ESRD can affect the pharmacokinetic disposition of drugs subject to nonrenal clearance.
Cytochrome P450 (CYP)
enzymes, including
CYP3A, and multiple intestinal and hepatic
drug transporters are thought to mediate this process, but the extent to which
kidney disease alters the function of these
proteins in humans is unknown. We used
midazolam and
fexofenadine to assess
CYP3A (intestinal and hepatic) and
drug transport, respectively, in patients with
ESRD and healthy control subjects. We evaluated the effect of
uremia on
CYP3A and transporter expression in vitro by incubating normal rat hepatocytes and enterocytes with serum drawn from study participants.
ESRD dramatically reduced nonrenal transporter function, evidenced by a 63% decrease in clearance (P < 0.001) and a 2.8-fold increase in area under the plasma concentration-time curve for
fexofenadine (P = 0.002), compared with control subjects. We did not observe significant differences in
midazolam or
1'-hydroxymidazolam clearance or area under the curve after
oral administration, suggesting that
CYP3A function is not changed by
ESRD. Changes in hepatocyte and enterocyte
protein expression in the presence of uremic serum were consistent with in vivo results. These findings demonstrate a mechanism for altered
drug disposition in
kidney disease, which may partially account for the high rates of
drug toxicity in this population.