0021-972x/92/7501-0315$03.00/0 Journal of Clinical Endocrmology and Metabolism Copyright 0 1992 by The Endocrine Society

Vol. 75, No. 1 Printed m U.S.A.

Comments

Abnormal Overnight in Subjects Receiving VENETSANA

KYRIAZOPOULOU

Department of Medicine, Division Hospital, Rion Patras, Greece

Dexamethasone Suppression Rifampicin Therapy AND

of

Endocrinology,

APOSTOLOS University

G. VAGENAKIS* of

Patras Medical

ABSTRACT

R

IFAMPICIN is a widely used drug for the treatment of tuberculosis. It is known that rifampicin is a potent inducer of the hepatic mixed oxygenase enzymes involved in drug metabolism. Patients receiving rifampicin for treatment of tuberculosis have increased liver cytochrome P450 activity and intense proliferation of smooth endoplasmic reticulum (1, 2). We previously reported (3) that rifampicin induces profound alterations in cortisol metabolism when administered to patients with primary adrenal failure receiving adequate corticosteroid replacement therapy. The half-life and systemic clearance of hydrocortisol decreased and increased by 35%, respectively. More important was the observation that three patients with primary adrenal insufficiency developed frank adrenal crisis during rifampicin administration despite adequate corticosteroid replacement therapy. These findings prompted us to evaluate whether in patients receiving rifampicin therapy, the standard overnight dexamethasone suppression test maintains its reliability as a procedure to exclude Cushing’s syndrome in these patients. It appears that the dexamethasone suppression test in patients receiving rifampicin therapy may mislead the physician to diagnose nonexisting Cushing’s syndrome.

mentation committee of the hospital. The standard 1-mg overnight dexamethasone suppression test was performed in all subjects (4). Serum cortisol was measured at 0700 h, and 1 mg dexamethasone was administered at 2300 h. The next morning, another 0700 h serum cortisol measurement was obtained. Subsequently, rifampicin (600 mg/day, orally) was administered for 10 days, and 24 h after the last dose of rifampicin, the overnight 1-mg dexamethasone test was repeated in 8 of the 16 subjects. In the remaining 8 subjects, the I-mg dexamethasone test was repeated in three, the 2mg test in three, the 3-mg test in 1, and the 4-mg test in another. Serum cortisol was measured with a commercial cortisol RIA kit (Amersham International, Aylesbury, Buckinghamshire, England). All measurements in all individuals were made in the same assay. The intraassay coefficient of variation was 2-5%. In the 8 patients who received the various doses of dexamethasone, the serum dexamethasone concentration was measured according to the method of Evans et ~2. (5) (kindly performed in the laboratory of Dr. G. Chrousos, NIH, Bethesda, MD). The expected serum dexamethasone concentration measured in Dr. Chrousos’s laboratory in 8 normal individuals 8 h after 1 mg oral dexamethasone varied from 11.2-23.4 nmol/L.

and Methods

Results

Sixteen healthy male volunteer physicians, 20-47 yr old, from the Department of Medicine participated in the study. Informed consent was obtained from all subjects, and the experimental protocol was approved by the human experiReceived June 28, 1991. * To whom requests for reprints

should

School, University

cortisol was completely prevented (575 + 114 us. 434 + 82). In the remaining 8 rifampicin-treated subjects, the inhibitory effect of 1, 2, or 3 mg dexamethasone on serum cortisol was not observed. When 4 mg dexamethasone were administered, the serum cortisol level was 193 nmol/L, above the expected normal suppression value. The plasma dexamethasone concentration was very low after rifampicin treatment (range, 1.2-4.8 nmol/L). We conclude that when patients are treated with rifampicin, the standard overnight dexamethasone suppression test not only has no diagnostic value, but can be very misleading. (J Clin Endocrinol Metab 75: 315-317, 1992)

We have studied the effects of rifampicin on the overnight l-mg dexamethasone suppression test usually employed to exclude suspected Cushing’s syndrome. Previous observations indicate that in humans, rifampicin profoundly attenuates the biological effects of hydrocortisol and prednisolone, probably by increasing the metabolism of these drugs in the liver. The study was carried out in 16 normal volunteers. All subjects had a normal overnight l-mg dexamethasone suppression test (468 2 86 vs. 32 + 21 nmol/L; mean + SD). In 8 subjects treated with rifampicin (600 mg) for 10 days, the inhibitory effect of dexamethasone on serum

Materials

Test

The serum cortisol levels in eight patients who received 1 mg dexamethasone overnight before and after rifampicin therapy are shown in Table 1 and Fig. 1. The serum cortisol level before dexamethasone administration was normal before and after rifampicin therapy (468 + 86 and 575 + 114 nmol/L, respectively; mean + SD). Dexamethasone adminis-

be addressed.

315

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 November 2015. at 13:54 For personal use only. No other uses without permission. . All rights reserved.

COMMENTS

316 TABLE 1. Serum cortisol (nanomoles administration of 1 mg dexamethasone receiving rifampicin therapy Before Subject

After

rifampicin

rifampicin

no. Control

Post-Da

Control

Post-Da

425 621 441 356 433 557 497 414

38 25 30 11 11 36 17 30

375 647 626 549 598 705 441 659

342 383 430 378 458 607 405 471

1 2 3 4 5 6 7 8

Mean

per L) after the (Dex) in eight patients

f SD

468

-t 86

32 f

21

575

+ 114

434

+ 82

tration completely suppressed serum cortisol in all subjects before rifampicin treatment (32 + 21 nmol/L), but was ineffective after rifampicin treatment (434 + 82 nmol/L). The postdexamethasone serum cortisol level after rifampicin therapy was above the cut-off level of less than 136 nmol/L, which is considered a normal suppression value that virtually excludes Cushing’s syndrome. In the remaining eight subjects (Table 2), despite the high doses of dexamethasone administered, serum cortisol failed to suppress below the 136 nmol/ L level even when 4 mg dexamethasone were administered after rifampicin treatment. The serum dexamethasone concentration measured 8 after the l- to 4-mg dose varied from 1.2-4.8 nmol/L, well below the expected serum concentration of 11.2-23.4 nmol/L after the l-mg dose in normal volunteers. Discussion The present study clearly demonstrates that in normal individuals with normal serum cortisol suppression after a

JCE & M. 1992 Vol75.Nol

l-mg dexamethasone (overnight dexamethasone suppression test), rifampicin therapy renders the test abnormal. This response was predicted from our previous work and that of others (3, 6-8), but the magnitude of the inhibitory effect of rifampicin on dexamethasone upon cortisol suppression was unexpected. In a previous study of patients treated with rifampicin and receiving hydrocortisol (3), we observed that the clearance rate of the steroid was increased by approximately 35%, and the half-life was decreased by 35%. Similar findings were reported for prednisolone in rifampicin-treated patient by McAllister et al. (6). Based on this figure, we assumed that rifampicin treatment may interfere with the bioavailability of dexamethasone to some extent, similar to hydrocortisol, and therefore, the serum cortisol concentration would be appropriately affected, at least by 35-40% suppression. This, however, was not proved to be the case. Rifampicin administration completely prevented the inhibitory action of a standard dexamethasone dose administered for the overnight suppression test. Even when the dose of dexamethasone was doubled or tripled, the inhibitory effect was not apparent. Only when 4 mg dexamethasone were employed was a substantial, but still abnormal, inhibitory response of dexamethasone on cortisol suppression observed. Although direct pharmacokinetic study of dexamethasone was not performed, it appears that the effect of rifampicin on the bioavailability of dexamethasone was more pronounced than that of hydrocortisol and prednisolone. To our knowledge, no complete report on the bioavailability of dexamethasone in subjects treated with rifampicin was available in the English literature. However, in a paper that appeared in 1985 in the Japanese literature (9), it was reported that in patients receiving rifampicin therapy for tuberculosis, the half-life of

Control

----_ ----_ -mm------

- - - - - Dexamethasone ----_ --------_ es--_ -----

(1 mg)

T 500

FIG. 1. Overnight dexamethasone pression test in patients receiving picin therapy.

suprifam-

Serum

Cortisol

Before

Rifampicin

After

Rtfampicin

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 November 2015. at 13:54 For personal use only. No other uses without permission. . All rights reserved.

COMMENTS TABLE concentrations therapy

2. Serum cortisol and dexamethasone (nanomoles per L) in patients

Serum

Subject 00.

BE3Sd

2 3 4 5 6 7 8 u Normal

Cortisol

Post-Dex

552 607 554 662 558 635 577 524

1

range

after

(Dex) receiving

Serum

111 601 662 610 425 469 452 193 l-mg

dose, 11.2-23.4

Dex”

1.2 2.0 2.3 3.3 1.2 3.0 1.8 4.8

rifampicin

Dose

of Dex

bw) 1 1

1 2 2 2 3 4

rim/L.

dexamethasone was decreased3-fold, and the clearance rate was increased 5-fold. The kinetics of cortisol metabolism were comparable to our findings (4). It appears, therefore, that the removal of dexamethasone by the liver was greatly accelerated compared to that of cortisol and prednisolone, probably by several orders of magnitude, and was the main reason for the failure to suppressserum cortisol, even when the amount of dexamethasone administered was increased 4-fold. This is strengthened by the determination of serum dexamethasoneconcentrations after rifampicin therapy. The serum dexamethasone levels observed 8 h after the l- to 4mg dose were 5-10 times lower than those in normal individuals measured 8 h after the administration of 1 mg dexamethasone for the overnight dexamethasone suppression test (5). This suggeststhat the serum concentration and presumably the quantity of dexamethasone reaching the pituitary or hypothalamus in patients receiving rifampicin were not sufficient to inhibit ACTH or CRH secretion. Inappropriately low plasma dexamethasone levels have been reported in some normal individuals who failed to suppress plasma cortisol after the administration of 1 mg dexamethasone (10). Several other possiblemechanismscan be effectively ruled out. First, displacement of dexamethasone from its binding proteins by rifampicin is unlikely, since dexamethasone was given at least 24 h after the last dose of rifampicin. It is known that the rifampicin half-life after 1 week of administration is 2.7 h (1). Second, an interaction of rifampicin with the steroid at the receptor or postreceptor level is also highly unlikely, since the actions of steroids on the nucleus and the creation of new RNA polymerase initiation sites are not inhibited by rifampicin, and therefore, the actions of steroids at the nuclear level are not affected (11). Third, the probability of impaired absorption of steroid by rifampicin can be excluded, since dexamethasone was administered at least 24 h after the last dose of rifampicin. Fourth, the possibility of stressinduced by rifampicin through its well known gastroin-

testinal side-effects is unlikely, since no symptoms were reported by the treated subjects, and the basal serum cortisol levels were not affected by rifampicin therapy. Whatever the mechanism of interaction in patients treated with rifampicin, the dexamethasone suppression test is rendered highly abnormal and, if applied in these patients, may mislead the physician to suspect nonexisting Cushing’s syndrome. Although the time required to restore pituitary ACTH suppressibility to normal after rifampicin withdrawal was not studied, it is prudent to discontinue rifampicin therapy for 15 days before performance of the dexamethasone suppression test. This time has been found to be sufficient to normalize metoprolol metabolism after rifampicin withdrawal (12). Acknowledgment We wish measurement

to thank Dr. George Chrousos of dexamethasone concentrations

(NIH, Bethesda, MD) in the samples,

for

References 1. Mignet JP, Mavier I’, Soussy CJ, Phumeaux D. 1977 Induction of hepatic enzymes after administration of rifampicin in man. Gastroenterology. 72~924-6. 2. Schoene 8, Fleischman RA, Remmer H, Van Oldershausen HF. 1973 Determination of drug metabolizing enzymes in needle biopsies of human liver. Eur J C%n Pharmacoi. 4:65-73. 3. Kyriazopoulou V, Parparousi 0, Vagenakis AG. 1984 Rifampicininduced adrenal crisis in Addisonian patients receiving corticosteroid replacement therapy. J Clin Endocrinol Metab. 59:1204-6. 4. Liddle GW. 1960 Tests of uituitarv-adrenal SuDDressibilitv in the diagnosis of Cushing’s syndrome. J Clin Endocrinx Metab.

Abnormal overnight dexamethasone suppression test in subjects receiving rifampicin therapy.

We have studied the effects of rifampicin on the overnight 1-mg dexamethasone suppression test usually employed to exclude suspected Cushing's syndrom...
318KB Sizes 0 Downloads 0 Views