Effect of Histamine H2-receptor Antagonists on. Acetaminophen and its Metabolites in Human Plasma

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1 Jpn. J. Pharm. Health Care Sci. Effect of Histamine H2-receptor Antagonists on Acetaminophen and its Metabolites in Human Plasma Hiroki Itoh* and Masaharu Takeyama Department of Clinical Pharmacy, Oita University Hospital Received October 17, 2003 Accepted November 14, 2003 The effect of histamine H2-receptor antagonists on plasma concentrations of acetaminophen was investigated with respect to hepatic metabolism. Acetaminophen (1000 mg) was administered orally together with ranitidine (300 mg), nizatidine (300 mg), nizatidine (150 mg) or placebo to five healthy male volunteers. Venous blood samples were taken before and after administration and plasma acetaminophen and acetaminophen conjugates (glucuronide and ) were measured by high-performance liquid chromatography. The pharmacokinetic parameters were calculated from the plasma acetaminophen concentration-time curves for each volunteer. With ranitidine, compared with placebo, plasma acetaminophen concentrations were significantly increased from 15 to 120 min. and plasma acetaminophen glucuronide conjugate concentrations were significantly decreased from 15 to 45 min. With nizatidine, as compared with placebo, plasma acetaminophen concentrations were significantly increased from 45 to 120 min. and 45 to 60 min. for the high and low doses of the drug, respectively. Acetaminophen glucuronide concentrations were significantly decreased from 30 to 45 min. and at 30 min., respectively, for the high and low doses of nizatidine, respectively. However, with ranitidine and nizatidine, plasma acetaminophen concentrations were not significantly altered. Co-administration with ranitidine or nizatidine reduces plasma acetaminophen glucuronide concentrations and increases plasma acetaminophen concentrations dose-dependently. These effects of ranitidine and nizatidine could result from inhibition of glucuronyltransferase. Therefore, care is necessary when administering acetaminophen together with ranitidine or nizatidine. Key words \acetaminophen, ranitidine, nizatidine, metabolism Introduction Acetaminophen has analgesic and antipyretic effects and is widely used to treat pain and fever. The side-effects are hepatitis, renal failure, agranulocytosis, anaemia, dermatitis, allergy, sterile pyuria and thrombocytopenia1). Acetaminophen is poorly absorbed from the stomach, but rapidly absorbed from the small intestine. The major metabolic pathways of a therapeutic dose of acetaminophen in humans are glucuronidation and sulphation, which account for about 60 % and 30% of its metabolism, respectively2). Peak plasma concentrations are usually reached min after oral administration, and the half-life in plasma is approximately 120 min in a therapeutic dose. However, acute overdosage causes fatal hepatic damage. The histamine H2-receptor antagonists, which are widely used clinically to treat peptic ulcers, gastroesophageal reflux diseases and gastritis, are potent inhibitors of gastric acid secretion3). The dysfunction of gastrointestinal motility is responsible for some upper abdominal symptoms, nausea, vomiting, dyspepsia and epigastric pain4). Histamine H2- receptor antagonist is frequently given in combination with acetaminophen. In this study, we examined the effects of histamine H2- receptor antagonists on acetaminophen metabolism by measuring the plasma concentrations of acetaminophen and its conjugates before and after administration of acetaminophen with ranitidine or nizatidine to five healthy male volunteers. Materials and Methods Acetaminophen (Calonal tablets, Showa Yakuhin Kako Co., Ltd., Tokyo, Japan), ranitidine (Zantac tablets ; Sankyo Co., Ltd, Tokyo, Japan) and nizatidine (Acinon capsules, Zeria Pharmaceutical Co., Ltd., Osaka, Japan) were used. Lactose (Merck hoei Co., Ltd., Osaka, Japan) was used as placebo. Standard acetaminophen and acetaminophen glucuronide were purchased from Sigma chemical Co. (St. Louis,

2 68 MO). Standard acetaminophen was supplied by Hokuriku Seiyaku Co., Ltd. (Fukui, Japan). All other reagents were of analytical reagent grade from commercial sources. 2. Subjects Five healthy male volunteers, aged years (median 26 years), weighing kg (median 62 kg), participated in the study. Each subject received information about the scientific purpose of the study, which was approved by our Ethics Committee at Oita University, and gave informed consent. The subjects did not receive any medication one week before the study, and fasted for 12 h before the study commenced and during the experiments. 3. Study schedule Acetaminophen (1000 mg) together with ranitidine (300 mg), nizatidine (300 mg), nizatidine (150 mg) or placebo were administered orally with 100 ml water. Each subject was administered these drugs at an interval of three weeks. The dose of ranitidine and nizatidine in this study was the same as a daily dose in clinical therapy. Venous blood samples (10 ml) were taken from a forearm vein before and at 15, 30, 45, 60, 90, 120 and 180 min after acetaminophen administration. This study was carried out from 0800 to 1100 h. 4. Determination of acetaminophen and acetaminophen metabolites The concentrations of acetaminophen, acetaminophen glucuronide and acetaminophen were determined by the modified method of Mineshita et al5) and Brunner & Bai6). The plasma samples were deproteinized with 5% perchloric acid and centrifuged at 5000 g for 2 min. The supernatant was filtered through a membrane filter (Sample 4-LH, 0.45 and then applied onto high-performance liquid chromatography (HPLC). HPLC was carried out using a C18 column (Cosmosil 5C 18-AR, Nacalai Tesque) at 45 with UV detection at 254 nm. The mobile phase was 1% acetic acid/0.1 M potassium dihydrogen phosphate (3 : 97), at a flow rate of 1.0 ml/min. The recovery of acetaminophen, acetaminophen glucuronide and acetaminophen in plasma using this extraction procedure was 91.8 Results The concentration-time curves of acetaminophen, acetaminophen glucuronide and acetaminophen in plasma from the five male volunteers are shown in Figure 1-6. Mean peak plasma acetaminophen concentrations were significantly elevated from 18.3 } 2.3 ƒêg/ml (placebo-coadministration) to 34.1 } 1.1 ƒêg/ml (ranitidine-coadministration) 30 min after administration (P ƒ 0.01). Plasma acetaminophen concentrations were increased significantly at 15 to 120 min (P ƒ 0.01). The AUC of acetaminophen was increased } ƒêg min/ml (placebo-coadministration) to } 32.2 ƒêg min/ml (ranitidine-coadministration) (P ƒ 0.01) (Fig. 1). The plasma acetaminophen glucuronide with ranitidine was significantly reduced at 15 to 45 min compared with placebo (P ƒ 0.01) (Fig. 2). Plasma acetaminophen concentrations with ranitidine were not significantly changed after administration compared with placebo (Fig. 3). 2. Effects of nizatidine (300 mg) on plasma concentrations Mean peak plasma acetaminophen concentartions were elevated from 18.3 } 2.3 ƒêg/ml (placebo-coadministration) to 21.0 } 2.8 ƒêg/ml (nizatidine-coadministration) 30 min after administration. Plasma acetaminophen concentrations with nizatidine were increased significantly at 45 to 120 min (P ƒ 0.01). The AUC of acetaminophen was increased } ƒêg min/ml (placebo-coadministration) to } ƒêg min/ml (nizatidine-coadministration) (P The plasma acetaminophen glucuronide with nizatidine was significantly reduced at 30 to 45 min concentrations of acetaminophen, acetaminophen glucuronide and acetaminophen were proportional to the peak area over the range , and ƒêg/ ml, respectively. 5. Statistical analysis All values are expressed as means } sd. The area under the plasma concentration-time (0-180 min) curve (AUC) was calculated using the trapezoidal method. Comparison of mean values were made by one-way analysis of variance and P ƒ 0.05 was considered statistically significant. Fig. 1. Plasma Acetaminophen Concentrations after Coadministration of Ranitidine ( œ), or Placebo value represents the mean } s.d. of concentrations in five volunteers. * *P ƒ 0.01 significantly different compared with placebo.

3 69 Fig.4. Plasma Acetaminophen Concentrations after Coadministration of 300 mg Nizatidine ( œ) and 150 mg Nizatidine ( ), Placebo ( ). Each Fig. 2. Plasma Acetaminophen Glucuronide Concentrations after Coadministration of Ranitidine ( œ), or Placebo ( ). Each value represents the value represents the mean s.d. of concentrations in five volunteers. * *P ƒ 0.01 significantly different compared with placebo. mean } s.d. of concentrations in five volunteers. significantly different compared with placebo. Fig. 5. Plasma Acetaminophen Glucuronide Concentrations after Coadministration of 300 mg Nizatidine ( œ) and 150 mg Nizatidine (111), Placebo ( ). Each value represents the mean s.d. of concentrations in five volunteers. *P ƒ 0.05 and * *P ƒ 0.01 significantly different compared with placebo. Fig. 3. Plasma Acetaminophen Sulphate Concentrations after Coadministration of Ranitidine ( œ), or Placebo ( ). Each value represents the mean } s.d. of concentrations in five volunteers. compared with placebo (P ƒ 0.01) (Fig. 5). Plasma acetaminophen concentrations with nizatidine were not significantly changed after administration compared with placebo (Fig. 6). 3. Effects of nizatidine (150 mg) on plasma concentrations Mean peak plasma acetaminophen concentartions were elevated from 18.3 } 2.3 ƒêg/ml (placebo-coadministration) to 20.2 } 0.9 ƒêg/ml (nizatidine-coadministration) 30 min after administration. Plasma acetaminophen concentrations Fig. 6. Plasma Acetaminophen Sulphate Concentrations after Coadministration of 300 mg Nizatidine Each value represents the mean } s.d. of concentrations in five volunteers. with nizatidine were increased significantly at 45 to 60 min (P ƒ 0.01). The AUC of acetaminophen was increased } ƒêg min/ml (placebo-coadministration) to } 73.5 ƒêg min/ml (nizatidine-coadministration) (P with nizatidine was significantly reduced at 30 min compared with placebo (P ƒ 0.05) (Fig. 5). Plasma aceta-

4 70 minophen concentrations with nizatidine were not significantly changed after administration compared with placebo (Fig. 6). Discussion Coadministration of acetaminophen with ranitidine or nizatidine increased acetaminophen concentrations and delayed acetaminophen glucuronide transformation. We found a pharmacokinetic interaction between acetaminophen and ranitidine or nizatidine when both drugs were coadministered. Acetaminophen is clinically effective as an analgesic and antipyretic treatment. Its absorption appears to be negligible from the stomach, but very rapid from the small intestine. The conventional oral dose of acetaminophen is mg, with a total daily dosage not exceeding 1.5 g. Although acetaminophen produces fewer side-effects than aspirin in therapeutic doses, skin rashes and other allergic reactions occur occasionally1). Acetaminophen is mainly metabolized by the liver to glucuronide and conjugates. The histamine H2-antagonists are widely used as an effective therapy for peptic ulcer diseases, gastroesophageal reflux diseases, gastritis and hyper-secretory states. Ranitidine and nizatidine have anti-acetylcholinesterase activity, and stimulate gastrointestinal motility and gastric emptyine. Emery et al8 reported that ranitidine caused 50% inhibition of glucuronide conjugation in cultured rat hepatocytes. Plasma concentrations of acetaminophen in rats after pretreatment with ranitidine were significantly increased compared with rats treated with acetaminophen alone9). Inhibition of acetaminophen glucuronyltransferase activity by ranitidine would reduce acetaminophen conjugation. Therefore we examined the effects of ranitidine and nizatidine on the hepatic metabolism of acetaminophen. The profiles of plasma acetaminophen, acetaminophen glucuronide and acetaminophen concentrations are indicated in Figure 1-6. In our study, plasma acetaminophen concentrations were affected by rantidine and nizatidine coadministration. Significant increases in peak plasma acetaminophen concentrations were found at 30 min with the coadministartion of ranitidine (1.9-times vs placebo). Plasma acetaminophen concentrations with ranitidine coadministration increased significantly from 15 to 120 min. Plasma acetaminophen glucuronide conjugate concentrations with ranitidine were decreased significantly at 15 to 45 min compared with placebo. Plasma acetaminophen conjugate concentrations did not change significantly. Thus, plasma acetaminophen concentrations would be increased in the process of absorption in the presence of ranitidine. Coadministration of ranitidine significantly increased the AUC of acetaminophen (approx. 1.6-times compared with placebo). This was probably due to the prevention of acetaminophen glucuronyltransferase by ranitidine9). Coadministration of nizatidine significantly increased plasma acetaminophen concentrations and the AUC of acetaminophen. Nizatidine at dose of 150 and 300 mg significantly increased the AUC of acetaminophen to } 73.5 and } Đg E min/ml, respectively, in a dosedependent manner. Plasma acetaminophen glucuronide concentrations with nizatidine (300 and 150 mg) were decreased significantly at min and 30 min, respectively. This study showed the coadministration of acetaminophen with ranitidine and nizatidine causes a dose-dependent, significant decrease in plasma acetaminophen glucuronide concentrations and increases in plasma acetaminophen concentrations. Thus, ranitidine and nizatidine may prevent the first-pass hepatic metabolism of acetaminophen and delay the extent of acetaminophen glucuronyltransferase activity during the process of absorption in the presence of ranitidine and nizatidine. The same effect was confirmed with cimetidine, not famotidine (data not shown). These findings are potentially important clinically, particularly if ranitidine and nizatidine can increase the toxicity of acetaminophen. Drugs become commercially available after non-clinical and clinical studies, but processes that take place after marketing are also important for pharmaceutical development. This type of study is extremely important and useful to clinicians and pharmacists10,11). From the viewpoint of postmarketing development, we are in the process of establishing indicators for the proper usage of pharmaceutical drugs. References 1) S.P. Clissold, Paracetamol and phenacetin, Drug., 32 (suppl 4), (1986). 2) J. Shibasaki, T. Koizumi, T. Tanaka, Drug Absorption, Metabolism, and Excretion. I. Some Pharamacokinetic Aspects of Metabolism of Acetanilide 4-Hydroxyacetanilide, Chem. Pharm. Bull., 16, (1968). 3) T.M. Lin, D.C. Evans, M.W. Warrick, R.P. Pioch, Actions of nizatidine, a selective histamine H2-antagonist, on gastric acid secretion in dogs, rats and frogs, J. Pharmacol. Exp. Ther., 239, (1986). 4) S. Ueki, M. Seiki, T. Yoneta, H. Aita, K. Chaki, Y. Hori, H. Morita, E. Tagashira, Z. Itoh, Gastroprokinetic activity of nizatidine, a new H2-receptor antagonist, and its possible mechanism of action in dogs and rats, J. Pharmacol. Exp. Ther., 264, (1992). 5) S. Mineshita, R. Eggers, N.R. Kitteringham, E.E. Ohnhaus, Determination of phenacetin and its major metabolites in human plasma and urine by highperformance liquid chromatography, J. chromatogr., 380, (1986). 6) L.J. Brunner, S. Bai, Simple and rapid assay for acetaminophen and conjugated metabolites in low-volume serum samples, J. Chromatogr. B., 732, (1999). 7) R.C. Heading, J. Nimmo, L.F. Prescott, P. Tothill, The dependence of paracetamol absorption on the rate of gastric emptying, Brit. J. Pharmac.,.47,

5 (1973). 8) S. Emery, H.G. Oldham, S.J. Norman, R.J. Chenery, The effect of cimetidine and ranitidine on paracetamol glucuronidation and sulphation in cultured rat hepatocytes, Biochem. Pharmacol., 34, (1985). 9) S.A. Rogers, K.C. Gale, J.F. Newton, J.G. Dent, T.B. Leonard, Inhibition by ranitidine of acetaminophen conjugation and its possible role in ranitidine potentiation of acetaminophen-induced hepatotoxicity, J. Pharmacol. Exp. Ther., 245, (1988). 10) H. Itoh, T. Nagano, T. Hayashi, M. Takeyama, Ranitidine increases bioavailability of acetaminophen by inhibiting first-pass glucuronidation in man, Pharm. Pharmacol. Commun., 6, (2000). 11) H. Itoh, T. Nagano, T. Hayashi, M. Takeyama, Effect of nizatidine on paracetamol and its metabolites in human plasma, J. Pharm. Phamacol., 54, (2002).