Pharmacokinetics Metabolic pathway for<unk>  <unk> . Active metabolites are highlighted.<unk>  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 1–2 hours, and the average plasma half-life is 26 to 80 minutes for<unk>  and 3–5 hours for drug plus metabolites. 20 to 30% are bound to plasma proteins while circulating in the bloodstream.<unk>  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 thiodeoxyguanosine 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<unk>  metabolism are thiouric acid (38%) and various methylated and hydroxylated purines, which are excreted via the urine. Mechanism of action<unk>  inhibits purine synthesis. Purines are needed to produce DNA and RNA. By inhibiting purine synthesis, less DNA and RNA are produced for the synthesis of white blood cells, thus causing immunosuppression.<unk>  is converted within tissues to 6-MP, some of which is converted, in turn, to 6-thioguanine by the addition of an amino group. Both 6-MP and 6-thioguanine are conjugated with ribose, and then phosphorylated to form the nucleotides thioinosinic acid and thioguanylic acid, respectively. These nucleotides masquerade, respectively, as inosinic acid and guanylic acid; the former is the starting point for purine nucleotide biosynthesis, while the latter is one of the building blocks of DNA and RNA. * The nucleotides are incorporated into newly synthesized (but nonfunctional) DNA, halting replication. * The nucleotides act to inhibit glutamine-phosphoribosyl pyrophosphate amidotransferase (GPAT), one of the enzymes involved in purine biosynthesis, one of the earlier steps in the synthesis of DNA and RNA. They achieve GPAT inhibition through a form of negative feedback called product inhibition. Because actively replicating cells (such as cancer cells and the T cells and B cells of the immune system) are most active in synthesizing purine, making new DNA, these cells are most strongly affected. * A portion of the nucleotides is additionally phosphorylated to the triphosphate forms. These bind to GTP-binding protein Rac1, blocking synthesis of the protein Bcl-xL, thus sending activated T cells and mononuclear cells into apoptosis (programmed cell death). Increased apoptosis of mononuclear cells is seen in inflammatory bowel disease patients treated with<unk> .
Azathioprine
Hydroxychloroquine
Etanercept
Aminophenazone
Tofacitinib
Teriflunomide
Leflunomide
Sirolimus