GASTROENTEROLOGY
1991;101:889-894
The Effect of Histamine Hz-Receptor Blockade on Bismuth Absorption From Three Ulcer-Healing Compounds CHUKA U. NWOKOLO, EMILY J. PREWETT, MARK HUDSON, and ROY E. POUNDER University
Department
of Medicine, Royal Free Hospital School of Medicine, London, England
Twelve healthy male subjects were dosed with six regimens: ranitidine and De-Noltab (tripotassium dicitrato bismuthate; Gist-Brocades Ltd., Weybridge, England), placebo and De-Noltab, ranitidine and Pepto-Bismol liquid [bismuth salicylate; Procter & Gamble (Health and Beauty Care) Ltd., Egham, England], placebo and Pepto-Bismol, ranitidine and Roter tablets (bismuth subnitrate; Roter Pharma Ltd., Ashford, England), and placebo and Roter. Ranitidine, 300 mg, or placebo was administered at 10 PM (night before) and at 7 AM;at 9 AM,the oral dose of bismuth was either 2 De-Noltabs, 3 30-mL doses of Pepto-Bismol liquid, or 2 Roter tablets. When predosed with placebo, the median integrated 8-hour plasma bismuth concentration was significantly greater after dosing with De-Noltabs than after dosing with either Pepto-Bismol or Roter (61,8,and 8 ng * h/mL, respectively), with a similar trend for 8-hour median urinary bismuth excretion (213, 40, and 6 pg, respectively). When predosed with ranitidine, only after De-Noltab administration were there significant increases in the 8-hour plasma bismuth concentration (147 ng - h/mL), and 8-hour urinary bismuth excretion (686 Pg). Eliminating intragastric acidity may enhance bismuth absorption after oral dosing with De-Noltabs by maintaining intragastric tripotassium dicitrato bismuthate as a colloidal suspension.
reatment with an oral bismuth-containing compound appears to be a vital part of any therapeutic regimen that successfully eradicates Helicobacter pylori from the antral mucosa (1,2). Bismuth alone rarely eliminates H. pylori (3-6), and it remains uncertain whether bismuth’s beneficial effect is due to topical penetration of the gastric mucosa or to systemic absorption (5,6). Three bismuth-containing compounds are avail-
T
AF M. SAWYERR,
able for treatment of dyspepsia or peptic ulceration in the United Kingdom and much of Europe: tripotassium dicitrato bismuthate (De-Noltabs; Gist-Brocades Ltd., Weybridge, England), bismuth salicylate [PeptoBismol; Procter & Gamble (Health and Beauty Care) Ltd., Egham, England], and bismuth subnitrate (Roter tablets; Roter Pharma Ltd., Ashford, England). Recent studies have shown major variations in the pharmacokinetics of the three compounds; oral dosing with De-Noltabs is followed by rapid absorption of bismuth into the plasma and continued urinary excretion of excess bismuth for at least 12 weeks after a standard course of treatment (6,7). By contrast, oral dosing with either Pepto-Bismol or Roter tablets is followed by no change in plasma bismuth concentration (8,9). There are few data concerning the mechanism or site of bismuth absorption in humans (10). The purpose of the present series of experiments was to observe the effect of a pharmacological alteration of intragastric acidity on bismuth absorption after oral dosing with the three bismuth compounds. Earlier experiments suggested that bismuth is absorbed within 15-30 minutes of oral dosing with De-Noltabs, suggesting a proximal site of absorption (7). Intragastric acidity, the major variable in the proximal gastrointestinal tract, can be decreased by treatment with antisecretory drugs or possibly during the initial phase of H. pylori infection. The object of the present study was to determine whether decreased intragastric acidity affects the absorption of oral doses of bismuth. Materials Their
and Methods
Twelve healthy male subjects took part in the study. median age was 22 years (range, 20-29 years) and
c 1991 by the American Gastroenterological Association 0016~5085/91/$3.00
890
NWOKOLO
ET AL
their median weight was 76 kg (range, 69-95 kg). All had normal hepatorenal function, as determined by routine biochemistry. Each subject was studied on six occasions, with a minimum of 1 week between studies. The subjects were dosed with either ranitidine, 300 mg, or placebo at 10 PM; they fasted overnight and received a further dose of either ranitidine, 300 mg, or placebo at 7 AM. At 9 AM, while still fasting, the subjects received oral dosing with bismuth, in the form of 2 De-Noltabs, 30 mL PeptoBismol (additional 30 mL administered at 9:30 AM and 10 AM], or 2 Roter tablets. Thus there were six dosing options: ranitidine and De-Noltab, placebo and De-Noltab, ranitidine and Pepto-Bismol, placebo and Pepto-Bismol, ranitidine and Roter, and placebo and Roter. The subjects were rotated through these options according to a predetermined LatinSquare design. The dosing with ranitidine and placebo was double-blind, but the dosing with bismuth compounds was not blinded because of the major physical differences of the three compounds. The subjects were provided with a standard breakfast at lo:05 AM and a sandwich lunch at 1:05 PM; they ate a self-selected diet from 5 PM -9 AM. An IV cannula (Vasculon; Viggo AB, Helsingborg, Sweden) was inserted into a forearm vein and flushed with 50 U heparin in z mL 0.9% saline between samples. Two blood samples were taken at a:40 AM and a:55 AM to measure the predosing plasma bismuth concentration. Twelve additional samples were taken between 9 AM and 5 PM at predetermined times. The blood samples were centrifuged immediately, and the plasma was stored at -20°C until analysis. A single urine sample was taken from each subject before the first and last studies, and its bismuth concentration was measured. During each study, a 24-hour urine sample was collected in two aliquots: 9 AM-5 PM and 5 PM-9 AM. The volume of the samples was measured, and aliquots were stored at -20’C until analysis. The analysis of the plasma and urine samples for bismuth concentration was performed by atomic absorption spectrophotometry at Rooney Laboratories Ltd. (Basingstoke, Hampshire, England) (13). The technique has a coefficient of variance of 5%, and the level of detection of bismuth in the assay is 1 ng/mL. Statistical analysis of observed differences was by the Wilcoxon rank sum test for paired data. The study was approved by the Ethics Committee of the Royal Free Hospital, and all subjects gave written consent before entering the study.
Vol. 101, No. 4
GASTROENTEROLOGY
De-Noltabs Plasma.
concentration
The median peak plasma bismuth was 37 ng/mL (range, 5-105 ng/mL)
and occurred
30 minutes
after
dosing
with
the pla-
cebo and De-Noltabs regimen. When the subjects received the combination of ranitidine and DeNoltabs, the median peak plasma bismuth concentration occurred 10 minutes earlier and was increased to 72 ng/mL (range, 13-135 ng/mL). When the subjects were predosed with ranitidine, the median plasma bismuth concentration remained consistently above the upper 95% confidence limit of the placebo and De-Noltabs from 20 minutes after dosing to the end of the study [Figure 1). Compared with the placebo and De-Noltabs regimen, the median 8-hour integrated plasma bismuth concentration increased significantly when the subjects were dosed with the ranitidine and De-Noltabs regimen from 61 ng . h/mL (range, 17-189 ng . h/mL) to 147 ng - h/mL (range, 24-348 ng . h/mL); P = 0.025 (Figure 2). Urinary excretion. Compared with the placebo and De-Noltabs regimen, the urinary bismuth excretion (O-8 hours) after dosing increased significantly when the subjects received the ranitidine and De-Noltabs regimen from 213 Fg (range, 62-2808 Fg) to 686 Fg (range, 51-7200 kg); P = 0.041. Urinary bismuth excretion increased nonsignificantly 8-24 hours after dosing with the ranitidine and De-Noltabs regimen, from 66 p,g (range, 18-1048 Fg) to 117 pg (range, 27-850 pg) (Figure 3). Renal clearance of bismuth. The increases in plasma bismuth concentration and urinary bismuth excretion associated with ranitidine predosing were not caused by changes in renal bismuth clearance. Calculated from the 0-8-hour data, the median renal Bismuth (ng/ml)
‘11:
Results The urinary bismuth concentration before entry to the study was < 1 ng/mL in every subject. Before the sixth experiment, the median urinary bismuth concentration was 2 ng/mL (range,
1991;101:889-894
The Effect of Histamine Hz-Receptor Blockade on Bismuth Absorption From Three Ulcer-Healing Compounds CHUKA U. NWOKOLO, EMILY J. PREWETT, MARK HUDSON, and ROY E. POUNDER University
Department
of Medicine, Royal Free Hospital School of Medicine, London, England
Twelve healthy male subjects were dosed with six regimens: ranitidine and De-Noltab (tripotassium dicitrato bismuthate; Gist-Brocades Ltd., Weybridge, England), placebo and De-Noltab, ranitidine and Pepto-Bismol liquid [bismuth salicylate; Procter & Gamble (Health and Beauty Care) Ltd., Egham, England], placebo and Pepto-Bismol, ranitidine and Roter tablets (bismuth subnitrate; Roter Pharma Ltd., Ashford, England), and placebo and Roter. Ranitidine, 300 mg, or placebo was administered at 10 PM (night before) and at 7 AM;at 9 AM,the oral dose of bismuth was either 2 De-Noltabs, 3 30-mL doses of Pepto-Bismol liquid, or 2 Roter tablets. When predosed with placebo, the median integrated 8-hour plasma bismuth concentration was significantly greater after dosing with De-Noltabs than after dosing with either Pepto-Bismol or Roter (61,8,and 8 ng * h/mL, respectively), with a similar trend for 8-hour median urinary bismuth excretion (213, 40, and 6 pg, respectively). When predosed with ranitidine, only after De-Noltab administration were there significant increases in the 8-hour plasma bismuth concentration (147 ng - h/mL), and 8-hour urinary bismuth excretion (686 Pg). Eliminating intragastric acidity may enhance bismuth absorption after oral dosing with De-Noltabs by maintaining intragastric tripotassium dicitrato bismuthate as a colloidal suspension.
reatment with an oral bismuth-containing compound appears to be a vital part of any therapeutic regimen that successfully eradicates Helicobacter pylori from the antral mucosa (1,2). Bismuth alone rarely eliminates H. pylori (3-6), and it remains uncertain whether bismuth’s beneficial effect is due to topical penetration of the gastric mucosa or to systemic absorption (5,6). Three bismuth-containing compounds are avail-
T
AF M. SAWYERR,
able for treatment of dyspepsia or peptic ulceration in the United Kingdom and much of Europe: tripotassium dicitrato bismuthate (De-Noltabs; Gist-Brocades Ltd., Weybridge, England), bismuth salicylate [PeptoBismol; Procter & Gamble (Health and Beauty Care) Ltd., Egham, England], and bismuth subnitrate (Roter tablets; Roter Pharma Ltd., Ashford, England). Recent studies have shown major variations in the pharmacokinetics of the three compounds; oral dosing with De-Noltabs is followed by rapid absorption of bismuth into the plasma and continued urinary excretion of excess bismuth for at least 12 weeks after a standard course of treatment (6,7). By contrast, oral dosing with either Pepto-Bismol or Roter tablets is followed by no change in plasma bismuth concentration (8,9). There are few data concerning the mechanism or site of bismuth absorption in humans (10). The purpose of the present series of experiments was to observe the effect of a pharmacological alteration of intragastric acidity on bismuth absorption after oral dosing with the three bismuth compounds. Earlier experiments suggested that bismuth is absorbed within 15-30 minutes of oral dosing with De-Noltabs, suggesting a proximal site of absorption (7). Intragastric acidity, the major variable in the proximal gastrointestinal tract, can be decreased by treatment with antisecretory drugs or possibly during the initial phase of H. pylori infection. The object of the present study was to determine whether decreased intragastric acidity affects the absorption of oral doses of bismuth. Materials Their
and Methods
Twelve healthy male subjects took part in the study. median age was 22 years (range, 20-29 years) and
c 1991 by the American Gastroenterological Association 0016~5085/91/$3.00
890
NWOKOLO
ET AL
their median weight was 76 kg (range, 69-95 kg). All had normal hepatorenal function, as determined by routine biochemistry. Each subject was studied on six occasions, with a minimum of 1 week between studies. The subjects were dosed with either ranitidine, 300 mg, or placebo at 10 PM; they fasted overnight and received a further dose of either ranitidine, 300 mg, or placebo at 7 AM. At 9 AM, while still fasting, the subjects received oral dosing with bismuth, in the form of 2 De-Noltabs, 30 mL PeptoBismol (additional 30 mL administered at 9:30 AM and 10 AM], or 2 Roter tablets. Thus there were six dosing options: ranitidine and De-Noltab, placebo and De-Noltab, ranitidine and Pepto-Bismol, placebo and Pepto-Bismol, ranitidine and Roter, and placebo and Roter. The subjects were rotated through these options according to a predetermined LatinSquare design. The dosing with ranitidine and placebo was double-blind, but the dosing with bismuth compounds was not blinded because of the major physical differences of the three compounds. The subjects were provided with a standard breakfast at lo:05 AM and a sandwich lunch at 1:05 PM; they ate a self-selected diet from 5 PM -9 AM. An IV cannula (Vasculon; Viggo AB, Helsingborg, Sweden) was inserted into a forearm vein and flushed with 50 U heparin in z mL 0.9% saline between samples. Two blood samples were taken at a:40 AM and a:55 AM to measure the predosing plasma bismuth concentration. Twelve additional samples were taken between 9 AM and 5 PM at predetermined times. The blood samples were centrifuged immediately, and the plasma was stored at -20°C until analysis. A single urine sample was taken from each subject before the first and last studies, and its bismuth concentration was measured. During each study, a 24-hour urine sample was collected in two aliquots: 9 AM-5 PM and 5 PM-9 AM. The volume of the samples was measured, and aliquots were stored at -20’C until analysis. The analysis of the plasma and urine samples for bismuth concentration was performed by atomic absorption spectrophotometry at Rooney Laboratories Ltd. (Basingstoke, Hampshire, England) (13). The technique has a coefficient of variance of 5%, and the level of detection of bismuth in the assay is 1 ng/mL. Statistical analysis of observed differences was by the Wilcoxon rank sum test for paired data. The study was approved by the Ethics Committee of the Royal Free Hospital, and all subjects gave written consent before entering the study.
Vol. 101, No. 4
GASTROENTEROLOGY
De-Noltabs Plasma.
concentration
The median peak plasma bismuth was 37 ng/mL (range, 5-105 ng/mL)
and occurred
30 minutes
after
dosing
with
the pla-
cebo and De-Noltabs regimen. When the subjects received the combination of ranitidine and DeNoltabs, the median peak plasma bismuth concentration occurred 10 minutes earlier and was increased to 72 ng/mL (range, 13-135 ng/mL). When the subjects were predosed with ranitidine, the median plasma bismuth concentration remained consistently above the upper 95% confidence limit of the placebo and De-Noltabs from 20 minutes after dosing to the end of the study [Figure 1). Compared with the placebo and De-Noltabs regimen, the median 8-hour integrated plasma bismuth concentration increased significantly when the subjects were dosed with the ranitidine and De-Noltabs regimen from 61 ng . h/mL (range, 17-189 ng . h/mL) to 147 ng - h/mL (range, 24-348 ng . h/mL); P = 0.025 (Figure 2). Urinary excretion. Compared with the placebo and De-Noltabs regimen, the urinary bismuth excretion (O-8 hours) after dosing increased significantly when the subjects received the ranitidine and De-Noltabs regimen from 213 Fg (range, 62-2808 Fg) to 686 Fg (range, 51-7200 kg); P = 0.041. Urinary bismuth excretion increased nonsignificantly 8-24 hours after dosing with the ranitidine and De-Noltabs regimen, from 66 p,g (range, 18-1048 Fg) to 117 pg (range, 27-850 pg) (Figure 3). Renal clearance of bismuth. The increases in plasma bismuth concentration and urinary bismuth excretion associated with ranitidine predosing were not caused by changes in renal bismuth clearance. Calculated from the 0-8-hour data, the median renal Bismuth (ng/ml)
‘11:
Results The urinary bismuth concentration before entry to the study was < 1 ng/mL in every subject. Before the sixth experiment, the median urinary bismuth concentration was 2 ng/mL (range,
