Summary
The single dose pharmacokinetics of diflunisal were studied in 4 groups of 6 young volunteers: control men, control women, women taking low estrogen oral contraceptive steroids (OCS), and women smokers (10–20 cigarettes/day).
The plasma clearance of diflunisal was significantly higher in men (0.169 ml·min−1·kg−1) and in women on OCS (0.165 ml·min−1·kg−1) as compared to control women (0.108 ml·min−1·kg−1). Partial metabolic clearances of diflunisal by the three conjugative pathways (phenolic and acyl glucuronide formation, sulphate conjugation) were all increased in men and women OCS users as compared to control women. Statistically significant increases, however, were only observed for the partial metabolic clearance of diflunisal by phenolic glucuronidation between men and women (2.91 vs. 1.85 ml·min−1 respectively), and for the partial clearance by acyl glucuronidation between OCS users and control women (4.81 vs. 3.01 ml·min−1 respectively).
Smoking resulted in a moderate increase (35%) in plasma diflunisal clearance. However, a significant reduction in total urinary recovery of diflunisal and its glucuronide and sulphate conjugates was found in smokers (70.5% in smokers as compared to 84.2–87.2% in the 3 other study groups). Consequently, smoking may have induced hydroxylation, a minor oxidative metabolic pathway of diflunisal recently discovered in man.
Similar content being viewed by others
References
Tocco DJ, Breault GO, Zacchei AG, Steelman SL, Perrier CV (1975) Physiological disposition and metabolism of 5-(2′,4′-difluorophenyl) salicylic acid, a new salicylate. Drug Metab Disp 3: 453–466
Loewen GR, McKay G, Verbeeck RK (1986) Isolation and identification of a new major metabolite of diflunisal in man. The sulfate conjugate. Drug Metab Dis 14: 127–131
Loewen GR, Herman RJ, Ross SG, Verbeeck RK (1988) Effect of dose on the glucuronidation and sulphation kinetics of diflunisal in man: single dose studies. Br J Clin Pharmacol 26: 31–39
Verbeeck RK, Dickinson RG, Pond SM (1988) Biliary excretion of diflunisal conjugates in patients with T-tube drainage. Eur J Clin Pharmacol 34: 423–426
Bock KW, Lilienblum W, Fischer G, Schirmer G, Bock-Hennig BS (1987) Induction and inhibition of conjugating enzymes with emphasis on UDP-glucuronyltransferases. Pharm Ther 33: 23–27
Faed EM, Dobbs BR, Lee D (1984) Glucuronidation and elimination of diflunisal in the isolated perfused rat liver: effect of pretreatment with phenobarbitone, clofibric acid and spironolactone. Arch Int Pharmacodyn Ther 272: 4–16
Lin JH, Chen I-W, Ulm EH, Duggan DE (1987) Differential effects of phenobarbital on ester and ether glucuronidation of diflunisal in rats. J Pharmacol Exp Ther 242: 1013–1018
Loewen GR, Macdonald JI, Verbeeck RK (1989) High-performance liquid chromatographic method for the simultaneous quantitation of diflunisal and its glucuronide and sulfate conjugates. J Pharm Sci 78: 250–255
Faed EM (1984) Properties of acyl glucuronides: implications for study of the pharmacokinetics and metabolism of acidic drugs. Drug Metab Rev 15: 1213–1249
Gibaldi M, Perrier D (1982) Pharmacokinetics, 2nd ed. Dekker, New York
Zar JH (1984) Biostatistical analysis, 2nd ed. Englewood Cliffs, Prentice-Hall
Miners JO, Attwood J, Birkett DJ (1983) Influence of sex and oral contraceptive steroids on paracetamol metabolism. Br J Clin Pharmacol 16: 503–510
Greenblatt DJ, Divoll M, Harmatz JS, Shader RI (1980) Oxazepam kinetics: effects of age and sex. J Pharmacol Exp Ther 215: 86–91
Divoll M, Greenblatt DJ, Harmatz JS, Shader RI (1981) Effect of age and gender on disposition of temazepam. J Pharm Sci 70: 1104–1107
Greenblatt DJ, Divoll M, Locnister A, Harmatz JS, Shader RI (1979) Lorazepam kinetics in the elderly. Clin Pharmacol Ther 26: 103–113
Miners JO, Robson RA, Birkett DJ (1984) Gender and oral contraceptive steroids as determinants of drug glucuronidation: effects on clofibric acid elimination. Br J Clin Pharmacol 18: 240–243
Stoehr GP, Kroboth PD, Juhl RP, Wender DB, Phillips JP, Smith RB (1984) Effect of oral contraceptives on triazolam, temazepam, alprazolam and lorazepam kinetics. Clin Pharmacol Ther 36: 683–690
Patwardhan R, Mitchell MC, Johnson R, Schenker S (1983) Differential effects of oral contraceptive steroids on the metabolism of benzodiazepines. Hepatology 3: 248–253
Abernethy DR, Greenblatt DJ, Ochs HR, Weyers D, Divoll M, Harmatz JS, Shader RI (1983) Lorazepam and oxazepam kinetics in women on low dose oral contraceptives. Clin Pharmacol Ther 33: 628–632
Mucklow JC, Fraser HS, Bulpitt CJ, Kahn C, Mould B, Dollery CT (1980) Environmental factors affecting paracetamol metabolism in London factory and office workers. Br J Clin Pharmacol 10: 67–74
Miners JO, Attwood J, Birkett DJ (1984) Determinants of acetaminophen metabolism: effect of inducers and inhibitors of drug metabolism on acetaminophen's metabolic pathways. Clin Pharmacol Ther 35: 480–486
Bock KW, Wiltfang J, Blume R, Ullrich D, Bircher J (1987) Paracetamol as a test drug to determine glucuronide formation in man. Effects of inducers and of smoking. Eur J Clin Pharmacol 31: 677–683
Ochs HR, Greenblatt DJ, Knuchel M (1985) Kinetics of diazepam, midazolam, and lorazepam in cigarette smokers. Chest 87: 223–226
Ochs HR, Greenblatt DJ, Otten H (1981) Disposition of oxazepam in relation to age, sex, and cigarette smoking. Klin Wochenschr 59: 899–903
Macdonald JI, Reid RS, Edom RW, Verbeeck RK (1989) Identification of a hydroxylated metabolite of diflunisal in man. The FASEB Journal 3: A424
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Macdonald, J.I., Herman, R.J. & Verbeeck, R.K. Sex-difference and the effects of smoking and oral contraceptive steroids on the kinetics of diflunisal. Eur J Clin Pharmacol 38, 175–179 (1990). https://doi.org/10.1007/BF00265980
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00265980