Characterization of hepatic cytochrome p4503A activity in patients with end-stage renal disease.
BACKGROUND
The cytochrome p450 (CYP) oxidative enzyme system, located primarily in the liver and small intestine, is responsible for metabolism and detoxification of numerous endogenous and exogenous substances. The most abundant CYP enzyme, CYP3A, is known to be involved in the metabolism of more than 200 commonly used medications. In experimental models of renal failure, both hepatic function and CYP enzyme content are reduced; however, direct evidence in humans is lacking. Evaluation of drug metabolism in patients with end-stage renal disease is important because these patients use a large number of medications and are at risk of adverse reactions and drug-drug interactions.


METHODS
We measured hepatic CYP3A activity at baseline and after rifampin (INN, rifampicin) enzyme induction in 12 patients with end-stage renal disease and 12 healthy, age-matched controls. Hepatic CYP3A phenotype was characterized with the erythromycin breath test, and enzyme induction capacity was evaluated with a short course of rifampin (600 mg/d for 6 days).


RESULTS
The end-stage renal disease group had 28% lower baseline erythromycin breath test values than controls (P <.05); however, enzyme induction capacity after rifampin administration was similar between groups (P =.70).


CONCLUSIONS
The findings suggested that one mechanism by which patients with end-stage renal disease are at increased risk of drug toxicity is reduced activity of the CYP3A enzyme pathway.
Dowling
Thomas C
TC
Department of Medicine, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. tdowling@rx.umaryland.edu
Briglia
Andrew E
AE
Fink
Jeffrey C
JC
Hanes
Donna S
DS
Light
Paul D
PD
Stackiewicz
Lucy
L
Karyekar
Chetan S
CS
Eddington
Natalie D
ND
Weir
Matthew R
MR
Henrich
William L
WL
D000328:Adult; D000368:Aged; D000904:Antibiotics, Antitubercular / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000378:metabolism*; D001944:Breath Tests; D051544:Cytochrome P-450 CYP3A; D004790:Enzyme Induction / Q000187:drug effects; D004917:Erythromycin; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000201:enzymology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis / Q000378:metabolism*; D010641:Phenotype; D011446:Prospective Studies; D011500:Protein Synthesis Inhibitors; D012293:Rifampin / Q000494:pharmacology
D000904:Antibiotics, Antitubercular; D011500:Protein Synthesis Inhibitors; D004917:Erythromycin; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D012293:Rifampin