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Chronic Inhibition of CYP3A is Temporarily Reduced by Each Hemodialysis Session in Patients With End‐Stage Renal Disease
Author(s) -
Egeland Erlend Johannessen,
Witczak Bartlomiej J.,
Zaré Hasse Khiabani,
Christensen Hege,
Åsberg Anders,
Robertsen Ida
Publication year - 2020
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1875
Subject(s) - dialysis , hemodialysis , medicine , end stage renal disease , fexofenadine , cyp3a , pharmacology , dosing , pharmacokinetics , uremia , renal function , organic anion transporting polypeptide , chemistry , cytochrome p450 , transporter , metabolism , biochemistry , gene
Drug dosing is challenging in patients with end‐stage renal disease. Not only is renal drug elimination reduced, but nonrenal clearance pathways are also altered. Increasing evidence suggest that uremia impacts drug metabolizing enzymes and transporters leading to changes in nonrenal clearance. However, the exact mechanisms are not yet fully understood, and the acute effects of dialysis are inadequately investigated. We prospectively phenotyped cytochrome P450 3A (CYP3A; midazolam) and P‐glycoprotein (P‐gp)/organic anion‐transporting proteins (OATP; fexofenadine) in 12 patients on chronic intermittent hemodialysis; a day after (“clean”) and a day prior to (“dirty”) dialysis. Unbound midazolam clearance decreased with time after dialysis; median (range) reduction of 14% (−3% to 41%) from “clean” to “dirty” day ( P = 0.001). Fexofenadine clearance was not affected by time after dialysis ( P = 0.68). In conclusion, changes in uremic milieu between dialysis sessions induce a small, direct inhibitory effect on CYP3A activity, but do not alter P‐gp/OATP activity.