Evaluation of the influence of diabetes mellitus on antipyrine metabolism and CYP1A2 and CYP2D6 activity.
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.


METHODS
Prospective, controlled study.


METHODS
Research facility. Patients. Fifteen patients with type 1 and 16 with type 2 diabetes, and 16 healthy controls.


METHODS
Each subject simultaneously received antipyrine 10 mg/kg, caffeine 100 mg, and dextromethorphan 30 mg.


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.


CONCLUSIONS
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.
Matzke
G R
GR
Department of Pharmaceutical Sciences, School of Pharmacy, and Center for Clinical Pharmacology, University of Pittsburgh, Pennsylvania 15261, USA.
Frye
R F
RF
Early
J J
JJ
Straka
R J
RJ
Carson
S W
SW
D000107:Acetylation; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics* / Q000652:urine; D000983:Antipyrine / Q000493:pharmacokinetics* / Q000652:urine; D000996:Antitussive Agents / Q000493:pharmacokinetics / Q000652:urine; D002110:Caffeine / Q000493:pharmacokinetics / Q000652:urine; D000697:Central Nervous System Stimulants / Q000493:pharmacokinetics / Q000652:urine; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D003915:Dextromethorphan / Q000493:pharmacokinetics / Q000652:urine; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000652:urine; D005260:Female; D006207:Half-Life; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011446:Prospective Studies
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000996:Antitussive Agents; D000697:Central Nervous System Stimulants; D002110:Caffeine; D003915:Dextromethorphan; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D000983:Antipyrine