Effect of intravenous iron supplementation on hepatic cytochrome P450 3A4 activity in hemodialysis patients: a prospective, open-label study.
BACKGROUND
Cytochrome P450 (CYP) 3A4 is an enzyme with activity dependent on the reduction of heme iron that is responsible for the metabolism of many drugs. CYP3A4 activity is reduced in hemodialysis (HD) patients and thus may be related to functional iron deficiency.


OBJECTIVE
The purpose of this study was to investigate the effect of IV iron supplementation on hepatic is CYP3A4 activity in HD patients.


METHODS
This prospective, open-label study was conducted in 12 iron-deficient (transferrin saturation <20% or ferritin <100 ng/L) HD patients on stable medication regimens. To probe for hepatic CYP3A4 activity, an erythromycin breath test (ERMBT) was administered before and after 1 g IV iron sucrose (administered as a 100-mg dose [20 mg/mL]), at each of 10 consecutive HD sessions). CYP3A4 activity was estimated by the percentage of administered (14)C exhaled in a single-breath collection after the test dose of erythromycin underwent demethylation by CYP3A4. The ERMBT was also administered to 7 age-, sex-, and race-matched healthy controls.


RESULTS
Twelve HD patients (6 Hispanic, 3 white, 3 Native American; 8 men, 4 women; mean [SEM] age, 56.2 [5.0] years; mean [SEM] weight, 77.0 [5.6] kg; and 7 controls (4 men, 3 women; mean [SEM] age, 51.3 [5.0] years; mean [SEM] weight, 77.5 [7.4] kg) were enrolled in the study. In the total HD population studied, mean (SEM) CYP3A4 activity did not change significantly after IV iron replacement (1.46 [0.27] vs 1.57 [0.24] (14)C exhaled/h). A subgroup of 7 HD patients had significantly lower CYP3A4 activity before IV iron replacement compared with the other 5 HD patients and controls (mean [SEM] 0.86 [0.24] vs 2.30 [0.26] and 2.10 [0.26] (14)C exhaled/h; P < 0.01). After IV iron replacement, mean (SEM) CYP3A4 activity increased in these 7 HD patients (120.1% [67.1%]); P = 0.04) and it was not statistically different from that of controls (1.50 [0.36] vs 2.10 [0.26]).


CONCLUSIONS
Overall, IV iron administration had no significant effect on hepatic CYP3A4 activity. However, in a subset of HD patients with low baseline CYP3A4 activity indicated by low ERMBT values, IV iron supplementation was associated with a potentially clinically relevant increase in hepatic CYP3A4 activity. Further studies are needed to clarify mechanisms and clinical implications of this interaction.
Pai
Amy Barton
AB
University of New Mexico College of Pharmacy, MSC09 5360, Albuquerque, NM 87131, USA. abpai@salud.unm.edu
Norenberg
Jeffrey
J
Boyd
Alex
A
Raj
Dominic
D
Chan
Lingtak-Neander
LN
D001944:Breath Tests; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004917:Erythromycin; D005260:Female; D005290:Ferric Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000077605:Ferric Oxide, Saccharated; D005937:Glucaric Acid; D006397:Hematinics / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D000090463:Iron Deficiencies; D008099:Liver / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D006435:Renal Dialysis; D013395:Sucrose / Q000008:administration & dosage* / Q000493:pharmacokinetics
D005290:Ferric Compounds; D006397:Hematinics; D013395:Sucrose; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; D000077605:Ferric Oxide, Saccharated; D005937:Glucaric Acid