College ofPharmacy and Allied Health Professionsl* and School ofMedicine,3 Wayne State University, Detroit,. Michigan 48202, and Departments ofPharmacy ...
Vol. 33, No. 11
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Nov. 1989, p. 1875-1877
0066-4804/89/111875-03$02.00/0 Copyright © 1989, American Society for Microbiology
Effects of Ciprofloxacin on Testosterone and Cortisol Concentrations in Healthy Males NANCY M. WAITE,"12 DAVID J. EDWARDS, 12* WENDY S. ARNOTT,1 AND LAWRENCE H. WARBASSE3,4 College of Pharmacy and Allied Health Professionsl* and School of Medicine,3 Wayne State University, Detroit, Michigan 48202, and Departments of Pharmacy Services2 and Medicine,4 Detroit Receiving Hospital, Detroit, Michigan 48201 Received 8 May 1989/Accepted 18 August 1989
Several inhibitors of oxidative drug metabolism inhibit the synthesis of endogenous compounds such
as
testosterone and cortisol. Since ciprofloxacin is a potent inhibitor of the metabolism of a number of drugs, we studied its effect on serum testosterone and cortisol concentrations in eight healthy male subjects. Blood samples were collected over a 12-h period under baseline conditions and following the first and final doses of ciprofloxacin (500 mg orally every 12 h for 4 days). No significant differences in concentrations or area under
the concentration-time curve were found when baseline values were compared with those observed for either testosterone or cortisol after ciprofloxacin administration. These results suggest that ciprofloxacin is unlikely to have either antiandrogenic side effects or clinical utility in lowering testosterone or cortisol concentration.
Ciprofloxacin is a member of a promising new class of antimicrobial agents known as the fluoroquinolones. These drugs are expected to be widely used because of their broad spectra of activity and favorable pharmacokinetic profiles, which allow for oral administration and prolonged dosing intervals. While clinical experience with these drugs has shown them to be relatively well tolerated, with a 3 to 10% incidence of adverse effects (20), numerous studies have documented their abilities to inhibit oxidative drug metabolism (6). Ciprofloxacin appears to be comparable to cimetidine in its ability to inhibit the metabolism of classical substrates such as antipyrine and theophylline (12, 19), while the related quinolones enoxacin and pipemidic acid have even greater effects. Oxidative biotransformation is important not only for the metabolism of drugs but also for the activation and degradation of a number of endogenous substances. Several compounds such as ketoconazole, metyrapone, and omeprazole (1, 4, 7, 8) which inhibit oxidative drug metabolism have also been found to have an inhibitory effect on steroidogenesis. Ketoconazole administration has resulted in significantly decreased testosterone concentrations and side effects such as gynecomastia, decreased libido, impotence, oligospermia, and azospermia (5, 16, 17). Ketoconazole and omeprazole have been shown to cause a blunted response to adrenocorticotropin hormone administration (3, 10, 16, 18), and there have been several reports of patients who have experienced adrenal insufficiency while receiving ketoconazole (2, 14). These effects on steroidogenesis have resulted in the clinical use of ketoconazole in diseases such as prostatic cancer, precocious puberty, hirsutism, and Cushing's disease (9, 11, 13, 21, 22). Metyrapone is a potent inhibitor of cortisol production, and as a result, its primary indication is to assess hypothalamic-pituitary function. Since ciprofloxacin appears to be a more potent inhibitor of oxidative drug metabolism than are any of these compounds and its effect on steroidogenesis has not been reported, the purpose of this investigation was to determine the effects of single and multiple doses of ciprofloxacin on serum testosterone and cortisol concentrations in healthy male subjects. *
MATERIALS AND METHODS
Subjects. Eight healthy male volunteers between the ages of 23 and 33 were recruited for this study. Before initiation of the study, a full medical evaluation (including medical history, physical examination, biochemical profile, and blood count) was obtained for each patient. Subjects abstained from all medications, alcohol, and caffeine-containing products throughout the study. The study was approved by the Human Investigation Committee at Wayne State University; written, informed consent was obtained from each participant.
Study design. Subjects received ciprofloxacin orally (500 Miles Pharmaceuticals) twice daily on an empty stomach (at 0800 and 2000 h) for 4 days. Blood samples for testosterone and cortisol determination were collected at 0, 2, 4, 6, 8, and 12 h, starting at 0800 h on the day before ciprofloxacin therapy. Samples were obtained at the same times after the first and final doses of ciprofloxacin. For comparison, one subject received a single dose of ketoconazole (400 mg) orally at 0800 h 2 weeks after the ciprofloxacin study. Blood samples for testosterone determination were also collected over a 12-h period following the administration of ketoconazole. Serum was stored at -20°C before being analyzed. Assays. Serum testosterone and cortisol concentrations were determined by radioimmunoassay (Diagnostic Products Corp.). The coefficient of variation was 12.5% for testosterone at a mean concentration of 3.35 ng/ml and 11.8% for cortisol at a mean concentration of 19.5 ,ug/dl. Ciprofloxacin did not interfere with either analytical procedure. Data analysis. Areas under the serum concentration-time curves (AUCs) for testosterone and cortisol were determined by the linear trapezoidal method. Differences in concentration in serum at eath time under baseline conditions and after the first and last doses of ciprofloxacin were statistically assessed by using analysis of variance for repeated measures, with P < 0.05 as the level of significance. AUCs at baseline were also compared with those determined after single and multiple doses of ciprofloxacin. mg;
Corresponding author. 1875
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RESULTS Testosterone concentrations obtained at baseline were not significantly different from concentrations obtained after the first and last doses of ciprofloxacin at any time (Fig. 1). No significant difference was found between the average AUCs over the 12-h study period under control conditions (60.6 ± 17.2 ng * h/ml), following the first dose of ciprofloxacin (66.3 + 9.6 ng * h/ml), or following the last dose of ciprofloxacin (59.9 + 16.2 ng * h/ml). Except for a 31% decrease in AUC in one subject following the final dose, no decreases of more than 16% in testosterone AUC were observed, and several subjects showed small increases during ciprofloxacin treatment. In the subject who received ketoconazole, testosterone concentrations decreased from 8.0 ng/ml at 0800 h to a minimum of 1.2 ng/ml at 1600 h (Fig. 2). Comparisons with baseline values showed that concentrations decreased to 23% of baseline 6 h following the dose and had returned to only 35% of the control value at 12 h. Testosterone AUCs for this subject decreased from 79.0 to 34.2 ng. h/ml (56.7% decrease) following administration of ketoconazole. No significant difference was observed between baseline serum cortisol concentrations and concentrations obtained after single and multiple doses of ciprofloxacin (Fig. 3). AUCs averaged 128.7 ± 19.6 ,ug* h/dl at baseline, 127.7 ± 39.4 ug * b/dl after the first dose of ciprofloxacin, and 118.1 + 28.6 p.g * h/dl following the final dose of ciprofloxacin (P > 0.05).
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FIG. 1. Mean serum testosterone concentrations at baseline and after the first and last doses of ciprofloxacin versus time.
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FIG. 2. Serum testosterone concentrations in one subject at baseline and after single doses of ketoconazole and ciprofloxacin versus time.
FIG. 3. Mean serum cortisol concentrations at baseline and after the first and last doses of ciprofioxacin versus time.
DISCUSSION
The cytochrome P-450 mixed-function oxidase system is involved with the metabolism of both exogenous and endogenous substances in a number of tissues. It is perhaps not surprising, then, that compounds such as ketoconazole, metyrapone, and omeprazole can inhibit both drug metabolism and steroidogenesis. However, these effects are difficult to predict, since the mixed-function oxidases are a heterogeneous group of enzymes with considerable substrate specificities. This may account in part for why ketoconazole is a more potent inhibitor of testosterone synthesis, while the effects of metyrapone are more pronounced on cortisol synthesis. In addition, there is considerable variability in the potencies of these compounds in inhibiting drug metabolism. In this study, we investigated the effects of ciprofloxacin, a documented inhibitor of oxidative drug metabolism, on circulating concentrations of testosterone and cortisol. Although no antisteroidogenic side effects have been reported with ciprofloxacin therapy, studies of rats have documented testicular atrophy and decreased spermatogenesis (20). Ciprofloxacin was found to have no significant effect on testosterone concentrations when baseline concentrations were compared with those obtained after single and multiple doses of ciprofloxacin. In addition, no significant differences in AUCs were observed. In contrast, the administration of ketoconazole to a single subject resulted in a maximal 77% decrease in testosterone concentration and a corresponding 56.7% decrease in AUC over the 12-h period studied. This validates the ability of the study to identify an alteration in endogenous testosterone concentrations secondary to the administration of a known inhibitor of testosterone syntheS1S.
The lack of effect of ciprofloxacin on circulating testosterone concentrations may indicate that ciprofloxacin is a relatively selective inhibitor of mixed-function oxidase activity, affecting the activities of enzymes involved in the metabolism of substrates such as theophyiline and antipyrine but not the activities of those involved in testosterone synthesis. Alternatively, ciprofloxacin may inhibit both the synthesis and degradation of testosterone, resulting in little or no effect on circulating testosterone concentrations. An analysis of testosterone precursor and metabolite concentration profiles would determine whether this is a viable explanation. It is also possible that poor penetration of ciprofloxacin into the testes, the primary site of testosterone production, accounts for the lack of effect on testosterone concentration. Although no specific data exist regarding
VOL. 33, 1989
CIPROFLOXACIN AND STEROID HORMONE CONCENTRATIONS
penetration into the testes, ciprofloxacin generally distributes well into soft tissues, including the prostate gland and prostatic and seminal fluids (15). Finally, administration of a higher dose of ciprofloxacin could result in detectable inhibition of testosterone synthesis, since compounds such as ketoconazole have a dose-dependent effect on testosterone concentrations (17). However, the dose administered in this study (1 g/day) is clinically used to treat moderate to severe infections, and doses greater than 750 mg twice daily are rarely indicated. Ciprofloxacin also had no effect on cortisol concentrations or AUCs after either single or multiple doses. This does not, however, preclude the possibility that cortisol synthesis is inhibited to some extent, since the effects of inhibitors such as ketoconazole are evident only when the body is physiologically stressed and requires an increase in the production and secretion of endogenous cortisol. To further investigate the possible inhibitory effect of ciprofloxacin on cortisol synthesis, cortisol response to adrenocorticotropin hormone should be studied with and without concurrent ciprofloxacin administration. On the basis of the results of this study, it appears that it is unlikely that ciprofloxacin has a clinically relevant effect on endogenous testosterone concentrations after single- or multiple-dose therapy. Therefore, it is not expected that antiandrogenic adverse effects will occur or that ciprofloxacin will be used to treat conditions in which it is beneficial to decrease testosterone concentrations. Ciprofloxacin is also unlikely to lower baseline cortisol concentrations. Further studies with other fluoroquinolones which are more potent inhibitors of oxidative metabolism, such as enoxacin, may be useful in determining whether the lack of effect of ciprofloxacin at doses used clinically is due to low inhibitory potency or relative selectivity for specific P-450 isozymes. ACKNOWLEDGMENTS Support for Nancy M. Waite was provided by a Medical Research Council of Canada fellowship. This study was supported in part by a WSU Biomedical Research Award.
LITERATURE CITED 1. Anderson, J. E., and T. F. Blaschke. 1986. Ketoconazole inhibits cyclosporine metabolism in vivo in mice. J. Pharmacol. Exp. Ther. 236:671-674. 2. Best, T. R., J. K. Jenkins, F. Y. Murphy, S. A. Nicks, K. L. Bussell, and D. L. Vesely. 1987. Persistent adrenal insufficiency secondary to low-dose ketoconazole therapy. Am. J. Med. 82:676-680. 3. Bradbrook, I. D., H. C. Gillies, P. J. Morrison, J. Robinson, H. J. Rogers, and R. G. Spector. 1985. Effects of single and multiple doses of ketoconazole on adrenal function in normal subjects. Br. J. Clin. Pharmacol. 20:163-165. 4. Brown, M. W., A. L. Maldonado, C. G. Meredith, and K. V. Speeg, Jr. 1985. Effect of ketoconazole on hepatic oxidative drug metabolism. Clin. Pharmacol. Ther. 37:290-297.
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5. De Coster, R., I. Caers, C. Haelterman, and M. Debroye. 1985. Effect of a single administration of ketoconazole on total and physiologically free plasma testosterone and 17 B-oestradiol levels in healthy male volunteers. Eur. J. Clin. Pharmacol. 29:489-493. 6. Edwards, D. J., S. K. Bowles, C. K. Svensson, and M. J. Rybak. 1988. Inhibition of drug metabolism by quinolone antibiotics. Clin. Pharmacokinet. 15:194-204. 7. Glynn, A. M., R. L. Slaughter, C. Brass, R. D'Ambrosio, and W. J. Jusko. 1986. Effects of ketoconazole on methylprednisolone pharmacokinetics and cortisol secretion. Clin. Pharmacol. Ther. 39:654-659. 8. Gugler, R., and J. C. Jensen. 1985. Omeprazole inhibits oxidative drug metabolism: studies with diazepam and phenytoin in vivo and 7-ethoxycoumarin in vitro. Gastroenterology 89:12351241. 9. Holland, F. J., L. Fishman, J. D. Bailey, and A. T. A. Fazekas. 1985. Ketoconazole in the management of precocious puberty not responsive to LHRH-analogue therapy. N. Engl. J. Med. 312:1023-1028. 10. Howden, C. W., C. J. Kenyon, G. H. Beastali, and J. L. Reid. 1986. Inhibition by omeprazole of adrenocortical response to ACTH: clinical studies and experiments on bovine adrenal cortex in vitro. Clin. Sci. 70:99-102. 11. Loli, P., M. E. Berselli, and M. Tagliaferri. 1986. Use of ketoconazole in the treatment of Cushing's syndrome. J. Clin. Endocrinol. Metab. 63:1365-1371. 12. Ludwig, E., E. Szekely, A. Csiba, and H. Graber. 1988. The effect of ciprofloxacin on antipyrine metabolism. J. Antimicrob. Chemother. 32:61-67. 13. Martikainen, H., J. Heikkinen, A. Ruokonen, and A. Kauppila. 1988. Hormonal and clinical effects of ketoconazole in hirsute women. J. Clin. Endocrinol. Metab. 66:987-991. 14. McCance, D. R., C. M. Ritchie, B. Sheridan, and A. B. Atkinson. 1987. Acute hypoadrenalism and hepatotoxicity after treatment with ketoconazole. Lancet i:573. 15. Neuman, M. 1988. Clinical pharmacokinetics of the newer antibacterial 4-quinolones. Clin. Pharmacokinet. 14:96-121. 16. Pont, A., J. R. Graybill, P. C. Craven, J. N. Galgiani, W. E. Dismukes, R. E. Reitz, and D. A. Stevens. 1984. High-dose ketoconazole therapy and adrenal and testicular function in humans. Arch. Intern. Med. 144:2150-2153. 17. Pont, A., P. L. Williams, S. Azhar, R. E. Reitz, C. Bochra, E. R. Smith, and D. A. Stevens. 1982. Ketoconazole blocks testosterone synthesis. Arch. Intern. Med. 142:2137-2140. 18. Pont, A., P. L. Williams, D. S. Loose, D. Feldman, R. E. Reitz, C. Bochra, and D. A. Stevens. 1982. Ketoconazole blocks adrenal steroid synthesis. Ann. Intern. Med. 97:370-372. 19. Schwartz, J., L. Jauregui, J. Lettieri, and K. Bachmann. 1988. Impact of ciprofloxacin on theophylline clearance and steadystate concentrations in serum. Antimicrob. Agents Chemother. 32:75-77. 20. Smith, C. R. 1987. The adverse effects of fluoroquinolones. J. Antimicrob. Chemother. 19:709-712. 21. Sonino, N. 1987. The use of ketoconazole as an inhibitor of steroid production. N. Engl. J. Med. 317:812-818. 22. Vanuytsel, L., K. K. Ang, K. Vantongelen, A. Drochmans, L. Baert, and E. Van Der Schueren. 1987. Ketoconazole therapy for advanced prostatic cancer: feasibility and treatment results. J. Urol. 137:905-908.
