Pharmacokinetics of Metronidazole in Patients with Enteric Disease Compared to Normal Volunteers

Abstract

Tablets of 500 mg metronidazole were given to 24 patients with intestinal diseases and to 10 healthy volunteers. The diagnoses included coeliac disease, ulcerative colitis, jejunoileal shunt, ileostomy, and Crohn’s disease. Both normal subjects and patients exhibited considerable variation in serum metronidazole concentrations. This applied particularly to the patients who had somewhat slower absorption and later occurrence of serum peaks than did the normal subjects. No major deviation occurred within any of the diagnostic groups. All but the ileostomy patients exhibited a lag before apparent absorption. The individual peaks occurred after 1.5–2.0 h and was 12.7 ± 2.1 μg/ml in all disease groups, except the ileostomy patients who exhibited a mean of 16.2 μg/ml. In the healthy subjects, the mean peak was 12.1 ± 4.6 μg/ml. A major finding was the observation that the patients as a group had a higher total area under the serum curves (AUC) than the volunteers. The AUC of normal volunteers was 108.1 μg · h · ml^––¹ compared to 260.5 μg · h · ml^––1 in the patients with ileostomy and 147.6 μg · h · ml^––1 for the others. The higher AUC values in the ileostomy group were associated with longer serum half-life values. The serum half-life was 8.3 h in the normals, 11.9 h with ileostomy and 7.2 h in the remainder. The normal individuals and the patients with ulcerative colitis had higher rates of absorption, those with coeliac disease or ileostomy lower absorption rates than was found elsewhere. The relative volume of distribution (the distribution coefficient) was the same in the healthy individuals as in each patient group, except for the ileostomy patients. The total body clearance was 1.94 liters/h in ileostomy, 3.68 liters/h in the other patients, and 5.43 liters/h in the normal subjects.

Serum Concentrations of Metronidazole and Its Main Metabolite in Patients with Active Crohn’s Disease: Correlation with Disease Activity and Therapeutic Efficacy?

“…While serum concentrations of metronidazole in normal individuals were in the same range in all studies [10][11][12][13], differing results were reported for Crohn's disease: Bergan et al [13] found markedly higher metronidazole serum concentra tions in patients with inactive Crohn's dis ease than reported by Melanderet al [14] and higher concentrations than in normal individuals, which has been related to in creased permeability of the diseased intes tinal mucosa for metronidazole. It was therefore of interest to determine serum concentrations of metronidazole and its main metabolite in patients with active Crohn's disease during oral therapy with metronidazole in different dosages and to look for a correlation between individual serum concentrations and disease activity and therapeutic efficacy.…”

“…In patients with inactive Crohn's dis ease, Bergan et al [13] found a mean me tronidazole serum concentration of about 13 /rg/ml 2 h after a single oral dose of 500 mg metronidazole, which is distinctly higher than the approximately 7.5 ¿ig/ml found in normal controls receiving the same dosage. This finding has been related to increased permeability of the diseased mucosa for metronidazole in Crohn's dis ease.…”

“…Serum concentrations of metronidazole have been studied in normal individuals [10][11][12][13] and patients with chronic inflam matory bowel diseases [13,14], including patients with Crohn's disease in a quies cent stage. While serum concentrations of metronidazole in normal individuals were in the same range in all studies [10][11][12][13], differing results were reported for Crohn's disease: Bergan et al [13] found markedly higher metronidazole serum concentra tions in patients with inactive Crohn's dis ease than reported by Melanderet al [14] and higher concentrations than in normal individuals, which has been related to in creased permeability of the diseased intes tinal mucosa for metronidazole.…”

Gastric aspiration by nasal intubation: an additional route of elimination for metronidazole [letter]

“…This unexpected observation compared to what has been published in literature (Bergan et al, 1981;Houghton et al, 1979) prompted us to perform a complementary study in seven patients, in which the oral administration was replaced by an intravenous infusion (for 3 days). In this situation there were no significant differences between AUCs which therefore ruled out an explanation based on the recovery from surgery of the patients.…”

Disposition of metronidazole and its effects on sulphasalazine metabolism in patients with inflammatory bowel disease.

“…Confficting data on its absorption are available. Bioavailability studies have suggested either normal (Bergan et al, 1981) or reduced absorption (Melander et al, 1977) but are unreliable due to the lack of study of an intravenous formulation.…”