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Br. J. clin. Pharmac. (1987), 24, 543-545

Oral during omeprazole therapy

P. J. PRICHARD', R. P. WALT', G. K. KITCHINGMAN', K. W. SOMERVILLE1, M. J. S. LANGMAN', J. WILLIAMS2 & A. RICHENS2 'Department of Therapeutics, University Hospital, Nottingham and 2Department of Pharmacology and Thera- peutics, University of Wales College of Medicine, Heath Park, Cardiff

1 In a double-blind crossover study 10 healthy males received either placebo or omepra- zole (40 mg day-') for 9 days, a single dose of phenytoin (300 mg) being taken on the seventh day. 2 Omeprazole significantly increased the area under the curve (0 to 72 h) of phenytoin (mean ± s.e. mean) from 121.6 ± 14.0 to 151.4 ± 13.6 ,ug ml-' h) (P < 0.01). 3 The peak concentration, and apparent elimination half-life of phenytoin also tended to be increased though not significantly. 4 The omeprazole-phenytoin interaction observed may be clinically important because of the low therapeutic index associated with phenytoin. Keywords omeprazole phenytoin interaction

Introduction Omeprazole, a substituted , is a study approved by the University of Nottingham potent inhibitor of secretion. It is Medical School Ethics Committee. effective in healing peptic ulcers at doses ranging In randomized order, each took either from 10 mg to 60 mg per day (Prichard et al., omeprazole 40 mg (2 x 20 mg as encapsulated 1985). A recent study has shown that omeprazole enteric coated granules; AB Hassle, ) or impairs the plasma clearance of both matching placebo, each morning for 9 days. and phenytoin when given intravenously (Gugler After a 2-week washout period the alternative & Jensen, 1985), possibly through inhibition of regimen was taken. Having fasted over-night, a hepatic cytochrome P-450 mono-oxygenases, single dose of oral phenytoin 300 mg (3 x 100 mg there being evidence that the benzimidazole Epanutin capsules; Parke Davis & Co) was taken moiety binds to microsomal cytochrome P-450 with the seventh dose of omeprazole/placebo (Dickens & Bridges, 1982), and that omeprazole and 200 ml of water. No food or drink was impairs antipyrine clearance in a dose-related allowed for a further 5 h. manner (Henry et al., 1984). Venous blood was collected immediately be- The omeprazole-intravenous phenytoin fore and at the following intervals after phenytoin interaction observed by Gugler & Jensen (1985), administration: 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, resulted in rather small elevations of plasma 32, 48, 56 and 72 h and serum separated. Samples phenytoin levels. Since phenytoin has a low were stored at -20° C until analysis. therapeutic index it is important to establish Serum phenytoin concentrations were deter- whether similar or greater changes might be mined by extraction and high pressure liquid observed during conventional oral treatment. according to the method which we have previously reported (Smart etal., 1985). Methods Inter-assay variability ranged from 5.1% for 0.5 ,ug ml-' to 3% for 5 ,ug ml-'. Intra-assay varia- Ten healthy male volunteers (aged 19-25 years, bility was 3%. The limit of sensitivity was 0.1 weight 63-92 kg) participated in a double-blind ,ug ml-l . Correspondence: Dr P. J. Prichard, Department of Therapeutics, University Hospital, Nottingham NG7 2UH 543 544 P. J. Prichard et al. Peak serum concentration (Cm.) and time to confidence limits (C.L.), 6% to 32%) with peak (tpk) were determined from the serum data. omeprazole treatment. There was, however, During the elimination phase, because serum one subject in whom the AUC decreased, and phenytoin concentrations were low, kinetics another in whom the change was minimal (Figure were assumed to be first-order. Apparent serum 2). The other kinetic parameters of peak pheny- elimination half-life (t½,) was calculated from the toin concentration, time to peak concentration, terminal elimination phase of the serum concen- and the apparent elimination half-life of pheny- tration profiles. The area under the curve was toin were not significantly altered although the calculated to the last detectable concentration peak concentration tended to be raised during or 72 h (AUCO.72h) by the trapezoidal rule. omeprazole treatment. Statistical comparisons were by Student's paired The apparent eliniination half-life of phenytoin t-test (two tailed). also appeared prolonged (Table 1). This however, was due largely to one subject who cleared the drug poorly (t½ on placebo 42.7 h; on omeprazole Results 98.4 h). If these extreme values are not con- sidered then the respective half-lives for pheny- Mean serum phenytoin concentration-time pro- toin on placebo and omeprazole were 15.2 ± 1.7 files, after placebo or omeprazole treatment, are (mean ± s.e. mean) h and 17.9 ± 1.8 h (P < 0.1; shown in Figure 1. Table 1 summarizes these 95% C.L. -1.2 to 6.7 h), with an increase pharmacokinetic data. in seven of the other nine patients whilst on The area under the curve (AUCo072 h) was omeprazole. significantly increased, by 19% (P < 0.01; 95%

220 r- E _ 3i Cu c 180 I- CD / 0 o 0.11 .) 1401- 0 4 8 16 24 32 48 56 72 E Time (h) 0 Figure 1 Serum phenytoin concentration-time pro- files during placebo ( ) or omeprazole (---) therapy Mean ± s.e. mean. 100h

Table 1 Serum pharmacokinetic parameters (mean ± s.e. mean) of phenytoin (300 mg) administered during either placebo or omeprazole (40 mg day') therapy 60 Parameter Placebo During omeprazole Cma, (I.Lg ml-') 3.77 ± 0.24 4.39 ± 0.32 tpk (h) 5.5 ± 0.9 5.3 ± 1.1 Placebo Omeprazole AUC (pug ml-' h) 121.6 ± 14.0 151.4 ± 13.6* t½(h) 17.9±3.1 25.9 ± 8.2 Figure 2 Area under the serum phenytoin concen- tration-time curves 0-72 h (AUC) during placebo or *P < 0.01 (paired t-test vs placebo) omeprazole therapy. Phenytoin/omeprazole interaction 545 Discussion The main finding of this double-blind placebo toin: omeprazole 60 mg day-' impairs antipyrine controlled crossover study is that oral omeprazole clearance by 14%, although no significant change can significantly increase the AUC of oral pheny- occurs with a lower dose (30 mg day-1) (Henry et toin. Although this interaction is not of the same al., 1984); and omeprazole (40 mg day-1) de- magnitude as that of and phenytoin creases the clearance of intravenous phenytoin (Iteogu et al., 1983; Calandre et al., 1981 quoted by 15% and increases the apparent elimination by Somogyi & Gugler, 1982), it is potentially half-life by 27% (Gugler & Jensen, 1985). In our clinically important because with the 'dose de- study, although the mean apparent elimination pendent' kinetics of phenytoin a small change in half-life ofphenytoin was increased in 8 of the 10 systemic availability of phenytoin with omepra- subjects whilst on omeprazole the change was zole administration could result in levels outside not sufficient to reach significance. the therapeutic range. Our results suggest that caution may be Whether the alteration in phenytoin avail- warranted when omeprazole is first given and ability with omeprazole is due to decreased when it is withdrawn in a person stabilized on elimination and/or increased absorption of phenytoin. phenytoin is indeterminable without kinetic data for intravenous phenytoin. Previous work, how- Financial assistance from Astra Pharmaceuticals is ever, suggests that omeprazole could significantly gratefully acknowledged. interfere with the hepatic elimination of pheny-

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