Characterization of hepatic cytochrome P4503A activity in patients with end-stage renal disease

Thomas C. Dowling, Andrew E. Briglia, Jeffrey C. Fink, Donna S. Hanes, Paul D. Light, Lucy Stackiewicz, Chetan S. Karyekar, Natalie D. Eddington, Matthew R. Weir, William L Henrich

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

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). Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)427-434
Number of pages8
JournalClinical Pharmacology and Therapeutics
Volume73
Issue number5
DOIs
StatePublished - May 1 2003
Externally publishedYes

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Cytochromes
Cytochrome P-450 Enzyme System
Chronic Kidney Failure
Cytochrome P-450 CYP3A
Enzyme Induction
Liver
Rifampin
Breath Tests
Erythromycin
Drug-Related Side Effects and Adverse Reactions
Drug Evaluation
Drug Interactions
Small Intestine
Renal Insufficiency
Theoretical Models
Phenotype
Enzymes

ASJC Scopus subject areas

  • Pharmacology

Cite this

Characterization of hepatic cytochrome P4503A activity in patients with end-stage renal disease. / Dowling, Thomas C.; Briglia, Andrew E.; Fink, Jeffrey C.; Hanes, Donna S.; Light, Paul D.; Stackiewicz, Lucy; Karyekar, Chetan S.; Eddington, Natalie D.; Weir, Matthew R.; Henrich, William L.

In: Clinical Pharmacology and Therapeutics, Vol. 73, No. 5, 01.05.2003, p. 427-434.

Research output: Contribution to journalArticle

Dowling, TC, Briglia, AE, Fink, JC, Hanes, DS, Light, PD, Stackiewicz, L, Karyekar, CS, Eddington, ND, Weir, MR & Henrich, WL 2003, 'Characterization of hepatic cytochrome P4503A activity in patients with end-stage renal disease', Clinical Pharmacology and Therapeutics, vol. 73, no. 5, pp. 427-434. https://doi.org/10.1016/S0009-9236(03)00056-0
Dowling, Thomas C. ; Briglia, Andrew E. ; Fink, Jeffrey C. ; Hanes, Donna S. ; Light, Paul D. ; Stackiewicz, Lucy ; Karyekar, Chetan S. ; Eddington, Natalie D. ; Weir, Matthew R. ; Henrich, William L. / Characterization of hepatic cytochrome P4503A activity in patients with end-stage renal disease. In: Clinical Pharmacology and Therapeutics. 2003 ; Vol. 73, No. 5. pp. 427-434.
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