In uremia

Unexpected elevated concentrations of free valproic acid, free phenytoin, and free carbamazepine are encountered in uremia. In uremia, the Fu of valproic acid can be as high as 20-30% compared with 8.45% as observed in healthy volunteers. In uremia, Fu of phenytoin can be as high as 30% whereas in normal volunteers the Fu is usually 10%. Uremia also modifies the disposition of a highly metabolized drug by changes in plasma protein binding or hepatic metabolism (72).

High free drug concentrations in uremia are related to hypoalbuminemia, as well as to the presence of endogenous uremic compounds that can displace strongly protein-bound drugs from protein-binding sites. Monaghan et al. studied in detail the relationship between serum creatinine, blood urea nitrogen, albumin, and the unbound fraction of phenytoin in patients who have undergone renal transplant. The authors concluded that the estimation of Fu of phenytoin in patients with a history of uremia and hypoalbu-minemia should not be based on measurement of serum creatinine and albumin (73).

Hippuric acid and indoxyl sulfate, the two other compounds that are present in elevated concentrations in uremia, can cause displacement of strongly protein-bound drugs (74). Takamura identified 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) as the major uremic toxin that causes impaired protein binding of furosemide. Oleate also plays a role (75). Other uremic compounds such as guanidine, methyl guanidine, and guanidinosuccinic acid do not cause any displacement of drug from protein binding. Another study indicates that several endogenous compounds with small molecular weights (<500) play significant roles in displacement of strongly protein-bound drugs, but mid-molecular uremic toxins do not displace drugs (76). Otagiri (77) in a recent review on drug protein binding commented that reduced protein binding of drugs in uremia can be explained by a mechanism that involves a combination of direct displacement by free fatty acids as well as a cascade of effects from free fatty acids and unbound uremic toxins.

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