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PLASMA ETHANOL, ENDORPHIN, AND GLUCOSE EXPERIMENT
694 INTERACTION OF CIMETIDINE WITH TETRACYCLINE ABSORPTION
SIR,-Dr Cole and colleagues (Sept. 6, p. 536) report that the urinary elimination of tetracycline from a 500 mg oral dose administered as capsules is significantly reduced when it is given concurrently with cimetidine. They attribute this to impaired dissolution of solid tetracycline at a higher intragastric pH since the effect of cimetidine is absent when a tetracycline solution is administered. Our study, of similar design to that of Cole et al., led to conclusions in some respect at variance with theirs.1 In a single dose crossover experiment six normal subjects received 500 mg tetracycline as tablets with either placebo or 400 mg cimetidine. The mean peak plasma tetracycline concentration and the area under the concentration/time curve were reduced by 40%, and the 72 h urinary tetracycline excretion was diminished by about 30%. These changes were all significant, and the urine result was similar to that of Cole et al. When multiple doses of cimetidine or placebo (400 mg 8 hourly and at bedtime) were given for 6 days and the tetracycline was administered on the fifth day of dosing, the within-subject variability of plasma and urinary tetracycline concentrations increased and there was no significant effect on mean peak plasma concentration, area under the concentration/time curve, or 72 h tetracycline excretion. The administration oftetracycline syrup (’Achromycin’) also yielded plasma and urinary tetracycline concentrations when given alone or with cimetidine which were not significantly different from those attained after administration of tetracycline tablets. The suggested explanation for the reduced bioavailability of tetracycline when given with cimetidine is that dissolution of tetracycline requires a low gastric pH because the alkaline conditions of the small intestine tend to inhibit further dissolution once gut.2The in vivo evidence for this hypothesis largely rests upon the experiments of Barr et awl. who found that concurrent administration of sodium bicarbonate, as distinct from antacids containing chelatable cations, reduced tetracycline absorption. This was not, however, observed by Kramer et al.who also found no evidence of impaired tetracycline bioavailability in patients with chronic achlorhydria. The great variability of tetracycline plasma levels after oral administration is well recognised but its causes are largely undetermined. Factors of known importance are food,4physical exercises and sleep.6The existence of this inherent variability in the pharmacokinetics of orally administered tetracycline requires that alterations in bioavailability produced by concurrent administration of other drugs must be large to achieve statistical and clinical significance. The absorption of aspirin is enhanced by cimetidine, but only when acid secretion is sufficiently suppressed for the intragastric pH to rise above 3 - 5.7It could well be that suppression of acid, and thus increase in intragastric pH, by cimetidine is variable thus accounting for the discrepancy of the results of these studies. In general, however, cimetidine does not appear to produce significant interactions with other drugs via effects on absorption. Thus no important effects occur when cimetidine is administered concurrently with enteric-coated prednisolone8 or ampicillin and co-trim-
undissolved drug particles reach this part of the
1. Fisher P, House F, Inns P, Morrison PJ, Rogers HJ, Bradbrook ID. Effect of cimetidine on the absorption of orally administered tetracycline. Br J Clin Pharmacol 1980; 9: 153-58. 2. Barr WH, Adir J, Garrettson L. Decrease of tetracycline absorption in man by sodium bicarbonate. Clin Pharmacol Ther 1971; 12: 279-84. 3. Kramer PA, Chapron DJ, Benson J, Mercik SA. Tetracycline absorption in elderly patients with achlorhydria. Clin Pharmacol Ther 1978; 23: 467-72. 4. Welling PG, Koch PA, Lau CC, Craig WA. Bioavailability of tetracycline and doxycycline in fasted and nonfasted subjects. Antimicrob Ag Chemother 1977; 11; 462-69. 5. Ylitalo P, Hinkka H, Neuronen PJ. Effect of exercise on the serum level and urinary excretion
6.
of tetracycline, doxycline
sulphamethisole.
Eur J
Clin Pharmacol
affect absorption. The major mechanism whereby cimetidine alters the disposition of other drugs appears to be via inhibition of microsomal metabolism. 10 H. J. ROGERS Departments of Pharmacology and Clinical Pharmacology F. R. HOUSE and Forensic Medicine, P. J. MORRISON Guy’s Hospital Medical School, I. D. BRADBOOK London SE1 9RT
PLASMA ETHANOL, ENDORPHIN, AND GLUCOSE EXPERIMENT
SIR,-I am pleased that Dr Kimball and colleagues (Aug. 23, p. 418) found support for the suggestion that some of the central effects of ethanol may be mediated by opioid peptides,1 but I am saddened by the poverty of their data. The literature on the relationship (or lack of it) between mental state and detectable levels of 9-endorphin immunoreactivity or bioassayable opioid activity is far more extensive than the single reference they cite; most of it is inconclusive. In their study Kimball et al. sought a correlation between levels of plasma ethanol and immunoassayable endorphin, but they failed to emphasise that the commercial endorphin assay they used has 50% cross-reaction (whether by weight or in molar terms is not clear from the manufacturer’s information) with the pituitary hormone, is-lipotrophin. is-lipotrophin is normally present in human plasma in a concentration (molar) greater than that of 9-endorphin.’,’ The study was performed, open, in a small number of volunteers and under no specified conditions. Plasma levels of endorphin immunoreactivity were later compared with "mood and demeanour" at the time of venepuncture. Although no details are given, Kimball et al. received the impression that mood matched plasma endorphin levels. From this uncontrolled attempt to correlate the results of a nonspecific radioimmunoassay with a subjective impression of mood in six subjects under poorly specified conditions, Kimball et al. wisely decided that, "Conclusions cannot be drawn from this study". If conclusions cannot be drawn from it, why is it submitted for publication, and why is it accepted? City Hospital, Nottingham NG5 1PD
K, Askari M, Johnson M. The effect of cimetidine on aspirin absorption. Gastroenterology 1979; 76: 1169. Morrison PJ, Rogers HJ, Bradbook ID, Parsons C. Concurrent administration ofcimetidine and enteric-coated prednisolone: effect on plasma levels of prednisolone. Br J Clin Pharmacol 1980; 10: 87-9.
W. J. JEFFCOATE
IRON TRANSPORT IN PREGNANCY
SIR,-Professor Page Faulk and colleagues (Aug. 23, p. 390) suggest that the human placental syncytiotrophoblast receptor for transferrin may bind apotransferrin for functions quite distinct from the traditional view of iron transport, and that this may also be true for the transferrin receptor on certain carcinoma cells. The main evidence leading to this assertion is their failure to demonstrate iron in human syncytiotrophoblast using the prussian blue reaction. We have determined the iron content of isolated, wellcharacterised syncytiotrophoblast microvillous plasma membranes by flameless atomic absorption spectroscopy and have demonstrated the presence of iron at a concentration of 170-230 ng (3-4 nmol) per mg membrane protein. Transferrin can be demonstrated in these preparations at a concentration of 7 -15 pig (01 - 0 - 2 nmol) 9.
Rogers HJ, James CA, Morrison PJ, Bradbrook ID. Efect of cimetidine on oral obsorption of ampicillin and cotrimoxazole. J. antimicrob Chemother 1980; 6: 297-300 MJ, Sibeon
10. Serlin
RG, Mossman S, Breckenridge AM, Williams JRB, Atwood JL, Willoughby JMT. Cimetidine: Interactions with oral anticoagulants in man. Lancet
1977; 12: 367-73. Adir J, Barr WH. Effect of sleep on bioavailability of tetracycline. J Pharm Sci 1977;
66: 1000-3 7. Khoury W, Geraci 8.
and
oxazole,9 these being drugs where changes in intragastric pH could
1. 2. 3.
1979; ii: 317-19. Jeffcoate WJ, Herbert M, Cullen MH, Hastings AG, Walder CP. Prevention of effects of alcohol intoxication by naloxone. Lancet 1979; ii: 1157-59. McLoughlin L, Lowry PJ, Ratter S, Besser GM, Rees LH. &bgr;-endorphin and &bgr;-MSH in human plasma. Clin Endocrinol 1980; 12: 287-80. Wardlaw SL, Frantz AG Measurement of &bgr;-endorphin in human plasma. J Clin Endocrinol Metab 1979; 48: 176-80.
SIR,-Dr Cole and colleagues (Sept. 6, p. 536) report that the urinary elimination of tetracycline from a 500 mg oral dose administered as capsules is significantly reduced when it is given concurrently with cimetidine. They attribute this to impaired dissolution of solid tetracycline at a higher intragastric pH since the effect of cimetidine is absent when a tetracycline solution is administered. Our study, of similar design to that of Cole et al., led to conclusions in some respect at variance with theirs.1 In a single dose crossover experiment six normal subjects received 500 mg tetracycline as tablets with either placebo or 400 mg cimetidine. The mean peak plasma tetracycline concentration and the area under the concentration/time curve were reduced by 40%, and the 72 h urinary tetracycline excretion was diminished by about 30%. These changes were all significant, and the urine result was similar to that of Cole et al. When multiple doses of cimetidine or placebo (400 mg 8 hourly and at bedtime) were given for 6 days and the tetracycline was administered on the fifth day of dosing, the within-subject variability of plasma and urinary tetracycline concentrations increased and there was no significant effect on mean peak plasma concentration, area under the concentration/time curve, or 72 h tetracycline excretion. The administration oftetracycline syrup (’Achromycin’) also yielded plasma and urinary tetracycline concentrations when given alone or with cimetidine which were not significantly different from those attained after administration of tetracycline tablets. The suggested explanation for the reduced bioavailability of tetracycline when given with cimetidine is that dissolution of tetracycline requires a low gastric pH because the alkaline conditions of the small intestine tend to inhibit further dissolution once gut.2The in vivo evidence for this hypothesis largely rests upon the experiments of Barr et awl. who found that concurrent administration of sodium bicarbonate, as distinct from antacids containing chelatable cations, reduced tetracycline absorption. This was not, however, observed by Kramer et al.who also found no evidence of impaired tetracycline bioavailability in patients with chronic achlorhydria. The great variability of tetracycline plasma levels after oral administration is well recognised but its causes are largely undetermined. Factors of known importance are food,4physical exercises and sleep.6The existence of this inherent variability in the pharmacokinetics of orally administered tetracycline requires that alterations in bioavailability produced by concurrent administration of other drugs must be large to achieve statistical and clinical significance. The absorption of aspirin is enhanced by cimetidine, but only when acid secretion is sufficiently suppressed for the intragastric pH to rise above 3 - 5.7It could well be that suppression of acid, and thus increase in intragastric pH, by cimetidine is variable thus accounting for the discrepancy of the results of these studies. In general, however, cimetidine does not appear to produce significant interactions with other drugs via effects on absorption. Thus no important effects occur when cimetidine is administered concurrently with enteric-coated prednisolone8 or ampicillin and co-trim-
undissolved drug particles reach this part of the
1. Fisher P, House F, Inns P, Morrison PJ, Rogers HJ, Bradbrook ID. Effect of cimetidine on the absorption of orally administered tetracycline. Br J Clin Pharmacol 1980; 9: 153-58. 2. Barr WH, Adir J, Garrettson L. Decrease of tetracycline absorption in man by sodium bicarbonate. Clin Pharmacol Ther 1971; 12: 279-84. 3. Kramer PA, Chapron DJ, Benson J, Mercik SA. Tetracycline absorption in elderly patients with achlorhydria. Clin Pharmacol Ther 1978; 23: 467-72. 4. Welling PG, Koch PA, Lau CC, Craig WA. Bioavailability of tetracycline and doxycycline in fasted and nonfasted subjects. Antimicrob Ag Chemother 1977; 11; 462-69. 5. Ylitalo P, Hinkka H, Neuronen PJ. Effect of exercise on the serum level and urinary excretion
6.
of tetracycline, doxycline
sulphamethisole.
Eur J
Clin Pharmacol
affect absorption. The major mechanism whereby cimetidine alters the disposition of other drugs appears to be via inhibition of microsomal metabolism. 10 H. J. ROGERS Departments of Pharmacology and Clinical Pharmacology F. R. HOUSE and Forensic Medicine, P. J. MORRISON Guy’s Hospital Medical School, I. D. BRADBOOK London SE1 9RT
PLASMA ETHANOL, ENDORPHIN, AND GLUCOSE EXPERIMENT
SIR,-I am pleased that Dr Kimball and colleagues (Aug. 23, p. 418) found support for the suggestion that some of the central effects of ethanol may be mediated by opioid peptides,1 but I am saddened by the poverty of their data. The literature on the relationship (or lack of it) between mental state and detectable levels of 9-endorphin immunoreactivity or bioassayable opioid activity is far more extensive than the single reference they cite; most of it is inconclusive. In their study Kimball et al. sought a correlation between levels of plasma ethanol and immunoassayable endorphin, but they failed to emphasise that the commercial endorphin assay they used has 50% cross-reaction (whether by weight or in molar terms is not clear from the manufacturer’s information) with the pituitary hormone, is-lipotrophin. is-lipotrophin is normally present in human plasma in a concentration (molar) greater than that of 9-endorphin.’,’ The study was performed, open, in a small number of volunteers and under no specified conditions. Plasma levels of endorphin immunoreactivity were later compared with "mood and demeanour" at the time of venepuncture. Although no details are given, Kimball et al. received the impression that mood matched plasma endorphin levels. From this uncontrolled attempt to correlate the results of a nonspecific radioimmunoassay with a subjective impression of mood in six subjects under poorly specified conditions, Kimball et al. wisely decided that, "Conclusions cannot be drawn from this study". If conclusions cannot be drawn from it, why is it submitted for publication, and why is it accepted? City Hospital, Nottingham NG5 1PD
K, Askari M, Johnson M. The effect of cimetidine on aspirin absorption. Gastroenterology 1979; 76: 1169. Morrison PJ, Rogers HJ, Bradbook ID, Parsons C. Concurrent administration ofcimetidine and enteric-coated prednisolone: effect on plasma levels of prednisolone. Br J Clin Pharmacol 1980; 10: 87-9.
W. J. JEFFCOATE
IRON TRANSPORT IN PREGNANCY
SIR,-Professor Page Faulk and colleagues (Aug. 23, p. 390) suggest that the human placental syncytiotrophoblast receptor for transferrin may bind apotransferrin for functions quite distinct from the traditional view of iron transport, and that this may also be true for the transferrin receptor on certain carcinoma cells. The main evidence leading to this assertion is their failure to demonstrate iron in human syncytiotrophoblast using the prussian blue reaction. We have determined the iron content of isolated, wellcharacterised syncytiotrophoblast microvillous plasma membranes by flameless atomic absorption spectroscopy and have demonstrated the presence of iron at a concentration of 170-230 ng (3-4 nmol) per mg membrane protein. Transferrin can be demonstrated in these preparations at a concentration of 7 -15 pig (01 - 0 - 2 nmol) 9.
Rogers HJ, James CA, Morrison PJ, Bradbrook ID. Efect of cimetidine on oral obsorption of ampicillin and cotrimoxazole. J. antimicrob Chemother 1980; 6: 297-300 MJ, Sibeon
10. Serlin
RG, Mossman S, Breckenridge AM, Williams JRB, Atwood JL, Willoughby JMT. Cimetidine: Interactions with oral anticoagulants in man. Lancet
1977; 12: 367-73. Adir J, Barr WH. Effect of sleep on bioavailability of tetracycline. J Pharm Sci 1977;
66: 1000-3 7. Khoury W, Geraci 8.
and
oxazole,9 these being drugs where changes in intragastric pH could
1. 2. 3.
1979; ii: 317-19. Jeffcoate WJ, Herbert M, Cullen MH, Hastings AG, Walder CP. Prevention of effects of alcohol intoxication by naloxone. Lancet 1979; ii: 1157-59. McLoughlin L, Lowry PJ, Ratter S, Besser GM, Rees LH. &bgr;-endorphin and &bgr;-MSH in human plasma. Clin Endocrinol 1980; 12: 287-80. Wardlaw SL, Frantz AG Measurement of &bgr;-endorphin in human plasma. J Clin Endocrinol Metab 1979; 48: 176-80.