Chronic Inhibition of CYP3A is Temporarily Reduced by Each Hemodialysis Session in Patients With End‐Stage Renal Disease

Chronic Inhibition of CYP3A is Temporarily Reduced by Each Hemodialysis Session in Patients With End‐Stage Renal Disease

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. Howe...

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Veröffentlicht in:Clinical pharmacology and therapeutics 2020-10, Vol.108 (4), p.866-873
Hauptverfasser: Egeland, Erlend Johannessen, Witczak, Bartlomiej J., Zaré, Hasse Khiabani, Christensen, Hege, Åsberg, Anders, Robertsen, Ida
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container_end_page 873
container_issue 4
container_start_page 866
container_title Clinical pharmacology and therapeutics
container_volume 108
creator Egeland, Erlend Johannessen
Witczak, Bartlomiej J.
Zaré, Hasse Khiabani
Christensen, Hege
Åsberg, Anders
Robertsen, Ida
description 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.
doi_str_mv 10.1002/cpt.1875
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title Chronic Inhibition of CYP3A is Temporarily Reduced by Each Hemodialysis Session in Patients With End‐Stage Renal Disease
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