Caffeine as a metabolic probe: Validation of its use for acetylator phenotyping

Tang, Boxin; Kadar, D.; Li, Qian; Iriah, Jessie; Yip, James; Kalow, W.

doi:10.1038/clpt.1991.82

Cited by 99 publications

(64 citation statements)

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“…value 0.55 reported by Tang et al [9]. The MRs measured by caffeine differed by collection period (spot, overnight) possibly due to alteration in clearance created by changes in organ blood flow following changes in posture.…”

Section: Discussionmentioning

confidence: 78%

“…Additionally the formation of 1MU which is further metabolised by xanthine oxidase may be significant. Tang et al [9] observed that the products of xanthine oxidase may be ignored if the observed MR is not within 10% of the antimode in young healthy individuals; within the 10% level, fast acetylators may be misclassified as slow. Thus, MRs calculated without measuring AAMU [12,171 or without accounting for the products of xanthine oxidase activity [16] may be misleading.…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, spot urines apparently distinguished slow from fast acetylators while no such distinction was possible from urines collected overnight. An antimode of 0.26 was assumed for spot urines compared with a reported value of 0.34 for both night and day collections for NAT2 [9]. The rank correlation between the two caffeine collections indicated significant variation between these data sets.…”

Section: Discussionmentioning

confidence: 99%

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Caffeine as a metabolic probe: NAT2 phenotyping

Notarianni

Dobrocky

Godlewski

et al. 1996

Brit J Clinical Pharma

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Caffeine has been used to determine acetylator phenotype for some 15 years but the interpretation of metabolic ratios with this substance raises theoretical and methodological issues. N-acetyltransferase type 2 (NAT2) status was assessed in 23 young healthy subjects using both caffeine overnight and spot urine samples, and sulphadimidine. Frequency distribution analysis of the metabolic ratios of NAT2, indicated two distinct groups for sulphadimidine, and for caffeine spot but not overnight samples. Spearman's rank correlation values were low indicating differences between the data sets for sulphadimidine and spot caffeine samples. Correlation between the two urine collection periods for caffeine was poor. The complex metabolism of caffeine may compromise its value as a probe for determining acetylator phenotype until the effects of important variables are better understood.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Caffeine as a metabolic probe: NAT2 phenotyping

Notarianni

Dobrocky

Godlewski

et al. 1996

Brit J Clinical Pharma

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“…C'est une substance ubiquitaire et relativement non toxique même à fortes doses, métabolisée par la voie de la N-acétylation et recommandée comme marqueur pour la détermination du phé-notype d'acétylation par plusieurs auteurs [26][27][28][29][30][31]. Le métabo-lisme de la caféine a été étudié in vivo et in vitro chez l'Homme et plus d'une dizaine de métabolites urinaires ont été déter-minés par CLHP [31][32][33].…”

Section: Introductionunclassified

Détermination du polymorphisme d’acétylation de la N-acétyltransférase 2 dans la population sénégalaise par utilisation du test à la caféine

Touré¹,

Cabral²,

Diop³

et al. 2012

Ann Toxicol Anal

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Résumé -Introduction : L'isoniazide (INH) est métabolisée par une N-acétyltransfèrase (NAT), la NAT2. Il existe de nombreux polymorphismes de la NAT2 qui peuvent être associés à des toxicités ou à des échecs thérapeutiques au cours d'un traitement par INH. Objectif : L'objectif de ce travail est de déterminer l'indice d'acétylation de la NAT2 dans la population sénégalaise afin de les répartir en acétyleurs lents et rapides. Méthodes : L'étude du profil d'acétylation a été effectuée sur des urines de 247 sujets en utilisant la caféine comme marqueur. La proportion molaire du 5-acétamino-6-formylamine-3-méthyluracile (AFMU) sur le 1-méthylxanthine (1X) a été déterminée. La répartition de la population étudiée en phénotype lent ou rapide a été réalisée en se basant sur l'antimode = 0,55. Les sujets possédant un rapport ([AFMU]/[1X]) inférieur à 0,55 sont considérés comme des acétyleurs lents et ceux dont le rapport est >0,55 sont des acétyleurs rapides. Résultats : Les résultats obtenus ont montré une ségrégation en deux modes apparents de capacité d'acétylation dans la population sénégalaise testée avec 63,8 % et 36,2 % d'acétyleurs lents et rapides respectivement. Conclusion : La réponse au traitement de maladies comme la tuberculose dépend du polymorphisme d'acétylation de la NAT2, il est donc important de connaître le phénotype de la NAT2 chez les sujets atteints de tuberculose pour éviter des effets indésirables tels que l'hépatotoxicité ou la neurotoxicité. Mots clés : N-acétyltransférase, polymorphisme, indice d'acétylation, test caféineAbstract -Introduction: Isoniazid (INH) is metabolized by an N-acetyltransferase (NAT), the NAT2. There are many of NAT2 polymorphisms that may be associated to toxicity or therapeutic failure of INH. Objective: The objective of this study is to determine the index of acetylation of NAT2 in the Senegalese population. Methods: The study of the profile of acetylation was performed on urine from 247 subjects using caffeine as a marker. The molar ratio of 5-acetamino-6-formyl amine-3-methyluracil (AFMU) on the 1-methylxanthine (IX) was determined. The distribution of the population studied in slow or fast phenotype was performed based on the antimode = 0.55. Subjects who have ratio ([AFMU]/[IX]) less than 0.55 are considered slow acetylators and those, whose ratio is >0.55, are rapid acetylators. Results:The results showed segregation of two apparent modes of acetylation capacity in the Senegalese population tested with 63.8% and 36.2% of slow and fast acetylators respectively. Conclusion: Response to treatment of diseases such as tuberculosis depends on the polymorphism of NAT2 acetylation, it is significant to know the phenotype of NAT2 in patients with tuberculosis to avoid such side effects as hepatotoxicity or neurotoxicity.

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“…Details of the phenotyping protocol and the bioanalytical method of the caffeine metabolites including its actual performance data (accuracy and precision) in the measurement of samples derived from this study have been recently reported by Jetter et al 41 In brief, NAT2 activity was determined by calculating urinary molar metabolic ratios of (AFMU þ AAMU)/(AFMU þ AAMU þ 1X þ 1U). 42 Metabolic ratios below 0.21 were defined as acceptance criterion to conclude an SA phenotype, whereas ratios X0.32 were required to conclude an RA phenotype. Subjects with intermediate ratios between these categories were considered not unequivocally classifiable and did not qualify for inclusion into the study.…”

Section: Subjects and Study Designmentioning

confidence: 99%

The role of Gilbert's syndrome and frequent NAT2 slow acetylation polymorphisms in the pharmacokinetics of retigabine

Hermann¹,

Borlak

Munzel

et al. 2006

Pharmacogenomics J

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Retigabine (RGB) is an investigational antiepileptic drug, which undergoes extensive UGT1A1, 1A9 and 1A4-mediated N-glucuronidation and Nacetylation. The mono-acetylated metabolite of RGB has some pharmacological activity and is denoted AWD21-360. We investigated whether the pharmacokinetics (PK) of RGB and AWD21-360 are altered in subjects with Gilbert's syndrome (GS) and/or with frequent N-acetyltransferase 2 (NAT2) slow acetylator (SA) polymorphisms. Based on consistent genotyping and phenotyping screening results, 37 Caucasian subjects (21-46 years; 31 men, six women) were assigned to one of the following groups:. Subjects received single and multiple (b.i.d.) 200-mg oral RGB doses over 5 days. Blood samples were collected up to 60 h after dosing for plasma PK of RGB and AWD21-360. Group comparisons were performed by ANOVA. Single-dose PK of RGB and AWD21-360 and multipledose PK of RGB did not differ significantly between groups. After multiple dose treatment, RA subjects showed a significantly higher total exposure to AWD21-360 of about 32% (95% CI 101.9-172.5) relative to SA subjects (P ¼ 0.0362). The UGT1A1 metabolic capacity (i.e. presence or absence of GS), however, did not significantly affect the overall exposure to AWD21-360. The results indicate that the PK of RGB is unaltered in individuals with GS, in subjects with NAT2 SA status, and in carriers of both variants, whereas the total exposure to AWD21-360 is significantly related to the RA or SA status of subjects. Results further suggest that metabolic switching to the mono-acetylated metabolite AWD21-360 may partially compensate for the impaired glucuronidation capacity in GS subjects. RGB treatment showed no significant differences in tolerability and safety between groups.

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Caffeine as a metabolic probe: Validation of its use for acetylator phenotyping

Cited by 99 publications

References 0 publications

Caffeine as a metabolic probe: NAT2 phenotyping

Caffeine as a metabolic probe: NAT2 phenotyping

Détermination du polymorphisme d’acétylation de la N-acétyltransférase 2 dans la population sénégalaise par utilisation du test à la caféine

The role of Gilbert's syndrome and frequent NAT2 slow acetylation polymorphisms in the pharmacokinetics of retigabine

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