Caffeine as a metabolic probe: NAT2 phenotyping

Notarianni, L. J.; Dobrocky, P; Godlewski, Grzegorz; Jones, Roy; Bennett, Peter N.

doi:10.1111/j.1365-2125.1996.tb00178.x

Cited by 9 publications

(6 citation statements)

References 23 publications

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“…Twenty‐four healthy nonsmoking volunteers were enrolled who were not taking any over‐the‐counter or prescribed medications when they presented to the research clinic (a minimum of 12 hours free of such medications was required). Within 12 weeks before administration of study medication, participants completed a caffeine phenotype probe screening study to determine eligibility and acetylator status by analysis of urinary caffeine metabolites 28 , 29 . During the open‐label, single‐visit screening study, participants received a single oral dose of 200 mg caffeine (Vivarin) with 240 mL water following an overnight fast, having agreed to refrain from over‐the‐counter and prescription medications, as well as xanthine‐containing food and beverage ingestion, for at least 12 hours.…”

Section: Methodsmentioning

confidence: 99%

“…Values (ng/mL) were converted to nM, and the molar 5‐acetyl‐amino‐6‐formyl amino‐3‐methyluracil/1‐methylxanthine ratio for each participant was calculated. A slow acetylator phenotype was defined by a ratio of ≤0.55 and a fast acetylator phenotype by one of >0.55 28 , 29 . The mean (range) of ratios of the 12 participants identified as fast acetylators (7 men and 5 women) enrolled into this study was 1.18 (0.749–1.669) and that of the 12 participants identified as slow acetylators (7 men and 5 women) was 0.184 (0.00–0.39).…”

Section: Methodsmentioning

confidence: 99%

“…Within 12 weeks before administration of study medication, participants completed a caffeine phenotype probe screening study to determine eligibility and acetylator status by analysis of urinary caffeine metabolites. 28,29 During the open-label, single-visit screening study, participants received a single oral dose of 200 mg caffeine (Vivarin) with 240 mL water following an overnight fast, having agreed to refrain from overthe-counter and prescription medications, as well as xanthine-containing food and beverage ingestion, for at least 12 hours. The restriction on additional caffeine intake was instituted primarily to address safety concerns rather than a complete washout from previous caffeine intake.…”

Section: Study Participantsmentioning

confidence: 99%

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Pharmacokinetics, Pharmacodynamics, and Metabolism of Triethylenetetramine in Healthy Human Participants: An Open‐Label Trial

Poppitt

Othman

et al. 2010

The Journal of Clinical Pharma

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The selective Cu(II)-chelator, triethylenetetramine (TETA), is undergoing clinical trials for the treatment of heart failure in patients with diabetes. Recently, the authors showed that 2 acetylated metabolites, N(1)-acetyltriethylenetetramine (MAT) and N(1),N(10)-diacetyltriethylenetetramine (DAT), are formed in humans following oral TETA administration. Thus, it became necessary to determine whether the N-acetyltransferase (NAT) 2 phenotype has any effects on the pharmacological properties and safety profile of TETA. Twelve fast and 12 slow NAT2-phenotype healthy participants were recruited. After oral drug administration, the authors collected plasma and urine samples, measured plasma concentrations of TETA and its 2 metabolites along with concomitant urinary copper concentrations, and performed safety tests. They present, for the first time, the complete 24-hour pharmacokinetic profiles of TETA, MAT, and DAT in humans. There was no evidence for clear-cut differences in pharmacokinetic profiles between fast and slow acetylators. Pharmacodynamic analysis showed no significant differences in cupruresis between the 2 NAT2 phenotypes. Safety results were consistent with TETA being well tolerated, and no significant differences in safety profiles were observed between the 2 phenotypes. Based on these data, NAT2 phenotype does not affect TETA's pharmacokinetic, pharmacodynamic, or safety profiles. TETA may be acetylated via an alternative mechanism, such as that catalyzed by spermidine/spermine N(1)-acetyltranferase.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Study Participantsmentioning

confidence: 99%

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Pharmacokinetics, Pharmacodynamics, and Metabolism of Triethylenetetramine in Healthy Human Participants: An Open‐Label Trial

Poppitt

Othman

et al. 2010

The Journal of Clinical Pharma

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“…Two primers NAT2F 5′-TGGGCTTAGAGGCTATTT and NAT2R 5′-GAGTTGGGTGATACATACAC were designed using Primer Express version 2.0 software (Applied Biosystems Inc, Foster City, CA, USA) to amplify a 768 bp sequence of the second exon of the NAT2 gene which contains the relevant polymorphisms (G191A, C282T, T341C, C481T, G590A, A803G, G857A). Following purification (QIAgen PCR purification kits, QIAGEN, United Kingdom) amplicons were sequenced (3130xl Genetic Analyzer Applied Biosystem, Hitachi, Singapore) and phenotypes predicted from genotypes previously defined in a cohort of healthy Vietnamese volunteers in a study correlating urinary caffeine metabolites ratios with NAT2 genotypes (data not shown) [ 15 , 16 ].…”

Section: Methodsmentioning

confidence: 99%

Naïve-pooled pharmacokinetic analysis of pyrazinamide, isoniazid and rifampicin in plasma and cerebrospinal fluid of Vietnamese children with tuberculous meningitis

et al. 2016

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Background: Among the various forms of TB, tuberculous meningitis (TBM) is the most severe, with about 30 % mortality and 50 % of survivors left with neurological sequelae. Children suffer more frequently from TBM than adults and outcomes are often poor due to difficulties in making the diagnosis and uncertainty regarding the best anti-tuberculosis drug regimen. The aim of this prospective study was to describe the pharmacokinetics of pyrazinamide, isoniazid and rifampicin in plasma and cerebrospinal fluid of children with tuberculous meningitis treated with the standard TBM regimen. Methods: We performed a prospective observational study of 100 consecutively treated children (≤15 years of age) with tuberculous meningitis in Ho Chi Minh City, Vietnam. Children were treated according to the 2006 WHO recommended pediatric treatment regimen consisting of isoniazid (5 mg/kg), rifampicin (10 mg/kg) and ethambutol (15 mg/kg) for 8 months, with the addition of pyrazinamide (25 mg/kg) for the first 3 months and streptomycin (15 mg/kg) for the first 2 months. Pyrazinamide, isoniazid and rifampicin concentrations were measured in plasma at day 14 and in cerebrospinal fluid (CSF) at 1 month by HPLC-UV. A naïve-pooled noncompartmental data analysis was used to describe the pharmacokinetic properties of drugs in the two-age groups of children ≤ 4 years or > 4 years of age. Results: Younger children, when compared to older children, presented a higher body weight-normalized clearance and volume of distribution, and lower median total plasma exposures for the three studied drugs with −14 %, −22 % and −16 % for Pyrazinamide, Isoniazid and Rifampicin, respectively. In CSF, individual concentrations of isoniazid and pyrazinamide were comparable to that in plasma in both age groups; but rifampicin concentrations were lower than the minimum inhibitory concentration of susceptible bacteria in all but two children. Conclusions: There is an age-dependent variation in the plasma and cerebrospinal fluid pharmacokinetics of rifampicin, isoniazid and pyrazinamide. The safety and efficacy of higher doses of rifampicin should be investigated for the treatment of childhood tuberculous meningitis.

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“…Express version 2.0 software (Applied Biosystems Inc, Foster City, CA, USA), to amplify a 768 bp sequence of the relevant polymorphisms on the NAT2 gene (G191A, C282T, T341C, C481T, G590A, A803G, G857A). The phenotype were predicted from the genotype, using a previously defined correlation between genotype and urinary caffeine metabolite ratio in a cohort of healthy Vietnamese volunteers (54,57,58).…”

Section: Downloaded Frommentioning

confidence: 99%

Population Pharmacokinetic Properties of Antituberculosis Drugs in Vietnamese Children with Tuberculous Meningitis

Panjasawatwong

Wattanakul

Hoglund

et al. 2020

Antimicrob Agents Chemother

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Optimal dosing of children with tuberculous meningitis (TBM) remains uncertain and are currently based on the treatment of pulmonary tuberculosis in adults. This study aimed to investigate the population pharmacokinetics of isoniazid, rifampicin, pyrazinamide and ethambutol in Vietnamese children with TBM, to propose optimal dosing in these patients, and to determine the relationship between drug exposure and treatment outcome. One-hundred Vietnamese children with TBM were treated with an 8-month anti-tuberculosis regimen. Nonlinear mixed-effects modeling was used to evaluate the pharmacokinetic properties of the four drugs, and to simulate different dosing strategies. The pharmacokinetic properties of rifampicin and pyrazinamide in plasma were described successfully by one-compartment disposition models, while isoniazid and ethambutol in plasma were described by two-compartment disposition models. All drug models included allometric scaling of body weight and enzyme maturation during the first years of life. CSF penetration of rifampicin was relatively poor and increased with increasing protein levels in CSF, a marker of CSF inflammation. Isoniazid and pyrazinamide showed good CSF penetration. Currently recommended doses of isoniazid and pyrazinamide, but not ethambutol and rifampicin, were sufficient to achieve target exposures. Ethambutol dose cannot be increased because of ocular toxicity. Simulation results suggested that rifampicin dosing at 50 mg/kg/day would be required to achieve the target exposure. Moreover, low rifampicin plasma exposure was associated with an increased risk of neurological disability. Therefore, higher doses of rifampicin could be considered, but further studies are needed to establish the safety and efficacy of increased dosing.

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Caffeine as a metabolic probe: NAT2 phenotyping

Cited by 9 publications

References 23 publications

Pharmacokinetics, Pharmacodynamics, and Metabolism of Triethylenetetramine in Healthy Human Participants: An Open‐Label Trial

Pharmacokinetics, Pharmacodynamics, and Metabolism of Triethylenetetramine in Healthy Human Participants: An Open‐Label Trial

Naïve-pooled pharmacokinetic analysis of pyrazinamide, isoniazid and rifampicin in plasma and cerebrospinal fluid of Vietnamese children with tuberculous meningitis

Population Pharmacokinetic Properties of Antituberculosis Drugs in Vietnamese Children with Tuberculous Meningitis

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