Abstract
Objective: The pharmacokinetics of brofaromine, a selective inhibitor of monoamine oxidase A, was evaluated in 12 frail elderly patients (66–92 y) and 12 healthy volunteers (20–35 y).
Methods: Quantitative liver function tests were performed to show whether brofaromine elimination in the elderly could be predicted from noninvasive assessment of CYP1A2 activity (caffeine clearance) or liver plasma flow (sorbitol clearance).
Results: In the elderly the AUC of brofaromine was significantly increased (e.g. for the 75 mg dose 43.2 vs 19.9 μmol*h·l−1, clearance was reduced (5.0 vs. 11.8 l·h−1), the volume of distribution was smaller (130 vs. 230 l), and the half-life was slightly increased (19.0 vs. 14.2 h). No significant correlation was observed between hepatic plasma flow and brofaromine clearance (r=0.41, P=0.05), whereas CYP1A2 activity and brofaromine clearance were tightly correlated (r=0.94, P<0.0001).
Conclusion: Caffeine clearance, a simple, noninvasive test of CYP1A2 activity, is predictive of brofaromine clearance.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bieck P, Firkusny L, Schick C, et al (1989) Monoamine oxidase inhibition by phenelzine and brofaromine in healthy volunteers. Clin Pharmacol Ther 45:260–269
Schiwy W, Heath W, Delini-Stula A (1989) Therapeutic and side-effect profile of a selective and reversible MAO-A inhibitor, brofaromine. Results of dose-finding trials in depressed patients. J Neural Transm 28:S33-S44
Robinson DS, Davis JM, Nies A, et al (1972) Aging and monoamineoxidase levels. Lancet 1:290–291
Robinson DS (1984) Age-related factors affecting antidepressant drug metabolism and clinical response. In: Nancy K (ed). Geriatric psychopharmacology. Elsevier North Holland, New York
Nolan L, O Malley K (1992) Adverse effects of antidepressants in the elderly. Drugs Aging 2:450–458
Hengen N, Jedrychowski M, Hoffmann E (1984) Pharmacokinetics of CGP 11 305 A in man after acute and prolonged oral treatment. In: Tipton KF, Dostert P, Strolin Benedetti M (eds) Monoamine oxidase and disease. Academic Press, London, pp 185–191
Woodhouse K, Wynne H (1988) Age-related changes in liver size and hepatic blood flow. The influence on drug metabolism in the elderly. Clin Pharmacokinet 15:287–294
Colli A, Buccino G, Cocciolo M, Parravicini R, Scaltrini G (1988) Disposition of a flow-limited drug (lidocaine) and a metabolic capacity-limited drug (theophylline) in liver cirrhosis. Clin Pharmacol Ther 44:642–649
Schnegg M, Lauterburg B (1986) Quantitative liver function in the elderly assessed by galactose elimination capacity, aminopyrine demethylation and caffeine clearance. J Hepatol 3:164–171
Zeeh J, Lange H, Bosch J, et al (1988) Steady-state extrarenal sorbitol clearance as a measure of hepatic plasma flow. Gastroenterology 95:749–759
Renner E, Wietholtz H, Huguenin P, Arnaud M, Preisig R (1984) Caffeine: a model compound for measuring liver function. Hepatology 4:38–46
Applegate W, Blass J, Williams T (1990) Instruments for the functional assessment of older patients. N Engl J Med 322:1207–1214
Qureshi N, Hodkinson H (1974) Evaluation of a ten-question mental test in the institutionalized elderly. Age Ageing 3:152–157
Schneider W, Keller B, Degen P (1988) Determination of a new monoamine oxidase inhibitor brofaromine in biological material by gas chromatography with electron-capture detection. J Chromatogr 488:275–282
Wahlländer A, Mohr S, Paumgartner G (1990) Assessment of hepatic function. Comparison of caffeine clearance in serum and saliva during the day and at night. J Hepatol 10:129–137
Bergmeyer HU, Gruber W, Gutmann I (1974) D-Sorbit. In: Bergmeyer HU (ed) Methoden der enzymatischen Analyse. Verlag Chemie, Weinheim, pp 1368–1375
Antonin KH, Kucher K, Fuchs L, Bieck PR, Schmidt E (1992) Investigation of dose proportionality and absolute bioavailability of brofaromine in healthy volunteers. Clin Neuropharmacol 15:430B.
Blanchard J, Sawers S (1983) The absolute bioavailability of caffeine in man. Eur J Clin Pharmacol 24:93–98
Cheng W, Murphy T, Smith M, Cooksley W, Halliday J, Powell L (1990) Dose-dependent pharmacokinetics of caffeine in humans: relevance as a test of quantitative liver function. Clin Pharmacol Ther 47:516–524
Pritchard F, Bryson J, Kernodle A, Benedetti T, Powell J (1992) Age and gender effects on odansetron pharmacokinetics: Evaluation of healthy aged volunteers. Clin Pharmacol Ther 51:51–55
Crooks J, O'Malley K, Stevenson I (1976) Pharmacokinetics in the elderly. Clin Pharmacokinet 1:280–296
Powell JR, Cate EW (1986) Induction and inhibition of metabolism. In: Evans WE, Schentag JJ, Jusko WJ (eds) Applied pharmacokinetics: principles of therapeutic drug monitoring. Applied Therapeutics, Spokane, Washington, pp 139–186
Wynne H, Cope L, Herd B, Rawlins M, James O, Woodhouse K (1990) The association of age and frailty with paracetamol conjugation in man. Age Ageing 19:419–424
Schellens J, van der Wart J, Danhof M, van der Velde E, Breimer D (1988) Relationship between the metabolism of antipyrine, hexobarbitone and theophylline in man as assessed by a “cocktail” approach. Br J Clin Pharmacol 26:373–384
Kalow W, Tang B (1991) Use of caffeine metabolite ratios to explore CYP1A2 and xanthine oxidase activities. Clin Pharmacol Ther 50:508–519
Tang-Liu D, Williams R, Riegelman S (1983) Disposition of caffeine and its metabolites in man. J Pharmacol Exp Ther 224:180–185
Kalow W, Tang B (1991) Caffeine as a metabolic probe: exploration of the enzyme-inducing effect of cigarette smoking. Clin Pharmacol Ther 49:44–48
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Zeeh, J., Bergmann, W., Platt, D. et al. Influence of age, frailty and liver function on the pharmacokinetics of brofaromine. Eur J Clin Pharmacol 49, 387–391 (1996). https://doi.org/10.1007/BF00203783
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00203783