Study of the bioavailability of pindolol in malabsorption

Transcription

1 Br. J. clin. Pharmac. (1984), 18, Study of the bioavailability of pindolol in malabsorption syndromes D. EVARD1, J-P. AUBRY2, Y. LE QUINTREC1, G. CHEYMOL2, & A. CHEYMOL2 'Service de Gastro-ent6rologie, Hopital Rothschild, 43 Boulevard de Picpus, Paris Cedex 12, France and 2Service de Pharmacologie, H6pital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, Paris Cedex 12, France Pindolol kinetics and bioavailability were studied after a single dose (oral 5 mg; intravenous 3 mg) in nine patients with malabsorption (two with villous atrophies, seven with short bowel syndromes) and in six healthy volunteers. After oral administration no significant differences were observed in bioavailability (59.4 ± 6.2% in patients vs 79.5 ± 8.6% in controls) and for most plasma and urinary pharmacokinetic parameters between the experimental and control groups as a whole. However, detailed analysis revealed decreased absorption for pindolol in two out of nine patients. After i.v. administration, apparent distribution volume was smaller (V: 2.10 ± kg-' vs kg-') and global elimination constant was larger (ke: h-1 vs h-1), in patients with malabsorption than in controls (P < 0.05). The smaller weight of patients and pharmacokinetic modifications due to the pathology could account for this. Keywords pindolol bioavailability malabsorption Introduction The pharmacokinetics of pindolol, a I- adrenoceptor blocker widely used in the treatment of arterial hypertension, have previously been studied in healthy subjects (Gugler et al., 1974) and in hypertensive subjects with either normal or impaired renal function (Lavene et al., 1977). In healthy subjects its bioavailability is high due to an excellent digestive absorption and a slight first pass effect (Meier & Nuesch, 1977). In hypertensive patients with chronic renal failure its bioavailability is slightly diminished (Lavene et al., 1977). No bioavailability studies have as yet been carried out in patients with malabsorption syndromes. The purpose of this work is to see whether an alteration of the absorption function of the small intestine could modify the bioavailability of pindolol. 632 Methods Subjects This study concerned nine patients with malabsorption, four women and five men, with a mean age of 48 ± 4.4 years, mean weight of 55.2 ± 4.6 kg and height m. Two presented with villous atrophies confirmed by jejunal biopsy and were on gluten-free diets. Seven presented with short bowel syndromes after ileal or jejuno-ileal resection (four cases of radiation enteritis, one jejunostomy after appendicectomy, one case of mesenteric thrombosis, one Crohn's disease). The length of the remaining small intestine, determined surgically and/or radiologically was on average 1.37 ± 0.15 m. For these nine patients daily stool fat was increased and D-xylose intestinal absorption decreased.

2 Six control subjects, four men and two women free from any organic pathology, having a mean age of years, a mean weight of 63.0 ± 3.13 kg and height of 1.69 ± 0.15 m were also tested. All subjects admitted in this study gave informed consent. Experimental procedure Each of the subjects in the study received pindolol by intravenous (3 mg over 6 min) and oral (a 5 mg tablet) routes, with an interval of at least 4 days between the two tests. The subjects fasted from 8 h prior to the test to 2 h after drug administration. During the test they stayed in bed. Ten venous blood samples were collected for 5 h after i.v. injection and 10 h after oral ingestion. The precise schedule can be seen on Figure 1. Urines were collected for 54 h following drug administration. Plasma and urine specimens were kept frozen until the time of measurement. This study used the fluorometric method of Pacha (1969), which measures intact pindolol. Pharmacokinetic parameters Plasma data For the intravenous route a twocompartment open model was used, and for the oral route a one-compartment open model. For each subject parameters were determined according to Gibaldi & Perrier (1982). For the i.v. route we calculated the apparent rate constants (a and 13), the elimination constant (ke), AUCQOO, total body clearance (CL,to), the apparent volume of distribution (V). For oral route we calculated the absorption (ka) and elimination (ke) constants, the lag time, tmax, Cmax, AUC>>, CLtot, V and the amount absorbed (F). Urinary data Accumulated urinary elimination of excreted intact pindolol (U a)) was determined over 0-54 h. Renal clearance was calculated: CLr = U oo/aucq,. The fraction absorbed was calculated by percentage of dosage eliminated in the urine: f = % p.o./% i.v. Data analysis In this study the mean results are given with the standard error of the mean (mean + s.e. mean). Control and experimental subjects were compared by means of a non-parametric Mann- Short report 633 Whitney test due to the small number of subjects. Results i.v. route Figure la represents the time course of plasma concentrations of pindolol in control and experimental subjects. The latter had significantly higher values than the former (P < 0.05) from the fifth to the thirtieth minute; the difference was no longer significant after 45 min. Thus it can be seen (Table 1) that in patients with malabsorption the apparent distribution volume, expressed per kg or not, was smaller than that of the controls (P < 0.05), the total elimination constant, keg was larger and the elimination half-life shorter than in controls (P < 0.05). CLtot and AUCzO, were the same for both groups. The quantity of intact pindolol excreted in the urine and the renal clearance showed no significant differences between controls and the patients with malabsorption (Table 1). Oral route The time course of the mean plasma level curves was the same in both groups (Figure lb): after a lag period respectively of 0.37 ± 0.07 h and h in control and patient groups, plasma pindolol levels rose to a maximum of and ng/ml and h later, and then fell to and 2.35 ± 0.29 ng/ml by 10 h. Likewise, the comparison of plasma pharmacokinetic parameters of the control and experimental groups as a whole'failed to show any significant differences (see Table 1). The values of the fraction absorbed calculated by AUC (F) and by percentage eliminated in the urine (f) are in close agreement. Accumulated urinary excretion and renal clearance values were not significantly different between those patients and control subjects. However in the experimental group two patients with complete ileal resection show particular features. The area under the curve was small (40.33, ng ml-' h respectively), compared to that of the control group, where the range was from 69.2 to ng ml-' h. Urinary excretion of pindolol was particularly low: 22% vs 26% for the lower limit of the range for controls. F value was clearly decreased in the first patient (31.4%) (range of the controls was 55 to 100%).

3 634 D. Evard et al. 100 a E 7.- o V.a E Cu 30 b I a 9 9 a Time (h) Figure 1 Pindolol plasma concentrations (mean ± s.e. mean) after single dose in control subjects (o----o) and in patients (0-0). (a) 3 mg i.v., (b) 5 mg orally.

4 -Sh-ort report O~00( +1 N +1 +1~~~~~~~~~~~~~~1+ ON00 00~ 'f _ ~~~ -~ I + '0 ~ ~ ~ ~ ~~~~~~~~0~ CC~~~~~~~~~~~~~~~~~~~~1 I11* ~~~~~~~~~~~~+ ISS t) +I+1+ 2,~~~ O0+I +I CC ~~~~~~~~~~~~~~ CC~~~~~~~~~~1 Ir~~~~ u)~ ~

5 636 D. Evard et al. It was not possible to establish an obvious relationship between intestinal absorption parameters (stool weight, steatorrhea, D-xylose absorption test) and intestinal absorption of pindolol (ka, Cmax, tmax, t1ag, AUC). Discussion The pathophysiology of alterations of the small bowel has been extensively studied in the last 10 years, but its effect on drug absorption has hardly been explored (Parsons, 1977). A few authors have focused in on the modifications brought about, in a small number of patients, by the creation of an intestinal short circuit. Backman et al. (1979) found the absorption of hydrochlorothiazide to be reduced by 50%. Likewise, that of phenytoin was significantly lowered (Kennedy & Wade, 1979). This was not the case for digoxin (Marcus et al., 1977), phenazone (Andreasen et al., 1977), ampicillin and propylthiouracyl (Klein et al., 1977). More publications have appeared concerning drug absorption in coeliac disease. Parsons (1977) and Parsons et al. (1975) showed that for a dozen antibiotics absorption was modified in either direction according to the drug considered. The rate of intestinal absorption of acetaminophen is slowed but this absorption is not quantitatively decreased (Holt et al., 1981). Only two studies have been carried out concerning,b-adrenoceptor blockers. In coeliac disease intestinal absorption of propranolol is accelerated and quantitatively increased. For practolol, which is less fat soluble, the absorption is delayed (Parsons et al., 1976). Schneider et al. (1976) found that in this disease plasma levels of propranolol are significantly higher than in healthy subjects only at 1 h. Unlike some previous studies the present work was simultaneously carried out in six control subjects and nine patients with malabsorption, with each group undergoing a pharmacokinetic test of pindolol by the oral and by intravenous routes in order to determine the drug's absolute bioavailability. The plasma parameters and urinary elimination measured in healthy subjects were similar to those previously published (Gugler et al., 1974; Lavene et al., 1977). The mean bioavailability reported by Meier & Nuesch (1977) in eight different studies was quite close to our value of 79.5 ± 8.6%. After oral route no significant differences were observed between the experimental and control groups as a whole for plasma concentration of pindolol and for the other plasma and urinary pharmacokinetic parameters. However a detailed analysis of the results provided some arguments in favour of a decreased digestive absorption of pindolol in two out of nine patients; habitual absorption tests failed to predict these modifications of bioavailability. Unexpectedly the test by intravenous route revealed a pharmacokinetic difference between patients and controls. We observed plasma levels values of pindolol higher in patients with malabsorption than in controls, which tended to decrease the apparent volume of distribution. Since total clearance and AUC>OO are not significantly different for both groups, the elimination constant ke is larger in patients with malabsorption and the half-life is shorter than in controls. Increased drug protein binding could be a possible hypothesis to explain this decreased volume of distribution. We know that a1-acid glycoprotein plays a major role in the plasma binding of several basic drugs such as propranolol and pindolol (Lemaire & Tillement, 1982). The binding of propranolol was found to be significantly increased in patients with rheumatoid arthritis or Crohn's disease, and a correlation existed between binding and the increased plasma concentrations of cr1-acid glycoprotein (Piafsky, 1980). These data do not yet exist for pindolol however, and our study did not investigate plasma protein binding. Thus no definite explanation can be given. The difference in weight between the two groups of subjects (63.0 ± 3.13 kg for controls and kg for patients with malabsorption) should be noted. In the majority of a group of patients with malabsorption syndromes pindolol was well absorbed, but a decrease in the absorption appeared in some persons. The most important pharmacokinetic anomaly observed concerns the distribution phase after intravenous route. Apparent volume of distribution was decreased in these patients, who all had a clear weight loss compared with controls.

6 References Andreasen, P. B., Dano, P., Kirk, H. & Griesen, G. (1977). Drug absorption and hepatic drug metabolism in patients with different types of intestinal shunt operation for obesity. A study with phenazone. Scand. J. Gastroenterol., 12, Backman, L., Beerman, B., Groschinsky-Grind, M. & Hallberg, D. (1979). Malabsorption of hydrochlorothiazide following intestinal shunt surgery: Clin. Pharmacokin., 4, Gerson, C. D., Love, E. H. & Lindenbaum, J. (1980). Bioavailability of digoxin tablets in patients with gastrointestinal dysfunction. Am. J. Med., 69, Gibaldi, M. & Perrier, D. (1982). Pharmacokinetics. New York: Marcel Dekker, Inc. Gugler, R., Herold, W. & Dengler, H. J. (1974). Pharmacokinetics of pindolol in man. Eur. J. clin. Pharmac., 7, Holt, S., Heading, R. C., Clements, J. A., Tothill, P. & Prescott, L. F. (1981). Acetaminophen absorption and metabolism in celiac disease and Crohn's disease. Clin. Pharmac. Ther., 30, Kennedy, M. C. & Wade, D. M. (1979). Phenytoin absorption in patients with ileojejunal bypass. Br. J. clin. Pharmac., 7, Klein, H., Kalpmann, J., Lumholtz, B. & Hansen, J. (1977). Drug absorption in intestinal shunt operations. Acta Pharmac. Tox. (Copenh.), 41-Suppl Lavene, D., Weiss, Y. A., Safar, M. E., Loria, Y., Agorus, N., Georges, D. & Milliez, P. L. (1977). Pharmacokinetics and hepatic extraction ratio of pindolol in hypertensive patients with normal and impaired renal function. Clin. Pharmac., 17, Lemaire, M. & Tillement, J.-P. (1982). The binding characteristics of some adrenergic beta-receptor antagonists to human serum proteins Biochem. Pharmac., 31, Short report 637 Marcus, E. I., Quinn, E. J., Horton, H., Jacobs, S., Pippin, S., Stafford, M. & Zunoski, C. (1977). The effect of jejunoileal bypass on the pharmacokinetics of digoxin in man. Circulation, 53, Meier, J. & Nuesch, E. (1977). Pindolol, a betaadrenoceptor blocking agent with a negligible first pass effect. Br. J. clin. Pharmac., 4, Pacha, W. L. (1969). A method for the fluorimetric determination of 4-(2-hydroxy-3-isopropylaminopropoxy)-indole (LB 46), a beta-blocking agent, in plasma and urine. Experientia, 25, Parsons, R. L. (1977). Drug absorption in gastrointestinal disease with particular reference to malabsorption syndromes. Clin. Pharmacokin., 2, Parsons, R. L., Hossak, G. & Paddock, G. M. (1975). The absorption of antibiotics in adult patients with coeliac disease. J. Antimicrob. Chemother., 1, Parsons, R. L., Kaye, C. M., Raymond, K., Trounce, J. R. & Turner, P. (1976). Absorption of propranolol and practolol in coeliac disease. Gut, 17, Parsons, R. L. & Paddock, G. M. (1975). Absorption of two antibacterial drugs, cephalexin and cotrimoxazole, in malabsorption syndromes. J. Antimicrob. Chemother., 1 (suppl), Piafksy, K. M. (1980). Disease-induced changes in the plasma binding of basic drugs. Clin. Pharmacokin., 5, Schneider, R. E., Babb, J., Bishop, H., Mitchard, M., Hoare, A. M. & Hawkins, C. F. (1976). Plasma levels of propranolol in treated patients with coeliac disease and patients with Crohn's disease. Br. med. J., 2, (Received February 17, 1984, accepted July 9, 1984)