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Evaluation of the Influence of Diabetes Mellitus on Antipyrine Metabolism and CYP1A2 and CYP2D6 Activity
Author(s) -
Matzke Gary R.,
Frye Reginald F.,
Early John J.,
Straka Robert J.,
Carson Stanley W.
Publication year - 2000
Publication title -
pharmacotherapy: the journal of human pharmacology and drug therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.227
H-Index - 109
eISSN - 1875-9114
pISSN - 0277-0008
DOI - 10.1592/phco.20.3.182.34775
Subject(s) - paraxanthine , dextromethorphan , cyp1a2 , caffeine , endocrinology , medicine , diabetes mellitus , cyp2d6 , chemistry , metabolism , pharmacology , drug metabolism , debrisoquine , pharmacokinetics , urine , type 2 diabetes , cytochrome p450
Study Objective . To evaluate the metabolism of antipyrine, a general metabolic probe, caffeine, a probe for cytochrome P450 (CYP) 1A2 and N ‐acetyltransferase activity, and dextromethorphan, a specific probe for CYP2D6 activity in patients with type 1 or 2 diabetes mellitus. Design . Prospective, controlled study. Setting . Research facility. Patients . Fifteen patients with type 1 and 16 with type 2 diabetes, and 16 healthy controls. Intervention . Each subject simultaneously received antipyrine 10 mg/kg, caffeine 100 mg, and dextromethorphan 30 mg. Measurements and Main Results . The pharmacokinetics of antipyrine and its primary metabolites were determined from saliva and urine samples. Type 1 diabetes had marked effects on antipyrine metabolism whereas type 2 disease did not alter the metabolism of any of the probe drugs. The apparent oral clearance of antipyrine was increased 72% in patients with type 1 disease compared with controls (p=0.0001). In addition, formation clearances of 4‐hydroxyantipyrine and 3‐hydroxymethylantipyrine were increased by 74% and 137% in those patients relative to controls. The caffeine metabolic index (paraxanthine/caffeine) was increased 34% (p=0.11), and N ‐acetylation and CYP2D6 phenotype were not altered. Conclusion . The metabolism of antipyrine is increased in patients with type 1 diabetes. Based on in vitro reports of antipyrine metabolism and current caffeine metabolic index data, the predominant effect of type 1 diabetes appears to be an increase in CYP1A2 activity. Assessment of the effect of the disease on other specific CYP metabolic pathways is warranted.