Disposition of metronidazole and its effects on sulphasalazine

Transcription

1 Br. J. clin. Pharmac. (1986), 21, Disposition of metronidazole and its effects on sulphasalazine metabolism in patients with inflammatory bowel disease J. L. SHAFFER*,' A. KERSHAW2 & J. B. HOUSTON2 Departments of Medicine' and Pharmacy2, Hope Hospital (University of Manchester School of Medicine), Salford M6 8HD and University Department of Pharmacy, Manchester M13 9PT 1 The pharmacokinetics of metronidazole were studied after oral and intravenous administration to seven patients with disease and five patients with ulcerative colitis. 2 The oral/intravenous availability ratio was in the patients and in the colitics (mean ± s.e. mean). Plasma clearance was h'1 and 4.1 ±.5 1 h-1, respectively. These differences were not statistically significant. 3 Ten of the patients on long term sulphasalazine were studied to observe the effect of 2 weeks metronidazole therapy on plasma sulphapyridine concentration. 4 The sulphapyridine concentration changed from ,ug ml-' to ,ug ml-1 in the patients and Fg ml-1 to plg m171 in the colitis group, pre- and post-metronidazole. These differences were not statistically significant. 5 These results suggest that metronidazole does not interfere with diazo-link splitting of sulphasalazine and that patients with disease handle metronidazole in a similar manner to patients with colitis. Keywords disposition metronidazole sulphasalazine inflammatory bowel ntroduction Metronidazole has been shown to be of value in the management of disease (Ursing et al., 1982) although its mechanism of action is unclear (Krook et al., 1981). 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. Sulphasalazine, which is widely used in these conditions is split by colonic bacteria to its constituents: sulphapyridine and the active moeity, 5-amino salicylic acid. Antibacterial drugs like ampicillin (Houston et al., 1982) and rifampicin (Shaffer & Houston, 1985) have been shown to reduce plasma sulphapyridine levels after administration of sulphasalazine. Metronidazole, by its antibacterial activity, may thus reduce sulphasalazine cleavage and impair its therapeutic efficacy. The present studies were designed to assess the disposition of metronidazole in patients with inflammatory bowel disease. The bioavailability was estimated under steady state conditions following 8-14 days treatment with oral metronidazole by comparison with an intravenous dose studied before the start of chronic treatment. n addition the effect of this therapy on azo reduction of sulphasalazine to yield sulphapyridine has been investigated. Methods Patients Seven patients with disease and five with ulcerative colitis were studied. They were Correspondence: Dr J. L. Shaffer, Department of Medicine, Hope Hospital (University of Manchester School of Medicine), Salford M6 8HD 431

2 432 J. L. Shaffer et al. well matched for age, weight and sex (Table 1) and gave their informed consent. All were outpatients with mild disease activity. All were taking sulphasalazine (2-4 g day1) but none took corticosteroids. No patient had received antibacterial therapy during the month prior to the study. The protocol was reviewed by the Salford Health Authority Ethics Committee. Metronidazole On the first study day a cannula was inserted into a forearwm vein. n the contralateral arm 4 mg of metronidazole was infused over 2 min. Blood samples (1 ml) were collected at, 7.5, 15, 3 min and at 1, 2, 3, 4, 6, 8, 12 and 24 h after the dose. The patients were then given metronidazole orally at a dose of 4 mg twice daily until they returned for a second study 8-14 days later. On this occasion plasma sampling was performed at, 1, 2, 3, 4, 6, 8 and 12 h after an oral 4 mg dose. The samples were assayed for metronidazole by h.p.l.c. (Gulaid etal., 1978), limit of detection.97,ug m[17, coefficient of variation of assay 5%. Sulphapyridine On the first study day plasma was taken to assay sulphapyridine concentrations. The patients continued taking their maintenance sulphasalazine dosage (2-4 g day-1) together with their metronidazole until the second study day when a further sample was collected. Sulphapyridine concentrations were assayed by the method of Shaw et al. (198), limits of detection-sulphapyridine 1.19 Fg ml[', acetylsulphapyridine 1.63 gg m[71. centration-time curve was calculated using the trapezoidal rule between time zero and infinity for the intravenous study and over the 12 h dosage interval for the oral study. Clearance and volume of distribution were calculated from the area under the curve following intravenous administration. Bioavailability was estimated from the product of the oral to intravenous area ratio and the intravenous to oral dose. Results Metronidazole plasma concentration-time curves for the two groups of patients can be seen in Figures 1 and 2. t should be noted that the plasma concentrations after oral dosing exceed those following intravenous administration as the former profile reflects the steady state resulting from multiple oral therapy. Thus the appro- i Ē 15 D 1 N ' 5 a) E ( - _- Jl T T 1i Pharmacokinetic indices The plasma half-life of metronidazole was calculated from least squares regression analysis of the terminal exponential of the plasma concentration-time profile. The area under the con- Table 1 Details of the patients Time (h) Figure 1 Plasma metronidazole concentrations in (± s.e. mean) in patients with disease () oral, () intravenous. Colitis Number 7 5 Age (mean ± s.e. mean) (years) 5.7 ± ± 7.1 M:F 4:3 3:2 Weight (kg) (mean ± s.e. mean) 66.4 ± ± 1.7 Disease duration (years) Surgery 3 right hemicolectomy.

3 1._ ECo G) CD 'a Cu Ulcerative colitis n- n v-~, t Metronidazole and sulphasalazine in inflammatory bowel disease Time (h) Figure 2 Plasma metronidazole concentrations (+ s.e. mean) in patients with ulcerative colitis () oral, (-) intravenous. priate comparison is between the areas under the curve for oral administration during the dosage interval (i.e. -12 h) and the total area under the curve following intravenous administration. The mean areas and the other pharmacokinetic data are shown in Table 2. Elimination half-lives within a given patient varied by as much as 2-4 h for both routes of administration. This difference was assumed to represent intrasubject variability as the direction of the change was not consistent. There was little difference in bioavailability, clearance and volume of distribution for the two patient groups. Following oral dosing maximum plasma concentrations were achieved by 2 h. There was no difference between the mean maximum concentrations of 15.8 (± 2.3),ug ml-[ and 13.6 (+ 1.9),ug m[17 in the and colitis groups, respectively. Good agreement between the zero Table 2 Pharmacokinetic parameters after oral and i.v. administration of metronidazole (mean + s.e. mean) t Colitis t½. i.v. (h) t,½ oral (h) 8.5 ± ±.5 V (1 kg-1).57 ±.1.58 ±.1 CL (l h-1) 3.2 ± ±.5 AUC oral (mg 1` h) 124 ± ± 11 AUC i.v. (mg ` h) F.97 ±.2.9 ±.1 and 12 h concentrations in the oral study indicated that a steady state had been achieved. Sulphapyridine The changes in the sulphapyridine concentrations in individual patients can be seen in Figure 3. n two of the disease patients sulphapyridine could not be detected in the blood. Further enquiries revealed that in both patients this was due to poor compliance. Total sulphapyridine concentrations (sulphapyridine plus its acetylated derivative) were initially 22.1 (± 2.9) jig ml-' and subsequently (+ 4.5),ug ml-l in the group and 26. (+ 6.),ug ml-' and 36.4 (+ 8.5),ug ml-' in the colitics. These differences were not significant by a Student's paired t-test. Discussion A previous study using a bioassay technique had suggested reduced bioavailability of metronidazole in disease (Melander et al., 1977) but because an intravenous formulation was not used conclusions based on that study should be guarded. n comparable studies in E 1 a)._ CL 6t- 5 _j _- 2 1 /Y A Ulcerative colitis Figure 3 Plasma sulphapyridine concentrations in patients before and after metronidazole therapy. The data on the left of each set of boxes refers to pretreatment and that on the right to post-treatment values.

4 434 J. L. Shaffer et al. normal volunteers (Houghton etal., 1979; Rabin etal., 198) bioavailability generally approached 1% and in our patients around 9%. Thus there is no evidence of impaired absorption or much inter-individual variation in patients with disease. This contrasts with our previous observation on prednisolone handling by disease patients (Shaffer et al., 1983). The design of our study was such that all the patients had the drug by the intravenous route first followed by the oral regime. This was to ensure that all patients were at steady state for the oral study in an attempt to reflect accurately the long term metronidazole usage required in treatment of disease. A study reported in abstract form has suggested no change in kinetics after many months of therapy thus supporting our conclusions (Jensen et al., 1984). Our data following intravenous metronidazole administration suggest that neither disease nor ulcerative colitis alter the disposition of the drug. Plasma clearance, volume of distribution and half-life values reported here are consistent with published data in normal volunteers (Houghton et al., 1979) and patients with cirrhosis (Daneshmend et al., 1982). The mechanism of action of sulphasalazine in disease is still unclear. The 5-ASA component is likely to be the active constituent as in ulcerative colitis. Whether the sulphasalazine is active or not, is unclear, but certainly the compound must be split in order to release 5-ASA. Thus although a measure of plasma sulphapyridine correlates poorly with disease activity it is a reasonable indirect method of assessing 5- ASA bioavailability in the gut lumen (Das et al., 1973). Although the patients with disease had lower plasma sulphapyridine values compared with patients with ulcerative colitis this was not statistically significant. There could be a Type error in our results, that is, the difference could be significant but the small numbers of patients may have prevented a statistical difference from emerging. However, even if this were true the plasma concentrations of sulphapyridine obtained after metronidazole therapy in the patient suggest considerable diazo-link splitting of sulphasalazine had occurred. We feel that these results show that there is no clinically important drug interaction between metronidazole and sulphasalazine and that the two drugs can be used together. We thank Professor L. A. Turnberg and Dr M. N. Marsh for permission to study their patients, Mrs Julie Rostron for typing this manuscript, and May & Baker for supplying the metronidazole. References Bergan, T., Bjerke, P. E. M. & Fausa,. (1981). Pharmacokinetics of metronidazole in patients with enteric disease compared to normal volunteers. Chemotherapy, 27, Daneshmend, T. K., Homeida, M., Kaye, C. M., Elumin, A. A. & Roberts, C. J. C. (1982). Disposition of oral metronidazole in hepatic cirrhosis and in hepatosplenic schistosomiasis. Gut, 23, Das, K. M., Eastwood, M. A., McManus, J. P. A. & Sircus, W. (1973). The metabolism of salicylazo sulphapyridine in ulcerative colitis. Gut, 14, Gulaid, A., Houghton, G. W., Lewellen,. R. W., Smith, J. & Thorne, P. S. (1978). Determination of metronidazole and its two major metabolites in biological fluids by high pressure chromatography. Br. J. clin. Pharmac., 6, Houghton, G. W., Smith, J., Thorne, P. S. & Templeton, R. (1979). The pharmacokinetics of oral and intravenous metronidazole in man. J. Antmicrobial Chemother., 5, Houston, J. B., Day, S. & Walker, J. (1982). Azo reduction of sulphasalazine in healthy volunteers. Br. J. clin. Pharmac., 14, Jensen, J. C., Schulte, H. & Gugler, R. (1984). Pharmacokinetics of metronidazole during long term chronic dosing. 9th nternational Congress of Pharmacology, 17 (abstract). Krook, A., Jarnerot, G. & Danielsson, D. (1981). Clinical effects of metronidazole and sulfasalazine on disease in relation to changes in the faecal flora. Scand. J. Gastroenterology, 16, Melander, A., Kahlmeter, G., Kamane, C. & Ursing, B. (1977). Bioavailability of metronidazole in fasting and non-fasting healthy subjects and in patients with disease. Eur. J. clin. Pharmac., 12, Rabin, H. R., Urtasun, R. C., Partington, J., Koziol, D., Sharon, M. & Walker, K. (198). High dose metronidazole, pharmacokinetics and bioavailability using an i.v. preparation and application for its use as a radiosensitiser. Curr. Treat. Res., 64, Shaffer, J. L. & Houston, J. B. (1985). The effect of rifampicin on sulphapyridine plasma concentrations following sulphasalazine administration. Br. J. clin. Pharmac., 19, Shaffer, J. L., Williams, S. E., Turnberg, L. A., Houston, J. B. & Rowland, M. (1983). Absorption of prednisolone in patients with disease. Gut, 24, Shaw, P. N., Aarons, L. & Houston, J. B. (198).

5 Metronidazole and sulphasalazine in inflammatory bowel disease 435 H.p.l.c. analyses of sulphasalazine and its metabolites. J. Pharm. Pharmac., 32, 67P. Ursing, B., Alm, T., Barany, F., Bergelin,., Gonrot- Norlin, K., Hoevels, J., Huitfeldt, B., Jarnerot, G., Krause, U., Krook, A., Lindstrom, B., Nordle,. & Rosen, A. (1982). A comparative study of metronidazole and sulphasalazine for active disease. The co-operative disease study in Sweden,. Result. Gastroenterology, 83, (Received 22 July 1985, accepted 13 November 1985)