Evaluation of caffeine as a test drug for CYP1A2, NAT2 and CYP2E1 phenotyping in man by in vivo versus in vitro correlations
作者:
Uwe Fuhr,
Karl Rost,
Reinald Engelhardt,
Michael Sachs,
Dieter Liermann,
C Belloc,
Philippe Beaune,
Susan Janezic,
Denis Grant,
Urs Meyer,
A Horst Staib,
期刊:
Pharmacogenetics
(OVID Available online 1996)
卷期:
Volume 6,
issue 2
页码: 159-176
ISSN:0960-314X
年代: 1996
出版商: OVID
关键词: phenotyping;cytochrome P450;N-acetyltransferase;caffeine
数据来源: OVID
摘要:
Caffeine is used to phenotype subjects in vivo for the cytochrome P450 isoforms CYP1A2 and CYP2E1, and for N-acetyltransferase type 2 (NAT2). However, how much of the variation in phenotyping parameters may be attributed to variations in CYP1A2 and CYP2E1 activities has not been determined. Therefore, this study intraindividually compared enzyme activities and/or content in liver samples with pharmacokinetic parameters of caffeine in vivo after administration of a test dose in 25 patients undergoing hepatectomy. Parameters measured in vitro were the high affinity components of caffeine 3-demethyIation and phenacetin O-deethylation, microsomal CYP1A2 and CYP2E1 immunoreactivity, and cytosolic sulfamethazine N-acetylation. Caffeine parameters in vivo included caffeine clearance from plasma and/or saliva, paraxanthine/caffeine ratios in plasma and saliva, plasma theophylline/ caffeine ratio, and several metabolite ratios from spot urine sampled 6h postdose. Correlations between parameters were determined using weighted linear regression analyses. Caffeine clearance and paraxanthine/caffeine ratios correlated most highly to intrinsic clearance of caffeine 3-demethylation and to CYP1A2 immunoreactivity (r=0.58-0.82), whereas urinary CYP1A2 ratios correlated less strongly with CYP1A2 parameters in vitro. Assignment of acetylator phenotype by urinary NAT2 ratios was concordant with sulfamethazineN- acetylation in vitro. In contrast to CYP1A2 paramters in vitro, CYP2E1 immunoreactivity was not related to the theophylline/caffeine plasma ratio. CYP1A2 activity, thus, is the major determinant of caffeine clearance and the paraxanthine/caffeine ratios in vivo, of which the saliva ratio 6 h postdose appears as the most advantageous parameter. The results confirm that phenotyping using caffeine provides valid estimates of CYP1A2 and NAT2 activity.
点击下载:
PDF
(1519KB)
返 回