Azathioprine - Pharmacokinetics

Pharmacokinetics

Azathioprine is absorbed from the gut to about 88%. Bioavailability varies greatly between individual patients, between 30 and 90%, because the drug is partly inactivated in the liver. Highest blood plasma concentrations, counting not only the drug itself but also its metabolites, are reached after one to two hours; and the average plasma half-life is 26 to 80 minutes for azathioprine and three to five hours for drug plus metabolites. 20 to 30% are bound to plasma proteins while circulating in the bloodstream.

Azathioprine is a prodrug, a substance that is not an active drug itself but is activated in the body. This happens in several steps; at first it is slowly and almost completely converted to 6-mercaptopurine (6-MP) by reductive cleavage of the thioether (–S–). This is mediated by glutathione and similar compounds in the intestinal wall, the liver and on red blood cells, without the aid of enzymes. 6-MP is metabolized analogously to natural purines, giving thioguanosine triphosphate (TGTP) and thio-deoxyguanosine triphosphate (TdGTP) via thioinosine monophosphate (TIMP) and several further intermediates. On a second path, the sulfur atom of 6-MP and TIMP is methylated. The end products of azathioprine metabolism are thiouric acid (38%) and various methylated and hydroxylated purines, which are excreted via the urine.