Several lines of emerging evidence indicate that kidney disease differentially affects uptake and efflux transporters and metabolic enzymes in the liver and gastrointestinal (GI) tract, and uremic toxins have been implicated as the cause. In patients with kidney disease, even drugs that are eliminated by nonrenal transport and metabolism could lead to important unintended consequences if they are administered without dose adjustment for reduced renal function. This is particularly so in the case of drugs with narrow therapeutic windows and may translate into clinically significant variations in exposure and response.