CYP3A4 and CYP2A6 activities marked by the metabolism of lignocaine and coumarin in patients with liver and kidney diseases and epileptic patients.
1. The in vitro hepatic metabolism of lignocaine to monoethylglycinexylide (MEGX) is mediated by CYP3A4 and that of coumarin to 7-hydroxycoumarin (7OHC) by CYP2A6. We investigated the usefulness of monitoring serum MEGX concentrations (after 1 mg kg-1 lignocaine i.v.) and urinary 7OHC excretion (after 5 mg coumarin p.o.) to reflect liver function in patients with liver (n = 36), kidney (n = 12) and epileptic (n = 12) disease and in control subjects (n = 20). The extent of liver disease was assessed using measurements of serum aminoterminal propeptide (PIIINP) and Child-Pugh grades. 2. Serum concentrations of MEGX were decreased in severe (4.6 +/- 3.0 s.d. ng ml-1), moderate (19.1 +/- 11.6 s.d. ng ml-1) and mild (32.8 +/- 14.2 s.d ng ml-1) liver disease as compared with controls (53.4 +/- 15.8 s.d ng ml-1). The excretion of 7OHC over 2 h was decreased in severe (18.0 +/- 10.3 s.d % of dose) and moderate (34.2 +/- 15.6 s.d %), but not in mild (49.7 +/- 19.0 s.d %) liver disease as compared with that in controls (56.2 +/- 11.6%). 3. In epileptic patients the urinary recovery of 7OHC was increased (2 h value 69.5 +/- 13.2 s.d %) suggesting enzyme induction. In contrast, serum MEGX concentration were low (40.0 +/- 14.1 s.d ng ml-1), possibly due to competition for CYP3A4 between lignocaine and antiepileptic drugs. 4. In patients with kidney disease serum MEGX concentration (56.5 +/- 26.1 s.d ng ml-1) was similar to that in controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Sotaniemi
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EA
Department of Internal Medicine, University of Oulu, Deaconess Institute of Oulu, Finland.
Rautio
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A
Bäckstrom
M
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Arvela
P
P
Pelkonen
O
O
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases; D002214:Capsules; D003374:Coumarins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000652:urine; D065637:Cytochrome P-450 CYP2A6; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004827:Epilepsy / Q000201:enzymology*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007527:Isoenzymes / Q000378:metabolism; D007674:Kidney Diseases / Q000201:enzymology*; D007677:Kidney Function Tests; D008012:Lidocaine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D008099:Liver / Q000201:enzymology / Q000502:physiology; D008108:Liver Diseases, Alcoholic / Q000201:enzymology*; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010446:Peptide Fragments / Q000097:blood; D011347:Procollagen / Q000097:blood; D014468:Umbelliferones / Q000652:urine
D002214:Capsules; D003374:Coumarins; D007527:Isoenzymes; D010446:Peptide Fragments; D011347:Procollagen; D014468:Umbelliferones; C041876:procollagen Type III-N-terminal peptide; C031477:7-hydroxycoumarin; D003577:Cytochrome P-450 Enzyme System; D008012:Lidocaine; C030123:coumarin; 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