Contribution of the human kidney to the metabolic clearance of drugs.

Abstract

To demonstrate that the human kidney is capable not only of filtering and secreting drugs and their metabolites, but also of carrying out conjugation reactions such as acyl glucuronidation, N-glucuronidation, and glycination. Plasma concentrations and renal excretion rates of drugs are measured and renal clearance is calculated in a series of selected pharmacokinetic studies in healthy human volunteers (some studies were conducted in the authors' laboratory and others were reported in the literature). BACKGROUND THEORY: It is generally agreed that the liver plays the dominant role in drug metabolism, and that the function of the kidneys is limited to excretion of parent drug and metabolites. This can be easily understood when a metabolite is present in both plasma and urine. When the metabolite is present in urine but is not measurable in plasma, then the possibility exists that the metabolite is formed by the kidneys. "Simple" excretion by the kidneys is demonstrated for sulfatroxazole/sulfamethoxazole. Ether glucuronides of codeine are formed in the liver, and the resulting glucuronide is excreted by the kidneys. Possible formation of N1- and N2-glucuronides by the kidneys is demonstrated for sulfadimethoxine, sulfametomidine, and sulfaphenazole. Acyl glucuronidation of probenecid and nalidixic acid is carried out by the kidneys. The acyl glucuronidation of probenecid shows a capacity-limited formation/excretion rate of 46 mg/h, which is subject dependent. During this process, the acyl glucuronidation of co-administered nalidixic acid is reduced from 53 to 16 percent compared with that of nalidixic acid alone. Probenecid and its acyl glucuronidation do not inhibit the ether glucuronidation of codeine in the liver, but only interfere with the active tubular secretion process. The acyl glucuronidation of the nonsteroidal antiinflammatory drug naproxen and its metabolite, O-desmethylnaproxen, may be carried out by the liver and kidneys. Glycination of benzoic acid and salicylic acid is carried out in both the liver and kidneys. It is difficult to recognize renal drug metabolism in the intact human body (in vivo); the glucuronides or conjugates must be measured via direct HPLC analysis. In cases where the metabolite is present in high concentrations in urine but not in blood, there may be an indication that the kidneys are responsible for the formation of the metabolite. Impaired kidney function not only affects renal excretion but may also affect renal metabolism.