Pharmacokinetic considerations in the treatment of inflammatory bowel disease

This review describes the pharmacokinetics of the major drugs used for the treatment of inflammatory bowel disease. This information can be helpful fo r the selection of a particular agent and offers guidance for effective and well tolerated regimens. The corticosteroids have a short elimination half-life (t(1/2)beta) of 1.5 to 4 hours, but their biological half-lives are much longer (12 to 36 hours ). Most are moderate or high clearance drugs that are hepatically eliminate d, primarily by cytochrome P450 (CYP) 3A4-mediated metabolism. Prednisone a nd budesonide undergo presystemic elimination. Any disease state or comedic ation affecting CYP3A4 activity should be taken into account when prescribi ng cortico steroids. Depending on the preparation used, 10 to 50% of an oral or rectal dose of m esalazine is absorbed. Rapid acetylation in the intestinal wall and liver ( t(1/2)beta 0.5 to 2 hours) and transport probably by P-glycoprotein affect mucosal concentrations of mesalazine, which apparently determine clinical r esponse. Any clinical condition influencing the release and topical availab ility of mesalazine might modify its therapeutic potential. Metronidazole has high (approximately 90%) oral bioavailability, with hepat ic elimination characterised by a t(1/2)beta of 6 to 10 hours and a total c learance of about 4 L/h/kg. Ciprofloxacin is largely excreted unchanged bot h renally (about 45% of dose) and extrarenally (25%), with a relatively sho rt t(1/2)beta (3.5 to 7 hours). Thus, renal function affects the systemic a vailability of ciprofloxacin. Both mercaptopurine and its prodrug azathiopr ine are metabolised to active compounds (6-thioguanine nucleotides; 6-TGN) by hypoxanthine-guanine phosphoribosyltransferase and to inactive metabolit es by the polymorphically expressed thiopurine S-methyltransferase (TPMT) a nd xanthine oxidase. Patients with low TPMT activity have a higher risk of developing haemopoietic toxicity. Both mercaptopurine and azathioprine have a short t(1/2)beta (1 to 2 hours) , but the t(1/2)beta of 6-TGN ranges from 3 to 13 days. Therapeutic respons e seems to be related to 6-TGN concentration. Almost complete bioavailabili ty has been observed after intramuscular and subcutaneous administration of methotrexate, which is predominantly (85%) excreted as unchanged drug with a t(1/2)beta of up to 50 hours. Thus, renal function is the major determin ant for disposition of methotrexate. Cyclosporin is slowly and incompletely absorbed. It is extensively metabolised by CYP3A4/5 in the liver and intes tine (median t(1/2)beta and clearance 7.9 hours and 0.46 L/h/kg, respective ly), and inhibitors and inducers of CYP3A4 can modify response and toxicity . Infliximab is predominantly distributed to the vascular compartment and eli minated with a t(1/2)beta between 10 and 14 days. No accumulation was obser ved when it was administered at intervals of 4 or 8 weeks. Methotrexate may reduce the clearance of infliximab from serum.