Venkatakrishnan et al. demonstrated that ketoconazole, and itraconazole among other azole antifungals are
all inhibitors of CYP isoenzymes in vitro, but their potencies are extremely varied depending on their
chemical structure and the CYP isoforms involved.
Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Effects of the antifungal agents on oxidative drug metabolism: clinical relevance. Clin
Pharmacokinet 2000; 38 (2): 111-80
For CYP3A4, ketoconazole
fluconazole.[293]
[291]
is a highly potent inhibitor followed by itraconazole[292] and
291. Maurice M, Pichard L, Daujat M, et al. Effects of imidazole derivatives on cytochromes P450 from human hepatocytes in primary culture.
FASEB J 1992; 6 (2): 752-8
292. von Moltke LL, Greenblatt DJ, Schmider J, et al. Midazolam hydroxylation by human liver microsomes in vitro: inhibition by fluoxetine,
norfluoxetine, and by azole antifungal agents. J Clin Pharmacol 1996; 36 (9): 783-91
Ketoconazole, itraconazole and fluconazole were all found to consistently impair the clearance of
midazolam.[284,297-303] Ketoconazole 400mg and itraconazole 200mg were found to increase the AUC of a
single 7.5mg oral dose of midazolam by 16-fold and 10-fold, respectively, resulting in a severe extension of
the hypnotic effect.[297]
284. Backman JT, Kivisto KT, Olkkola KT, et al. The area under the plasma concentration-time curve for oral midazolam is 400-fold larger
during treatment with itraconazole than with rifampicin. Eur J Clin Pharmacol 1998; 54 (1): 53-8
297. Olkkola KT, Backman JT, Neuvonen PJ. Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole
or itraconazole. Clin Pharmacol Ther 1994; 55 (5):481-5
298. Ahonen J, Olkkola KT, Neuvonen PJ. Effect of itraconazole and terbinafine on the pharmacokinetics and pharmacodynamics of
midazolam in healthy volunteers. Br J Clin Pharmacol 1995; 40 (3): 270-2
299. Ahonen J, Olkkola KT, Neuvonen PJ. The effect of the antimycotic itraconazole on the pharmacokinetics and pharmacodynamics of
diazepam. Fundam Clin Pharmacol 1996; 10 (3):314-8
300. Ahonen J, Olkkola KT, Neuvonen PJ. Effect of route of administration of fluconazole on the interaction between fluconazole and
midazolam. Eur J Clin Pharmacol 1997; 51 (5):415-9
301. Vanakoski J, Mattila MJ, Vainio P, et al. 150 mg fluconazole does not substantially increase the effects of 10 mg midazolam or the plasma
midazolam concentrations in healthy subjects. Int J Clin Pharmacol Ther 1995; 33 (9): 518-23
302. Olkkola KT, Ahonen J, Neuvonen PJ. The effects of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and
pharmacodynamics of intravenous and oral midazolam. Anesth Analg 1996; 82 (3): 511-6
303. Ahonen J, Olkkola KT, Takala A, et al. Interaction between fluconazole and midazolam in intensive care patients. Acta Anaesthesiol
Scand 1999; 43 (5): 509-14
Likewise, ketoconazole, itraconazole and fluconazole notably impaired the clearance of triazolam, causing
a several-fold increase in itsAUC.[304-307]
304. Varhe A, Olkkola KT, Neuvonen PJ. Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or
itraconazole. Clin Pharmacol Ther 1994; 56(6): 601-7
305. Varhe A, Olkkola KT, Neuvonen PJ. Fluconazole, but not terbinafine, enhances the effects of triazolam by inhibiting its metabolism. Br J
Clin Pharmacol 1996; 41 (4): 319-23
306. Greenblatt DJ, Wright CE, von Moltke LL, et al. Ketoconazole inhibition of triazolam and alprazolam clearance: differential kinetic and
dynamic consequences. Clin Pharmacol Ther 1998; 64 (3): 237-47
307. Varhe A, Olkkola KT, Neuvonen PJ. Effect of fluconazole dose on the extent of fluconazole-triazolam interaction. Br J Clin Pharmacol
1996; 42 (4): 465-70
Several case reports documenting significant interaction between ketoconazole and cyclosporin, causing an
increase in cyclosporin concentrations and in serum creatinine levels, have been reported in the literature
and were recently reviewed by Albengres and Tillement.[310] Gomez et al.[311] studied the effect of oral
ketoconazole on the disposition of cyclosporin after both intravenous and oral coadministration in healthy
volunteers. Ketoconazole-mediated reduction of cyclosporin clearance was found to be 3-fold higher after
oral than intravenous administration (4.9-fold vs 1.8-fold), suggesting major impairment of CYP3A4
activity at the intestinal rather than at the hepatic level and/or an involvement of intestinal Pglycoprotein.[311] Given this effect, numerous studies have been conducted to assess the potential role of
ketoconazole as a cyclosporin-sparing agent in transplant recipients. Themean reduction in cyclosporine
dosage required to guarantee the same daily exposure during addition of ketoconazole was 65 to 90%,
according to various investigators.[312-318]
310. Albengres E, Tillement JP. Cyclosporin and ketoconazole, drug interaction or therapeutic association? Int J Clin Pharmacol Ther Toxicol
1992; 30 (12): 555-70
311. Gomez DY, Wacher VJ, Tomlanovich SJ, et al. The effects of ketoconazole on the intestinal metabolism and bioavailability of
cyclosporine. Clin Pharmacol Ther 1995; 58 (1): 15-9
312. FirstMR, Schroeder TJ,Weiskittel P, et al. Concomitant administration of cyclosporin and ketoconazole in renal transplant recipients.
Lancet 1989; II (8673): 1198-201
313. Butman SM, Wild JC, Nolan PE, et al. Prospective study of the safety and financial benefit of ketoconazole as adjunctive therapy to
cyclosporine after heart transplantation. J Heart Lung Transplant 1991; 10 (3): 351-8
314. First MR, Schroeder TJ, Michael A, et al. Cyclosporine-ketoconazole interaction. Long-term follow-up and preliminary results of a
randomized trial. Transplantation 1993; 55 (5):1000-4
315. Patton PR, Brunson ME, Pfaff WW, et al. A preliminary report of diltiazem and ketoconazole. Their cyclosporine-sparing effect and
impact on transplant outcome. Transplantation 1994; 57 (6): 889-92
316. Keogh A, Spratt P, McCosker C, et al. Ketoconazole to reduce the need for cyclosporine after cardiac transplantation.NEngl J Med 1995;
333 (10): 628-33
317. Odocha O, Kelly B, Trimble S, et al. Cost-containment strategies in transplantation: the utility of cyclosporine-ketoconazole combination
therapy. Transplant Proc 1996; 28 (2): 907-9
318. Foradori A, Mezzano S, Videla C, et al. Modification of the pharmacokinetics of cyclosporine A and metabolites by the concomitant use
of Neoral and diltiazem or ketoconazole in stable adult kidney transplants. Transplant Proc 1998; 30 (5):1685-7
Likewise, clinically significant pharmacokinetic interactions may occur between azole antifungals and
tacrolimus. A pharmacokinetic study showed that the addition of 200mg of oral ketoconazole affected the
disposition of tacrolimus to a variable extent, depending on the route of administration, in 6 healthy
volunteers.[330] Whereas the intravenous clearance of tacrolimus was decreased moderately by 24%, the oral
clearance was decreased by 66% with a 16% increase in oral bioavailability, thus suggesting major
impairment of intestinal CYP3A4-mediated metabolism of tacrolimus and/or of intestinal P-glycoprotein
induced by coadministration of oral ketoconazole.
330. Floren LC, Bekersky I, Benet LZ, et al. Tacrolimus oral bioavailability doubles with coadministration of ketoconazole. Clin Pharmacol
Ther 1997; 62 (1): 41-9
Coadministration of ketoconazole 200mg for 10 days caused a mean increase of 129% in carbamazepine
trough concentrations with unchanged epoxide concentrations in patients with epilepsy, [343] because of the
high inhibition of CYP3A4-mediated carbamazepine metabolism.[26]
343. Spina E, Arena D, ScordoMG, et al. Elevation of plasma carbamazepine concentrations by ketoconazole in patients with epilepsy. Ther
Drug Monit 1997; 19 (5): 535-8
26. Kerr BM, Thummel KE, Wurden CJ, et al. Human liver carbamazepine metabolism. Role of CYP3A4 and CYP2C8 in 10,11-epoxide
formation. Biochem Pharmacol 1994; 47 (11):1969-79
itraconazole and ketoconazole are considered weaker inhibitors of CYP2C9 activity in vitro.
Critically ill patients represent a ‘special population’[397] in which peculiar pathophysiological conditions
and polytherapy including anti-infective agents frequently coexist, leading to clinically relevant
pharmacokinetic interactions. Some anti-infective agents may be responsible for overdosing of
coadministered drugs frequently used in critically ill patients (benzodiazepines, immunosuppressive agents,
theophylline, opioid analgesics, anticonvulsants, cardiovascular agents), mainly by impairing their
elimination from the body. The anti-infectives most likely to cause such interactions are macrolides
(especially troleandomycin and erythromycin), fluoroquinolones (especially enoxacin, ciprofloxacin and
norfloxacin) and azole antifungals (especially ketoconazole, fluconazole and itraconazole). Conversely,
others, particularly rifampicin, may cause underadministration because they increase elimination.
397. Walson PD. Therapeutic drug monitoring in special populations. Clin Chem 1998; 44 (2): 415-9
Patients with multiple medical problems taking multiple medications are at increased risk of drug–drug
interactions as new medications are added to their drug regimen (1,2). These interactions are complex and
may be difficult to predict despite an understanding of drug metabolism and mechanisms of action.
1. Hogan DB. Revisiting the O complex: urinary incontinence, delirium and polypharmacy in elderly patients. Can Med Assoc J 1997;
157(8):1071–1077.
2. Chung MK, Bartfield JM. Knowledge of prescription medications among elderly emergency department patients. Ann Emerg Med 2002;
39(6).
Ketoconazole, an imidazole antifungal agent, is an effective drug for treating fungal infections
[7]. It is a potent inhibitor of cytochrome P450 isoforms in vitro and in vivo, which results in
many clinically significant drug interactions with coadministered drugs [8,9].
7 Daneshmend TK, Warnock DW. Clinical pharmacokinetics of ketoconazole. Clin Pharmacokinet 1988; 14: 13–34.
8 Lomaestro BM, Piatek MA. Update on drug interactions with azole antifungal agents. Ann Pharmacother 1998; 32: 915–28.
9 Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Effects of the antifungal agents on oxidative drug metabolism: clinical
relevance. Clin Pharmacokinet 2000; 38: 111–80.
As ketoconazole could be prescribed to treat fungal infection in patients also receiving
rosiglitazone, there might be potential for a deleterious drug interaction. In addition, it has been
reported that ketoconazole had a comparable inhibitory effect on CYP2C8-catalysed paclitaxel 6hydroxylation to that of quercetin, a selective potent inhibitor of CYP2C8 [11]. Furthermore,
ketoconazole showed a potent inhibitory effect on CYP2C8-catalysed torsemide metabolism in
vitro [12].
These results suggest that ketoconazole may act as an inhibitor of CYP2C8 in addition to
CYP3A4. By contrast, another in-vitro study showed little inhibition of rosiglitazone metabolism
by ketoconazole, but concentrations of ketoconazole were far lower than therapeutic
concentrations. There have been no data in humans investigating a drug interaction between
ketoconazole and rosiglitazone.
11 Bun SS, Ciccolini J, Bun H, Aubert C, Catalin J. Drug interactions of paclitaxel metabolism in human liver microsomes. J
Chemother 2003; 15: 266–74.
12 Ong CE, Coulter S, Birkett DJ, Bhasker CR, Miners JO. The xenobiotic inhibitor profile of cytochrome P4502C8. Br J Clin
Pharmacol 2000; 50: 573–80.
The widely used azole antifungal agents ketoconazole and itraconazole are also potent inhibitors
of CYP3A4 [8–10]. These antifungal agents strongly interact with orally ingested midazolam and
triazolam, increasing the AUC values of these drugs by more than 10 fold [11, 12].
8 Watkins PB. Noninvasive tests of CYP3A enzymes. Pharmacogenetics 1994; 4: 171–84.
9 Von Moltke LL, Greenblatt DJ, Harmatz JS, Duan SX, Harrel LM, Cotreau-Bibbo MM, Pritchard GA, Wraight CE, Shader
RI. Triazolam biotransformation by human liver microzoms in vitro: effects of metabolic inhibitors and clinical confirmation
of a predicted interaction with ketoconazole. J Pharmacol Exp Ther 1996; 276:370–9.
10 Wilkinson GR. Cytochrome P4503A (CYP3A) metabolism: prediction of in vivo activity in humans. J Pharmacokinet
Biopharm 1996; 24: 475–90.
11 Olkkola KT, Backman JT, Neuvonen PJ. Midazolam should be avoided in patients receiving the systemic antimycotics
ketoconazole or itraconazole. Clin Pharmacol Ther 1994; 55:481–5.
12 Varhe A, Olkkola KT, Neuvonen PJ. Oral triazolam is potentially hazardous to patients receiving systemic antimycotics
ketoconazole or itraconazole. Clin Pharmacol Ther 1994; 56:
601–7.
Previous clinical studies suggested that itraconazole inhibited P-glycoprotein-mediated drug
transportation [20, 21]. A recent in vitro study supported these results [22]. However, since two
other benzodiazepines, midazolam and flunitrazepam, were not transported by P-glycoprotein in
vitro [23, 24], it is unlikely that brotizolam is a clinically significant P-glycoprotein substrate.
20 Jalava K-M, Partanen J, Neuvonen PJ. Itraconazole decreases renal clearance of digoxin. Ther Drug Monit 1997; 19: 609–
13.
21 Lilija JJ, Backman JT, Laitila J, Luurila H, Neuvonen PJ. Itraconazole increases but grapefruit juice greatly decreases
plasma concentrations of celiprolol. Clin Pharmacol Ther 2003; 73:192–8.
22 Miyama T, Takanaga H, Matsuo H, Yamano K, Iga T, Naito M, Tsuruo T, Ishizuka H, Kawahara Y, Sawada Y. PGlycoproteinmediated transport of itraconazole across the blood–brain barrier. Antimicrob Agents Chemother 1998; 42:
1738–44.
23 Schinkel AH, Wagenaar E, Mol CAAM, van Deemter L. PGlycoprotein in the blood–brain barrier of mice influence the
brain penetration and pharmacological activity of many drugs. J Clin Invest 1996; 97: 2517–24.
24 Takano M, Hasegawa R, Fukuda T, Yumoto R, Nagai J, Murakami T. Interaction with p-glycoprotein and transport of
erythromycin, midazolam and ketoconazole in Caco-2 cells. Eur J Pharmacol 1998; 358: 289–94.