Hepatitis A impairs the function of human hepatic CYP2A6 in vivo.
Hepatitis virus A (HVA) is a worldwide sporadic disease but its effects on pharmacokinetics and individual drug responses have not been studied. In this study, the 7-hydroxycoumarin (7OHC) excretion test used in vivo as a bioindex of hepatic CYP2A6 activity was performed in 20, previously healthy, acute jaundice HVA patients. Volunteers with an acute HVA were treated with one p.o. administration of 5 mg coumarin (Venalot). Among the patients, 11 were children (6-10 years; two girls and nine boys), the rest (15-40 years old) consisted of two men and seven women. Urinary excretion of 7OHC was measured after overnight fasting in four fractions: 0 h before any medication (to detect if any basal 7OHC excretion exits), and after a 5-mg coumarin capsule p.o., 0-2, 2-4 and 4-8 h fractions were collected and urine volumes were recorded. Urinary excretion of 7-hydroxycoumarin occurred to a similar extent in healthy adults and children. The first 2-h 7OHC excretion was decreased by 26% (P < 0.05) and total (0-8 h) 7OHC excretion was decreased by 37% (P<0.01) among HVA-positive adults (age range 15-40 years) compared with the values obtained from healthy volunteers. In 11 HVA-positive children (age 6-10 years), the first 2-h 7OHC excretion was only 20% (P < 0.0001) and the total 7OHC excretion 28% (P < 0.0001) of the value observed in healthy controls. These results suggest that (i) an acute HVA decreases the metabolic clearance of drugs such as coumarin which are rapidly metabolised by CYP2A6 and (ii) this decrease is even more prominent in children. Such metabolic responses may be of clinical importance and may also interfere with other drug therapy in these patients.
Pasanen
M
M
Department of Pharmacology and Toxicology, University of Oulu, Finland. markku.pasanen@oulu.fi
Rannala
Z
Z
Tooming
A
A
Sotaniemi
E A
EA
Pelkonen
O
O
Rautio
A
A
D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage; D001189:Aryl Hydrocarbon Hydroxylases; D002648:Child; D003374:Coumarins / Q000008:administration & dosage; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006506:Hepatitis A / Q000188:drug therapy / Q000201:enzymology* / Q000652:urine; D006801:Humans; D008099:Liver / Q000201:enzymology; D008111:Liver Function Tests; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D000637:Transaminases / Q000097:blood; D014468:Umbelliferones / Q000652:urine; D005723:gamma-Glutamyltransferase / Q000097:blood
D000925:Anticoagulants; D003374:Coumarins; D014468:Umbelliferones; C031477:7-hydroxycoumarin; D003577:Cytochrome P-450 Enzyme System; C030123:coumarin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D005723:gamma-Glutamyltransferase; D000637:Transaminases