Plasma concentrations and effects of oral methylprednisolone are considerably increased by itraconazole*

Varis, Tiina; Kaukonen, Kirsi‐Maija; Kivistö, Kari T.; Neuvonen, Pertti J.

doi:10.1016/s0009-9236(98)90066-2

Cited by 99 publications

(45 citation statements)

References 13 publications

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“…High-dose budesonide was primarily recommended to CF patients chronically infected with Pseudomonas aeruginosa [14], but has since been extended to include CF patients with other bacterial infections. Azoles such as ketoconazole and itraconazole are strong inhibitors of cytochrome P450 dependent CYP3A4, which is involved in the metabolism of budesonide [15][16][17]. Ketoconazole has an inhibitory effect on other cytochrome P450-dependent enzymes such as 17,20 desmolase, 16a-hydroxylase, 17a-hydroxylase, 18 hydroxylase and 11b-hydroxylase enzymes (listed with decreasing activity), thus potentially compromising steroidogenesis in the adrenals and gonads [18,19].…”

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confidence: 99%

Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide

Skov¹,

Main²,

Sillesen³

et al. 2002

Eur Respir J

132

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A recent case of iatrogenic Cushing's syndrome and complete suppression of the pituitary-adrenal-axis in a patient with cystic fibrosis (CF) and allergic bronchopulmonary aspergillosis treated with itraconazole as an antifungal agent, and budesonide as an anti-inflammatory agent led to a systematic assessment of this axis and gonadal function in all patients treated with itraconazole in the authors' CF centre. Itraconazole can inhibit CYP3A, thus interfering with synthesis of gluco- and mineralocorticoids, androgens and oestradiol as well as the metabolism of budesonide. The aim of this study was to evaluate adrenal and gonadal function in patients treated with itraconazole with or without budesonide.An adrenocorticotrophic hormone (ACTH) test (250 µg tetracosactid) was performed in 25 CF patients treated with both itraconazole and budesonide, and in 12 patients treated with itraconazole alone (six patients with CF and six with chronic granulomateous disease). Mineralocorticoid and gonadal steroid function were evaluated by measurements of plasma-renin, follicle stimulating hormone, luteinising hormone, progesterone, oestradiol, testosterone, serum-inhibin A and B. ACTH tests performed as part of a pretransplantation programme in an additional 30 CF patients were used as controls.Eleven of the 25 patients treated with both itraconazole and budesonide had adrenal insufficiency. None of the patients on itraconazole therapy alone nor the control CF patients had a pathological ACTH test. Mineralocorticoid and gonadal insufficiency was not observed in any of the patients. Only one patient with an initial pathological ACTH-test subsequently normalised, the other 10 patients improved but had not achieved normalised adrenal function 2–10 months after itraconazole treatment had been discontinued.Suppression of the adrenal glucocorticoid synthesis was observed in 11 of 25 cystic fibrosis patients treated with both itraconazole and budesonide. The pathogenesis is most likely an itraconazole caused increase in systemic budesonide concentration through a reduced/inhibited metabolism leading to inhibition of adrenocorticotrophic hormone secretion along with a direct inhibition of steroidogenesis. In patients treated with this combination, screening for adrenal insufficiency at regular intervals is suggested.

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mentioning

confidence: 99%

Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide

Skov¹,

Main²,

Sillesen³

et al. 2002

Eur Respir J

132

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“…The increase in methylprednisolone plasma concentration likely resulted from inhibition of hepatic metabolism of methylprednisolone by cytochrome P450-3A4. 19 Most p-glycoprotein inhibitors, including cyclosporine-A, are also competitive cytochrome P450-3A4 inhibitors. In fact, some investigators consider the two proteins to act in a coordinated and synergistic fashion within some tissues (eg, gastrointestinal epithelium, hepatocytes) to limit absorption or promote elimination of a large number of molecules.…”

Section: Discussionmentioning

confidence: 99%

Cyclosporine-A-mediated inhibition of p-glycoprotein increases methylprednisolone entry into the central nervous system

Bernards

2005

Spinal Cord

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Study design: Prospective, randomized, pharmacokinetic study. Objective: To determine if cyclosporine-A-mediated inhibition of p-glycoprotein would increase methylprednisolone entry into the central nervous system thereby permitting a reduction in the systemic methylprednisolone dose. Setting: Department of Anesthesiology, University of Washington, Seattle, USA. Methods: Microdialysis probes were used to obtain cerebrospinal fluid and gluteal muscle extracellular fluid samples for measurement of methylprednisolone concentration in pigs. At time zero, a methylprednisolone bolus was given and an infusion started. At 210 min, after reaching a stable methylprednisolone concentration, a cyclosporine-A bolus was given (either 10 or 30 mg/kg) and microdialysis samples collected until 420 min. Plasma samples were collected at 10, 30 min and then every 30 min until the study's end. Results: Cyclosporine-A bolus produced a dose-dependant increase in methylprednisolone concentration in plasma, muscle and cerebrospinal fluid. Importantly, the magnitude of the increase in cerebrospinal fluid was significantly greater than the increase in plasma and muscle. Conclusions: The relatively greater increase in cerebrospinal fluid concentrations of methylprednisolone is consistent with increased penetration of the blood-brain barrier secondary to cyclosporine-mediated p-glycoprotein inhibition. Theoretically, increased methylprednisolone entry into the central nervous system should allow a reduction in the systemic methylprednisolone dose and a consequent decrease in glucocorticoid-mediated side effects.

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“…Because hepatic cytochrome P4503A (CYP3A) is a predominant enzyme responsible for metabolizing the corticosteroids [5][6][7] and its activities varies more than 10-fold, [8][9][10] low hepatic CYP3A activity leads to a remarkable increase of corticosteroid levels and its effect. 7 Because hepatic CYP3A levels are significantly lower in patients with steroidinduced ONFH, 11 increased levels of steroids might lead to adverse events including bone necrosis.…”

Section: Introductionmentioning

confidence: 99%

“…7 Because hepatic CYP3A levels are significantly lower in patients with steroidinduced ONFH, 11 increased levels of steroids might lead to adverse events including bone necrosis.…”

Section: Introductionmentioning

confidence: 99%

Increased hepatic cytochrome P4503A activity decreases the risk of developing steroid‐induced osteonecrosis in a rabbit model

Masada

Iwakiri

Oda

et al. 2007

Journal Orthopaedic Research

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Low hepatic cytochrome P4503A (CYP3A) activities might play an important role for inducing osteonecrosis of the femoral head (ONFH) by corticosteroids. However, the relationship between hepatic CYP3A activity and steroid-induced ONFH is unknown. We have examined the relationship between hepatic CYP3A activity and the inducibility of ONFH in a rabbit model. Sixty rabbits were divided into three groups. Hepatic CYP3A inducer (phenobarbital, group P; n ¼ 15), inhibitor (itraconazole, group I; n ¼ 15), or saline (group C, n ¼ 30) was administrated for 3 weeks before intramuscular methylprednisolone. In groups P and I, hepatic CYP3A levels were measured by midazolam clearance before treatment (baseline) and before methylprednisolone injection. All animals were sacrificed 3 weeks after methylprednisolone injection and both femurs were harvested and examined histologically for osteonecrosis. Midazolam clearance was significantly increased and decreased, compared with baseline in groups P and I respectively (p < 0.0005, p < 0.002). The incidence of osteonecrosis in group P (33%) was significantly lower than in group I (100%) and group C (83%; p < 0.001 for both). The percentage necrotic area to whole bone marrow area on cross sections in group P (8.2 AE 5.9%) was significantly lower than in group I (69.8 AE 20.8%) and group C (51.5 AE 30.7%; p < 0.005 for both). Hepatic CYP3A activity inversely correlated with the incidence of osteonecrosis and extent of the necrotic area caused by the same dose of corticosteroids, suggesting possible prevention of the steroid-induced osteonecrosis by reducing steroid dose in poor corticosteroid metabolizers. ß

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Plasma concentrations and effects of oral methylprednisolone are considerably increased by itraconazole*

Cited by 99 publications

References 13 publications

Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide

Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide

Cyclosporine-A-mediated inhibition of p-glycoprotein increases methylprednisolone entry into the central nervous system

Increased hepatic cytochrome P4503A activity decreases the risk of developing steroid‐induced osteonecrosis in a rabbit model

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