Age and CYP3A4 and CYP2A6 activities marked by the metabolism of lignocaine and coumarin in man.
The effect of age on human liver drug-metabolizing ability was investigated by using probe drugs, metabolized by specific isozymes in liver, as an index. Formation of monoethylglycinexylide (MEGX) after i.v. infusion of lignocaine (1 mg/kg), metabolized by CYP3A4, and excretion of 7-hydroxycoumarin (7-OHC) after oral coumarin (5 mg) administration, hydroxylated by CYP2A6, were investigated in healthy young (< 25 years) and elderly (> 65 years) women and men (n = 10 in each group). MEGX content in young subjects (men 57.8 +/- 11.3 and women 52.9 +/- 13.1 ng/ml) did not diverge significantly but was reduced in elderly subjects (men 43.57 +/- 15.8 and women 29.2 +/- 13.6 ng/ml, p < 0.05 and 0.01, respectively). 7-OHC excretion at 2 h averaged 68.1 +/- 13.1 per cent (men) and 65.0 +/- 18.3 per cent (women) of the dose given in young subjects and was delayed in elderly persons (men 46.5 +/- 16.3 per cent and women 44.8 +/- 18.3 percent, p < 0.01 and 0.05, respectively). The change in probe drug metabolism was related to age (MEGX, r = -0.473 (men) and -0.682 (women) and 7-OHC; r = -0.690 (men) and -0.565 (women)). MEGX formation was reduced by 0.92 microgram/L per year and 7-OHC excretion by 0.85 per cent per year. The results indicate a decrease of CYP3A4 and CYP2A6 metabolic activities with age.
Sotaniemi
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Department of Internal Medicine and Pharmacology, University of Oulu, Finland.
Lumme
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Arvela
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Rautio
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D000328:Adult; D000367:Age Factors; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases; D003374:Coumarins / Q000378:metabolism*; D065637:Cytochrome P-450 CYP2A6; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008012:Lidocaine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D014468:Umbelliferones / Q000652:urine
D003374:Coumarins; D007527:Isoenzymes; D014468:Umbelliferones; D003577:Cytochrome P-450 Enzyme System; D008012:Lidocaine; C001173:monoethylglycinexylidide; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C104464:CYP3A protein, human; D065637:Cytochrome P-450 CYP2A6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human