharmacokinetics of mefloquine alone or in combination with artesunate.

A randomized comparative trial of the pharmacokinetics and pharmacodynamics of oral doses of mefloquine and of mefloquine in combination with artesunate was carried out on 20 Thai male patients with acute, uncomplicated falciparum malaria. The patients were randomized to receive either mefloquine alone (8 patients; 1250 mg of mefloquine--initial dose, 750 mg; followed 6 hours later by 500 mg), or in combination with oral artesunate (12 patients--initial dose, 200 mg of artesunate; followed by 750 mg and 500 mg of mefloquine 6 hours and 12 hours later, respectively). The patients who received mefloquine alone all showed initially good responses to the treatment, with mean +/- SD values for the fever clearance time (FCT) and parasite clearance time (PCT) of 44.7 +/- 43.1 hours and 82.3 +/- 52.3 hours, respectively. Two patients had recrudescences on day 20 and day 31 (RI response). The cure rate was 75%, and one patient had Plasmodium vivax in his peripheral blood on day 52. The patients who received the combination treatment were clinically markedly improved, with a relatively shorter FCT (31.2 +/- 12.4 hours) and significantly shorter PCT (47.5 +/- 19.6 hours). Four had recrudescences on days 12, 18, 26 and 33; the cure rate was 66%. Artesunate caused three significant changes in mefloquine pharmacokinetics: a decrease in the maximum concentration (Cmax: 1623 ng.ml-1 versus 2212 ng.ml-1); an increase in the clearance rate (Cl/f:2.9 ml.min-1.kg-1 versus 1.1 ml.min-1.kg-1); and an expansion of the volume of distribution (Vdz/f: 31.8 l.kg-1 versus 25.0 l.kg-1).

Adolescent↗