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The Influence of Codeine, Propantheline and Metoclopramide on Small Bowel Transit and Theophylline Absorption from a Sustained-Release Formulation

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The Influence of Codeine, Propantheline and Metoclopramide on Small Bowel Transit and Theophylline Absorption from a Sustained-Release Formulation Br. J. clin. Pharmac. (1992), 33, 305-308 The influence of codeine, propantheline and metoclopramide on small bowel transit and theophylline absorption from a sustained-release formulation DE K. SOMMERS', E. C. MEYER', M. VAN WYK', J. MONCRIEFF', J. R. SNYMAN' & R. J. GRIMBEEK2 Departments of Pharmacology' and Statistics2, University of Pretoria, Pretoria, South Africa 1 The effects of the anticholinergic agent, propantheline, the opiate, codeine, and the prokinetic agent, metoclopramide, on oral-caecal transit time and on the absorption of theophylline from a sustained-release formulation were examined in six healthy male volunteers. 2 A cross-over randomised sequence design was followed, allowing at least 2 weeks interval between studies. On each occasion 500 mg theophylline in a sustained-release formulation was taken simultaneously with 2 g sulphasalazine at zero time. On three of the four occasions one of the following treatments was given concurrently at -0.5 h, +3.5 h, and +7.5 h: 30mg codeine phosphate, 30 mg propantheline bromide, or 10 mg metoclopramide monohydrochloride. 3 The appearance of sulphapyridine in the plasma was used to assess oral-caecal transit time and the mean fraction absorbed-time profile of theophylline was calculated from serial serum theophylline concentration measurements using the Wagner-Nelson method. 4 Codeine increased the mean (s.d.) oral-caecal time (h) significantly (5.14 ± 0.94) compared with the control value (3.78 ± 0.34). Propantheline inhibited peristaltic contractions to such an extent that the oral-caecal transit time in five of the volunteers was between 9 and 25 h, while sulphapyridine appeared in the 9 h serum sample of the sixth. Metoclopramide did not significantly alter the oral-caecal transit time. 5 Despite the observed changes in oral-caecal transit time the rate and extent of theophylline absorption was similar with all regimens. Keywords theophylline sustained-release formulation codeine propantheline metoclopramide oral-caecal transit time small bowel transit Introduction Conventional studies of drug absorption and bioavail- whereby use is made of bacterial metabolism to release ability provide no information on any variability in sulphapyridine from sulphasalazine and hydrogen from absorption that may occur along the gastrointestinal lactulose prior to absorption from the large bowel. In tract. Thus, information on the rate and extent of practice the sulphasalazine/sulphapyridine method absorption at lower gastrointestinal sites and the manner provides a more accurate measure of oral-caecal transit in which it may be influenced by prokinetic and antikinetic time than the lactulose/breath hydrogen method drugs cannot be obtained from these investigations. (Staniforth, 1989). Since the small intestine is the most important site of The aim of the present study was to assess the effects absorption for most drugs any disturbances there could in man of the anticholinergic agent, propantheline; be of clinical importance. Manometric and radioscinti- the opiate, codeine; and the prokinetic agent, meto- graphic methods of evaluating small intestinal motor clopramide, on both the oral-caecal transit time and on function are subject to technical and interpretative the absorption of a model drug. A sustained-release pitfalls (Malagelada, 1990). Flora present in the large formulation of theophylline was chosen for the latter as bowel provide an alternative approach to this evaluation absorption following administration of this kind of Correspondence: Professor De K. Sommers, Department of Pharmacology, University of Pretoria, PO Box 2034, 0001 Pretoria, South Africa 305 306 De K. Sommers et al. formulation, which is not subject to rapid dissolution in the drug was given alone; AUC(O,t) = the area under the stomach, should more accurately reflect small bowel the serum concentration time curve for theophylline transit time than that from conventional formulations. from zero to time (t) calculated using the linear tra- The experiments were performed under fasting condi- pezoidal method; and AUC = the total area under the tions to prevent prolonged gastric residence of the solid serum concentration-time curve for theophylline when dosage form, which has to wait for a migrating motility given alone. complex before it can empty from the stomach (Davis et al., 1986). Statistical analysis The Friedman nonparametric two way analysis ofvariance was used to compare treatment modalities. Differences Methods were considered to be significant at the 5% level. Where significant differences were found, they were identified The subjects of the study were six healthy non-smoking by a multiple comparisons technique based on Friedman ambulatory male volunteers, mean age 21 years and sums (Hollander & Wolfe, 1973). mean weight 76.4 kg. None had cardiac, hepatic, endocrine or renal disease. The volunteers were re- quested to abstain from strenuous exercise, alcohol and caffeine containing beverages for at least 24 h before a Results trial session. Written informed consent was obtained after the protocol had been approved by the Ethics Table 1 shows the average (± s.d.) serum theophylline Committee of the University of Pretoria. concentrations and cumulative fractions of drug absorbed During each study session, after an overnight fast, the (fabs) after administration of the sustained-release subjects remained supine for the first 6 h after drug formulation on its own and after codeine, propantheline, administration. Sulphasalazine and the theophylline- and metoclopramide. Figure 1 shows the mean fraction containing preparation were taken at zero time with 250 absorbed-time profiles of theophylline after each regimen. ml water. Nothing else was ingested before breakfast The rate and extent of absorption were similar following which was provided 3 h later. A cannula with a heparin all treatments. lock was placed in an antecubital vein for blood sampling. The data in Table 2 show that codeine tended to Baseline samples were taken and, thereafter, blood prolong the oral-caecal transit time and that the percen- samples were obtained for measurement of serum theo- tage theophylline remaining to be absorbed from the phylline and sulphapyridine at 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, colon decreased from 58 to 33%. The mean time to 90% 6, 6.5, 7, 9, 25 and 30 h. absorption tended to be shorter than control, i.e. 7.1 A cross-over randomised sequence design was compared with 8.5 h, but this difference was not signifi- followed, allowing at least 2 weeks between the follow- cant. Similarly, mean time to 90% absorption was slightly ing four regimes, each taken simultaneously with 2 g but not significantly shorter with metoclopramide, and the sulphasalazine (non-enteric coated, uncrushed tablets). oral-caecal transit time and percentage theophylline (Salazopyrin®): (a) 1 x 200 mg plus 1 x 300 mg sustained- remaining to be absorbed from the colon were similar release formulation of theophylline (Theo-Dur®). to control values. Because of the 9 to 15 h gap in (b) Regime (a) at zero time with, in addition, the oral sampling times, it was impossible to measure the oral- administration of one of the following treatments at caecal transit time accurately after propantheline treat- -0.5 h, +3.5 h and +7.5 h: (i) codeine phosphate, 30 mg. ment. Sulphapyridine was present in the serum of only (ii) propantheline bromide (Pro-banthineg), 30 mg. one of the volunteers at 9 h but was present at 25 h in (iii) metoclopramide monohydrochloride (Maxolon T7I ), 10 mg. A standard breakfast consisting of bread- 'I rolls, scrambled eggs with ham, cheese, jam and fruit- 1 .0- ,go= ----- ! roi zitio-I Js14xI juice was provided. The oral-caecal transit time was defined as the time at which a serum concentration of 1 ,ug ml-' sulphapyridine was observed. Drug assay and pharmacokinetic analysis I A J The assays of serum theophylline and sulphapyridine 1 f; have been described previously (Sommers et al., 1990). The cumulative fraction of a dose absorbed (fabs) at each serum drug concentration following a single dose jiI.,j' .,*' T ,, was calculated using the Wagner-Nelson equation (Hendeles et al., 1984): .;- t.; .;:,.< .- .t....V mn_ i ...... ;iv AUC(O,t) + C(t)/k Figure 1 The mean fraction absorbed - time profiles of fabs - AUC theophylline from a sustained-release formulation given on its own (0) and with concurrent administration of codeine (A), C(t) = serum concentration of theophylline at time t; propantheline (A), or metoclopramide (0). Mean oral-caecal k = the elimination rate constant of theophylline when transit times were, respectively, 3.78, 5.14, > 9.0, and 4.0 h. Theophylline absorption 307 Table 1 Mean (± s.d.) serum theophylline concentrations (C, mg 1-1) and cumulative fraction of dosage absorbed (fab,) from the sustained release theophylline formulation without pretreatment (0) and after pretreatment with, respectively, codeine (c), propantheline (p), and metoclopramide (m) Time (h) 1 2 3 3.5 4 4.5 5 5.5 6 6.5 7 9 25 30 C(0) 1.3 2.0 2.8 3.0 3.4 3.8 4.4 4.7 5.1 5.3 5.6 6.3 2.8 2.3 (0.22) (0.31) (0.45) (0.45) (0.45) (0.67) (1.12) (0.67) (0.89) (0.89) (1.12) (1.57) (0.89) (0.89) C(c) 1.4 2.1 2.4 2.7 3.2 3.7 4.5 4.7 5.0 5.2 5.7 6.3 2.6 1.8 (0.89) (0.67) (0.67) (0.67) (0.67) (0.67) (0.89) (0.67) (0.67) (0.89) (0.45) (0.45) (0.45) C(p) 1.2 2.1 2.7 2.9 3.5 4.1 4.4 4.9 5.2 5.3 5.8 6.2 4.7 2.5 (0.45) (0.89) (1.12) (1.12) (1.57) (1.79) (2.01) (2.46) (2.46) (2.24) (2.24) (2.01) (2.24) (0.89) C(m) 1.5 2.5 2.8 3.5 4.3 4.8 5.3 5.9 6.4 6.9 7.5
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