Dose loading with delayed-release mesalazine: a study of tissue drug concentrations and standard pharmacokinetic parameters

Aims Tissue concentrations of 5-aminosalicylic acid (5ASA) and its metaboli tes may influence the clinical course of inflammatory bowel disease. Since the factors that determine tissue drug concentrations are unknown we have s tudied the relationships between the oral dose of delayed-release mesalazin e, rectal tissue drug concentrations and standard pharmacokinetic parameter s. Methods Twelve healthy volunteers were studied following 7 days treatment w ith 1.2, 2.4 and 4.8 g of delayed-release mesalazine daily. 5-aminosalicyli c acid and N-acetyl 5-aminosalicylic acid concentrations were measured in s erum, urine, stool and rectal tissue biopsies. Results Serum concentrations and 24 h urinary excretion of 5ASA and N-acety l 5ASA increased as the oral dose of mesalazine was increased from 1.2 g th rough 2.4 g to 4.8 g daily (serum area under curve (AUC):5ASA = 3.9, 15.4 a nd 46.8 mu g ml(-1) h, P < 0.0001; N-acetyl 5ASA = 17.2, 30.9 and 57.8 mu g ml(-1) h, P < 0.0001: urinary excretion: 5ASA = 1.8, 85.5 and 445 mg, P < 0.0001; N-acetyl 5ASA = 250, 524 and 1468 mg, P < 0.0001, respectively). Fa ecal 5ASA excretion increased as the oral dose increased from 1.2 g to 2.4 g but did not increase further with 4.8 g daily dosing whereas faecal N-ace tyl 5ASA excretion was similar at all three doses. Rectal tissue concentrat ions of 5ASA increased markedly, and N-acetyl 5ASA increased modestly, as t he dose of oral mesalazine increased from 1.2 g to 2.4 g daily but neither increased further with 4.8 g daily dosing. Conclusions The relationship between the ingested dose of delayed-release m esalazine and rectal tissue drug concentrations is complex. Factors other t han dose are likely to be important determinants of rectal tissue drug conc entrations.