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Re: Bromocriptine-anabolic steroid interaction in a body builder

Dear Editor

I read with interest the report of atrial fibrillation and syncope in a body builder taking anabolic steroids and bromocriptine.[1] Drs Manoharan, Campbell and O'Brien present an interesting and perceptive report of bromocriptine misuse. Several additional points can be made regarding this case. While the authors noted the effect of the fasting state on bromocriptine kinetics,[2] in addition bromocriptine and methandienone share the same metabolizing enzyme, cytochrome P450 3A4.[3,4] Bromocriptine clearance has been shown to decrease with the coadministration of other drugs involving cytochrome P450 3A4 such as the macrolide antibiotics.[5] Investigators recognised the dissociation between bromocriptine blood levels and therapeutic effects since the 1970s.[6] Over 20 years later, the clinical observations were finally explained by the work of Valente and colleagues[7] which demonstrated that hydroxylated bromocriptine metabolites are effective in reducing prolactin in the rat. Prior to this research, the specific receptor activity of bromocriptine metabolites was not characterised. In addition, possible cardiovascular effects of hydroxylated bromocriptine metabolites have not been fully investigated.

Finally, the authors note that bromocriptine had been studied in obese subjects in which weight loss and improved glucose tolerance were reported.[8] As a result of the observation of improved glycemic control after bromocriptine administration, clinical trials of bromocriptine in the treatment of Type 2 diabetes were conducted in the United States. The results of these trials were presented to the Food and Drug Administration at which time a relative risk of myocardial infarction of 2.9 after bromocriptine treatment was found.[9]

References

(1) Manoharan G, Campbell NPS, O'Brien C.J. Syncopal episodes in a young amateur body builder. Br J Sports Med 2002;36:67-8.

(2) Drewe J, Mazer N, Abisch E, et al. Differential effect of food on kinetics of bromocriptine in a modified release capsule and a conventional formulation. Eur J Clin Pharmacol 1988;35:535-41.

(3) Wynalda M, Wienkers L. Assessment of potential interactions between dopamine receptor agonists and various human cytochrome P450 enzymes using a simple in vitro inhibition screen. Drug Metab Dispos 1997;25:1211-4.

(4) Rendic S, Nolteernsting E, Schanzer W. Metabolism of anabolic steroids by recombinant human cytochrome P450 enzymes. Gas chromatographic-mass spectrometric determination of metabolites. J Chromatogr B Biomed Sci Appl 1999;735(1):73-83.

(5) Periti P, Mazzei T, Mini E, Novelli A. Pharmacokinetic drug interactions of macrolides. Clin Pharmacokinet 1992;23:106-31.

(6) Jenner P, Marsden CD, Reavill C. Evidence for metabolite involvement in bromocriptine-induced circling behavior. Br J Pharmacol 1979;66(1):103P-4P.

(7) Valente D, Delaforge M, Urien S, et al. Metabolite involvement in bromocriptine-induced prolactin inhibition in rats. J Pharmacol Exp Ther 1997;282:1418-24.

(8) Cincotta AH, Meier AH. Bromocriptine (Ergoset) reduces body weight and improves glucose tolerance in obese subjects. Diabetes Care 1996;19:667-70.

(9) Food and Drug Administration. Endocrinologic and Metabolic Drugs Advisory Committee. 70th Meeting. Bethesda,MD: Food and Drug Administration, May 14, 1998:Meeting Transcript, page 135.