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Pharmacokinetic Considerations in the Treatment of Inflammatory Bowel Disease

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Abstract

This review describes the pharmacokinetics of the major drugs used for the treatment of inflammatory bowel disease. This information can be helpful for the selection of a particular agent and offers guidance for effective and well tolerated regimens.

The corticosteroids have a short elimination half-life (t1/2 β) 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 eliminated, primarily by cytochrome P450 (CYP) 3A4-mediated metabolism. Prednisone and budesonide undergo presystemic elimination. Any disease state or comedication affecting CYP3A4 activity should be taken into account when prescribing corticosteroids.

Depending on the preparation used, 10 to 50% of an oral or rectal dose of mesalazine is absorbed. Rapid acetylation in the intestinal wall and liver (t1/2 β 0.5 to 2 hours) and transport probably by P-glycoprotein affect mucosal concentrations of mesalazine, which apparently determine clinical response. Any clinical condition influencing the release and topical availability of mesalazine might modify its therapeutic potential.

Metronidazole has high (approximately 90%) oral bioavailability, with hepatic elimination characterised by a t1/2 β of 6 to 10 hours and a total clearance of about 4 L/h/kg. Ciprofloxacin is largely excreted unchanged both renally (about 45% of dose) and extrarenally (25%), with a relatively short t1/2 β (3.5 to 7 hours). Thus, renal function affects the systemic availability of ciprofloxacin.

Both mercaptopurine and its prodrug azathioprine are metabolised to active compounds (6-thioguanine nucleotides; 6-TGN) by hypoxanthine-guanine phosphoribosyltransferase and to inactive metabolites by the polymorphically expressed thiopurine S-methyltransferase (TPMT) and xanthine oxidase. Patients with low TPMT activity have a higher risk of developing haemopoietic toxicity. Both mercaptopurine and azathioprine have a short t1/2 β (1 to 2 hours), but the t1/2 β of 6-TGN ranges from 3 to 13 days. Therapeutic response seems to be related to 6-TGN concentration.

Almost complete bioavailability has been observed after intramuscular and subcutaneous administration of methotrexate, which is predominantly (85%) excreted as unchanged drug with a t1/2 β of up to 50 hours. Thus, renal function is the major determinant for disposition of methotrexate. Cyclosporin is slowly and incompletely absorbed. It is extensively metabolised by CYP3A4/5 in the liver and intestine (median t1/2 β and clearance 7.9 hours and 0.46 L/h/kg, respectively), and inhibitors and inducers of CYP3A4 can modify response and toxicity.

Infliximab is predominantly distributed to the vascular compartment and eliminated with a t1/2 β between 10 and 14 days. No accumulation was observed when it was administered at intervals of 4 or 8 weeks. Methotrexate may reduce the clearance of infliximab from serum.

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Acknowledgements

This work was supported by the Robert Bosch Foundation, Stuttgart, Germany and the BMBF grant (FKZ 01 GG 9846). The secretarial help of Mrs S. Luginsland and Mrs H. Köhler is highly appreciated.

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  1. Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

    Matthias Schwab &  Ulrich Klotz

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  1. Matthias Schwab
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Correspondence to Ulrich Klotz.

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Schwab, M., Klotz, U. Pharmacokinetic Considerations in the Treatment of Inflammatory Bowel Disease. Clin Pharmacokinet 40, 723–751 (2001). https://doi.org/10.2165/00003088-200140100-00003

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