Acta pharmacol. et toxicol. 1977, 40, 584-588.

From the Department of Clinical Pharmacology, University of Lund, the Unit for Community Care Sciences, Dalby, and the Research Department, Analytical

Chemistry, AB KABI, Stockholm; Lund, Dalby and Stockholm, Sweden

Bioavailability of Oxazepam : Absence of Influence of Food Intake

BY

A. Melander, K. Danielson, J. Vessman and E. Wllhlin (Received October 15, 1976; Accepted January 10, 1977)

Abstract: The possible influence of food intake on the bioavailability of the anxiolytic drug oxazepam was assessed in eight healthy volunteers taking a single dose of the drug both on an empty stomach and together with a standardized breakfast meal. The serum concentrations of oxazepam were determined by gas chromatography on samples obtained before, and at numerous occasions up to 48 hours after drug administration. The results indicate that concomitant food intake has no essential influence on the bioavailability of oxazepam.

Key-words: Oxazepam - bioavailability - food intake - man.

A great number of drugs are administered by the oral route, oftcn together with a meal. However, only sparse information is available as to the possible influence of food intake on the gastrointestinal absorption of drugs. To obtain such information, a series of investigations has been initiated, in which the bioavailability of commonly used drugs is examined in subjects taking the drug both on an empty stomach and together with a standardized breakfast meal.

From the studies carried out hitherto, it is apparent that the influence of food intake vanes markedly between different drugs. Thus, food intake enhances the bioavailability of hydralazine (ME[.ANI)hR et al. 1977a) but reduces that of isoniazid (MELANDER et al. 1976a). Moreover, the absorption of sulphaisodimidine is not at all influenced by food intake (MELANDER et al. 1976b), although that of some other sulphonamides is delayed (PETERSON & FINLAND 1942; MACDONALD et al. 1967). On the other hand, food intake can enhance the bioavailability of both lipophilic drugs, e.g. spironolactone

OXAZEPAM BIOAVAILABILITY 5 85

(MELANDER et al. 1977b), and hydrophilic drugs, e.g. hydralazine (MELAN- DER et'al. 1977a). Hence, information concerning the effect of food intake on the bioavailability of a certain drug can be obtained only by direct studies on the drug in question. The present study deals with oxazepam, a benzo- diazepine which is increasingly used both as an anxiolytic and a hypnotic drugs. This has recently been examined with respect to its kinetics following oral ingestion on an empty stomach (PILBRANT et al. 1977; WRETLIND et al. 1976). The present results indicate that the bioavailability of oxazepam is unaffected by food intake.

Materials and methods

Eight clinically healthy volunteers, five males and three females, aged 18-39, weight range 56-85 kg, served as test subjects. Conventional liver function tests and routine blood status were normal in all. Each subject was extensively informed, and gave written consent. The investigation was approved by the ethical committee of the University of Lund.

Each subject ingested oxazepam on two different occasions: during fasting conditions, and together with a standardized breakfast meal. At least one week elapsed between the two tests. No other drugs were permitted one week before, or during, the study.

The tests were carried out as follows. After total abstention from food and liquid for ten hours (10 p. m.- 8 a.m.), the subject got a polyethene cannula inserted into an antebrachial vein. An initial 10 ml blood sample was then obtained. Thereafter, 1 tablet of 25 mg oxazepam, always from the same batch and brand - Sobrilm, AB KABI, Stockholm, Sweden - was ingested, either with 100 ml drinking water, or immediately after a standardized breakfast meal. The breakfast, prepared by a dietician, was composed identically with that of previous studies, and it consisted of 150 ml low-fat milk, 100 ml orange juice, 1 egg, 2 pieces of crisp bread, 5 g margarine, 20 g orange marmelade, and 20 g cheese. This equals 20 g (20 %) protein, 17 g (35 %) fat, 50 g (45 %) carbohydrates, and a total energy of 1,840 kJ (= 440 kcal). About 100 rnl non-sweetened, black coffee was included. The nurse collecting the blood samples controlled the eating and intake of the tablets. When the tablets were taken on an empty stomach, the subjects abstained from food and liquid for another two hours after the administration of the drug.

Blood samples (about 10 ml) were obtained before (0 hour) and at about 60, 90, 120, 150, 180, 240, 300, 360, 480 minutes, and 10, 24, 36, and 48 hours after drug ingestion. The exact time of blood sampling (when the sampling tube was half-filled) was recorded and used in the calculations and graphs.

The blood samples were kept at room temperature for about one hour. They were centrifuged, and serum was collected and frozen at -20" until assessed for its content of oxazepam. The method employed was a gas chromatographic technique (VESSMAN ef al. 1972).

The serum concentrations were plotted against time, and the peak concentrations (C,,,,), time to peak concentration (t,,,,,), average (mean) concentration (aver.conc.), elimination half-life (ti,*) and area (0 -+ 48 hours) under the serum concentration curve (AUC) were assessed by conventional methods. The statistical significance of differences was calculated by paired t-tests.

586 A. MELANDER ET AL.

Results

In some subjects, the peak concentrations (C,,,), average concentrations, and AUC values were larger when oxazepam had been taken on an empty stomach than when it was ingested with the meal (table 1). In other subjects, however, the opposite was observed (table l), and in some other subjects the differences between pre- and postprandial conditions were negligible (fig. 1 ; table 1). In all, neither the peak concentrations, average concentrations, nor the AUC values differed significantly between preprandial and postprandial conditions (table 1).

Similarly, there wa , no significant difference between the preprandial and the postprandial I,,,, values, even though they differed markedly within some individuals (table 1). The elimination half-lives (ti1.J showed little pre- versus postprandial variation, the difference not being significant (table 1).

Table 1. Estimates of kinetic parameters of oxazepam in eight healthy volunteers taking the drug (25 mg) both on an empty stomach and together with a standardized breakfast meal. C,,,,, = peak concentration, t,,, = time t o peak concentration, ti,, = elimination

half-life, AUC = area (0-t 48 hours) under the serum concentration curve.

Subject tmax tl/, AUC ratio fasting/ no. (ng x m1-1) (min.) (min.) (ng x min. x ml-1) non-fasting

Fasting: 1 2 3 4 5 6 7 8

Non-fasting: 1 2 3 4 5 6 7 8

295 343 266 382 305 300 25 1 237

261 305 309 392 372 309 242 184

Statistical signifi- cance of difference between fasting and non-fasting condi- tions (paired 1-tests) N.S.

189 136 91 62

116 150 152 91

247 181 152 60

118 159 120 305

461 445 388 565 542 512 420 345

422 390 410 565 497 471 592 355

132479 265782 125866 256958 206952 181697 144694 116387 140523 165726 158563 275528 245107 153782 109562 101558

0.94 1.60 0.79 0.93 0.84 1.18 1.32 1.15

N.S. N.S. N.S. N.S.

OXAZEPAM BIOAVAILABILITY 587

Fig. 1. Serum concentrations of oxazepam in a healthy vol'inteer (no. 7 in table 11 taking the drug (25 mg) both on an empty stomach (---) and together with a standardized breakfast meal (- - - - - -). There was no apparent difference between

fasting and non-fasting conditions (cf. table 1).

Discussion

The present study confirms previous observations on the absorption and elimination rates of oxazepam after single-dose administration on an empty stomach (PILBRANT et al. 1977; WRETLIND et al. 1977). I n addition, the present data indicate that neither the bioavailability nor the absorption rate of oxazepam - as reflected by the AUC values and the t,,,, values, respec- tively - is influenced by food intake. Moreover, the peak concentration seemed to be unaffected.

It is not known whether the peak concentration, the absorption rate, ot the total amount absorbed is the major determinant of the magnitude of the anxiolytic and hypnotic effect of oxazepam and other benzodiazepines. However, as neither of these parameters was affected by food intake, it seems that the effect of oxazepam would be the same irrespective of whether the drug is ingested with a meal or taken on an empty stomach. This is an apparent therapeutic advantage.

R E F E R E N C E S

Macdonald, H., V. A. Place, H. Falk & M. A. Darken: Effect of food on the absorp- tion of sulfonamides in man. Chemoterapia 1967, 12, 282-9.

Melander, A., K. Danielson, A. Hanson, L. Jansson, C. Rerup, B. ScherstCn, T. Thulin & E. Wlhlin: Reduction of isoniazid bioavailability in normal men by concomitant intake of food. Acta Med. Scand. 1976a, 200, 93-7.

Melander, A,, K. Danielson, A. Hanson, B. Rudell. B. Schersth, T. Thulin & E W%h-

588 A. MELANDER ET AL.

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Melander, A., K. Danielson, B. Schersth, T. Thulin & E. Wlhlin: Enhancement by concomitant food intake of canrenone bioavailability upon administration of spironolactone. Clin. Pharmacol. Therap. 1977b, in press.

Melander, A,, E. WPhlin, K. Danielson & C. Rerup: Influence of food intake on the bioavailability of sulfonamides. Acta Med. Scand. 1976b, 200, 497-500.

Peterson, 0. L. & M. Finland: The effect of food and alkali on the absorption and excretion of sulfonamide drugs after oral and duodenal administration. Amer. J. Med. Sci. 1942, 204, 581-7.

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Wretlind, M., A. Pilbrant, A. Sundwall & J. Vessrnan: Disposition of three benzodia- zepines after single oral administration in man. Acta pharrnacol. et toxicol. 1977, 40, Suppl. I, 28-39.