Effect of chronic renal failure on the disposition of highly hepatically metabolized drugs.

Abstract

The objective of this study was to investigate the effect of renal impairment on the disposition of an extensively metabolized drug, i.e., drug X. Drug X has a hepatic extraction ratio of less than 0.1 and free fraction in plasma of less than 1% in healthy volunteers. Pharmacokinetic (PK) parameters of drug X were obtained from subjects with normal renal function (I, n = 6), as well as in subjects with mild (II, n = 5), moderate (III, n = 7) and severe renal impairment (IV, n = 5). Disease-PK models were developed to describe the changes of PK parameters with respect to renal function measured by creatinine clearance. While experimentally observed data are presented for drug X, additional simulations were performed for other drugs that are extensively metabolized (extensive metabolism is defined as metabolism that accounts for more than 90% of total drug elimination). The simulated scenarios included drugs that have a low extraction ratio (ER) and with high plasma protein binding (PPB), low ER and with low PPB, high ER and with high PPB, or high ER and with low PPB. Systemic clearance of drug X, a low ER and high PPB drug, in renal patients depended on the simultaneous effects of renal disease on protein binding and intrinsic metabolic clearance. Protein binding of drug X was related to creatinine clearance in an inverse hyperbolic relationship, while the unbound intrinsic metabolic clearance declined linearly with creatinine clearance. Because the disease effects on these two factors offset each other in terms of total systemic clearance, the lowest total systemic clearance was not observed in the severely renal impairment patients, but rather in the moderately impaired group. Additional simulations showed that for low ER drugs that are highly metabolized, the pattern and magnitude of systemic clearance change in renal patients depended on how the disease affected PPB and/or intrinsic metabolic clearance. But the systemic clearance of high ER drugs would not be as susceptible to the effect of renal disease as that of low ER drug. Chronic renal disease should not be considered as an isolated event that affects only renally excreted drugs. Uremia may also modify the disposition of a highly metabolized drug by changes in plasma protein binding and/or hepatic metabolism.