Pharmacologically active drug metabolites: therapeutic and toxic activities, plasma and urine data in man, accumulation in renal failure

Clin Pharmacokinet. Nov-Dec 1976;1(6):426-43. doi: 10.2165/00003088-197601060-00003.


Drugs that are administered to man may be biotransformed to yield metabolites that are pharmacologically active. The therapeutic and toxic activities of drug metabolites and the species in which this activity was demonstrated are compiled for the metabolites of 58 drugs. The metabolite to parent drug ratio in the plasma of non-uraemic man and the percentage urinary excretion of the metabolite in non-uraemic man are also tabulated. Those active metabolites with significant pharmacological activity and high plasma levels, both relative to that of the parent drug, will probably contribute substantially to the pharmacological effect ascribed to the parent drug. Active metabolites may accumulate in patients with end stage renal disease if renal excretion is a major elimination pathway for the metabolite. This is true even if the active metabolite is a minor metabolite of the parent drug, as long as the minor metabolite is not further biotransformed and is mainly excreted in the urine. Minor metabolite accumulation may also occur if it is further biotransformed by a pathway inhibited in uraemia. Some clinical examples of the accumulation of active drug metabolites in patients with renal failure are: (a) The abolition of premature ventricular contractions and prevention of paroxysmal atrial tachycardia in some cardiac patients with poor renal function treated with procainamide are associated with high levels of N-acetylprocainamide. (b) The severe irritability and twitching seen in a uraemic patient treated with pethidine (meperidine) are associated with high levels of norpethidine. (c) The severe muscle weakness and tenderness seen in patients with renal failure receiving clofibrate are associated with excessive accumulation of the free acid metabolite of clofibrate. (d) Patients with severe renal insufficiency taking allopurinol appear to experience a higher incidence of side reactions, possibly due to the accumulation of oxipurinol. (e) Accumulation of free and acetylated sulphonamides in patients with renal failure is associated with an increase in toxic side-effects (severe nausea and vomiting, evanescent macular rash). (f) Peripheral neuritis seen after nitrofurantoin therapy in patients with impaired renal function is thought to be due to accumulation of a toxic metabolite. The high incidence of adverse drug reactions seen in patients with renal failure may for some drugs be explained in part, as the above examples illustrate, by the accumulation of active drug metabolites. Monitoring plasma levels of drugs can be an important guide to therapy. However, if a drug has an active metabolite, determination of parent drug alone may cause misleading interpretations of blood level measurements. The plasma level of the active metabolite should also be determined and its time-action characteristics taken into account in any clinical decisions based on drug level monitoring.

Publication types

  • Review

MeSH terms

  • Acetaminophen / metabolism
  • Acetohexamide / metabolism
  • Allopurinol / metabolism
  • Clofibrate / metabolism
  • Humans
  • Kidney Failure, Chronic / blood
  • Kidney Failure, Chronic / metabolism*
  • Kidney Failure, Chronic / urine
  • Lidocaine / metabolism
  • Meperidine / metabolism
  • Methyldopa / metabolism
  • Nitrofurantoin / metabolism
  • Pharmaceutical Preparations / metabolism*
  • Procainamide / metabolism
  • Sulfonamides / metabolism


  • Pharmaceutical Preparations
  • Sulfonamides
  • Acetaminophen
  • Methyldopa
  • Allopurinol
  • Nitrofurantoin
  • Lidocaine
  • Meperidine
  • Clofibrate
  • Procainamide
  • Acetohexamide