SKINmed: Dermatology for the Clinician (ISSN 1540-9740) is published bimonthly (Jan., March, May, July, Sept., Nov.

) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401,
Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy,
recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not
necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at BHarkinson@bos.blackwellpublishing.com or 781-388-8511.

Ta c r o l i m u s i n D e r m a t o l o g y : P a r t I

R e v i e w

Tacrolimus in Dermatology
Pharmacokinetics, Mechanism of Action,
Drug Interactions, Dosages, and Side
Effects: Part I
Virendra N. Sehgal, MD;1 Govind Srivastava, MD;2 Sunil Dogra, MD, DNB3

T
The advent of tacrolimus at the end of the acrolimus (FK506), a macrolide From the Dermato-
preceding century in the armamentarium of lactone produced by soil fungus Venereology (Skin/VD)
atopic dermatitis management was hailed as Streptomyces tsukubaensis, was origi- Centre, Sehgal Nursing
a breakthrough advance. It was, therefore, nally used intravenously or orally for preven- Home, Panchwati, Azadpur,
thought worthwhile to precisely review its tion of organ rejection after allogenic liver Delhi;1 the Skin Institute
origin and mechanism of action. Its topical or kidney transplant. Tacrolimus, especially and School of Dermatology,
application in the form of 0.03% to 0.1% through the topical route of administration, Greater Kailash, New Delhi;2
ointments is rapidly effective and safe in gained entry into therapy for inflammatory and the Department of
Dermatology, Venereology
pediatric and adult patients. Its use in atopic dermatoses,1 such as atopic dermatitis and
and Leprology, Institute
dermatitis ever since has been approved in psoriasis, which were found to respond to
of Medical Education and
Japan, the United States, Europe, and the this therapy without significant risk of toxic-
Research, Chandigarh, India3
Indian subcontinent. Thus, its local immu- ity.2 The interest in several other disorders
nosuppressive action was fairly intriguing. that respond to topical tacrolimus is gaining Address for correspondence:
Accordingly, its indications/uses were extend- momentum, and newer uses of the drug have Virendra N. Sehgal, MD, FNASc,
FAMS, FRAS (Lond), Dermato-
ed to cover several inflammatory dermatoses. come to light.312 Although tall claims about
Venereology (Skin/VD) Centre,
Vitiligo, psoriasis, alopecia areata, contact the benefit of tacrolimus in different disor-
Sehgal Nursing Home, A/6,
hypersensitivity, lichen planus, pyoderma ders have been made, it is still premature to
Panchwati, Delhi-110 033 India
gangrenosum, ichthyosis linearis circumflexa, comment on the surety of the benefits vis a E-mail: drsehgal@ndf.vsnl.net.in
and skin grafting/transplant are a few unap- vis side effects, including risk of the devel-
proved indications and uses, in addition to opment of cancers.13,14 The present review www.lejacq.com
miscellaneous dermatoses. At present, its ther- attempts to succinctly reflect the current ID: 6485

apeutic efficacy other then atopic dermatitis
is confined to case studies, and large studies
are warranted. At this point in time, therefore,
it is conceivable that tacrolimus use should
be carefully evaluated and used only when
the conventional treatment has failed to yield
favorable results. It deserves sizable caution
for use in various dermatologic conditions
pending its long-term safety and efficacy
data in large patient populations. (Skinmed.
2008;7:2730) 2008 Le Jacq
pharmacologic status of tacrolimus (part I)
and an emerging scenario of its repercussion
as a topical immunomodulator in inflamma-
tory dermatoses. Part II of this review will
take stock of its approved as well as unap-
proved indication/uses in sequence as per the
literature available thus far.
Inceptional Repercussions
The drug was initially isolated from a product
of Streptomyces tsukubaensis in the year 1987.

January February 2008 27

SKINmed: Dermatology for the Clinician (ISSN 1540-9740) is published bimonthly (Jan., March, May, July, Sept., Nov.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401,
Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy,
recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not
necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at BHarkinson@bos.blackwellpublishing.com or 781-388-8511.
Ta c r o l i m u s i n D e r m a t o l o g y : P a r t I
Figure 1. Molecular for-
mula for tacrolimus.
Figure 2. Mechanism of
action of tacrolimus.
Kino and colleagues15 studied the immuno-
suppressive effects of this novel drug in vitro,
while Sawada and colleagues16 recorded its in
vitro effects on the cloned T-cell activation.
The initial name, FK506, is attributable to the
complex formed by tacrolimus and its bind-
ing protein FKBP (FK506-binding protein).
It is a white crystalline powder of molecular
formula C44H69NO12 (Figure 1).
FK506 is an 822 kDa immunosuppressant in
the macrolide family that is grouped with
cyclosporine A.17 Topical tacrolimus was first
introduced in Japan in the year 1999, followed
by the United Sates in 2000 and Europe in 2001,
for the treatment of moderate to severe atopic
dermatitis. On March 10, 2005, the US Food
and Drug Administration (FDA) issued an alert
for health care professionals, advising them to
use tacrolimus as well as pimecrolimus only as
directed and only after other eczema treatments
have failed, due to a possible cancer risk.18
Pharmacokinetics
Topical tacrolimus is sufficiently absorbed
when the skin is inflamed. After an application
28
of 0.03% to 0.3% ointment, the peak levels
are reached after 3 to 6 hours of application,
which may vary from 0.05 to 0.25 ng/mL.19
Although topical tacrolimus penetrates less
readily in the intact or healing skin, its absorp-
tion is far better than that of cyclosporine A,
as the latter has a larger molecular weight
(1202.635) compared with tacrolimus (mol
weight 822.05).17,20,21 Whole blood level may
be monitored, however, to avoid exceed-
ing the safe limit of 5 to 20 ng/mL, which
is considered safe according to results from
transplant recipients.17 Unlike corticosteroids,
tacrolimus is not atrophogenic. At concentra-
tions that had efficacy similar to that of 0.13%
clobetasol, it did not cause atrophy of the skin
when used to treat inflammatory disorders.22
The oral absorption of tacrolimus is largely
incomplete, poor, and very erratic. It varies
from 13% to 23% in healthy persons, while it
is 7% to 27% in kidney transplant patients and
16% to 28% in adult liver transplant patients.
Under fasting conditions, its absorption was
maximum. The variability of absorption may
be due in part to poor aqueous solubility of
the drug in gastric secretions.1,23
Tacrolimus is largely metabolized in the liver
by the cytochrome P450 enzyme system via
monodemethylation and/or hydroxylation.
The drug is then excreted through the bile,
which displays most of its metabolites. Less
than 1% of the drug is excreted unchanged
in the urine.24
Mechanism of Action
Tacrolimus achieves immunosuppression
mainly by inhibiting T lymphocyte activa-
tion due to inhibition of interleukin 2 (IL-2)
transcription, which, in turn, decreases T lym-
phocyte responsiveness to foreign antigens.
Tacrolimus and its binding protein (FKBP)
form a complex, which then associates with
calcineurin, calcium, and calmodulin.
This results in inhibition of calcineurin phos-
phatase activity. This controls transcription
of genes that code for several inflamma-
tory mediators such as IL-2, granulocyte-
macrophage colony-stimulating factor, tumor
necrosis factor a, interferon g and other
interleukins requisite for the development
of immune response.2528 Thus, the early
phase of T-cell activation is blocked without
the impairment of exogenously administered
January February 2008
SKINmed: Dermatology for the Clinician (ISSN 1540-9740) is published bimonthly (Jan., March, May, July, Sept., Nov.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401,
Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy,
recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not
necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at BHarkinson@bos.blackwellpublishing.com or 781-388-8511.
cytokine response (Figure 2). Furthermore,
tacrolimus also inhibits the release of hista-
mine from mast cells and impairs de nova
prostaglandin synthesis. It also suppresses
the histamine release of the basophile. These
actions may reduce pruritus.2931
Drug Interactions
As tacrolimus is metabolized by the cyto-
chrome P450 enzyme system, the drugs
that are metabolized either by inhibiting or
inducing these enzyme systems may cause
either raised or lowered tacrolimus blood/
plasma levels (Table). Drugs that alter/impair
renal function should be used with cau-
tion as tacrolimus impairs the renal sys-
tem. Furthermore, since tacrolimus produces
immunosuppression, the use of live vaccines
should be avoided.23,32
Side Effects and Safety
Apart from mild to moderate burning, erythe-
ma, and pruritus, the use of tacrolimus oint-
ment can cause folliculitis,33 acne, Kaposis
varicelliform eruptions, eczema herpeticum,
and herpes simplex infections. Increased
skin sensitivity to hot and cold and alco-
hol intolerance have also been reported.1,23
Occurrence of recurrent skin tags,34 rosacea-
like granulomatous eruptions,35 rosaceiform
dermatitis,36 mucosal hyperpigmentation,37
tinea incognito,38 molluscum contagio-
sum,3941 and verruca vulgaris42 have recently
been reported. The cutaneous viral infection
in particular is alarming and may be caused
by local immunosuppression.
Although there is a theoretic concern that
topical immunomodulatory therapy with tac-
rolimus and pimecrolimus may increase the
risk of cancer, there is no evidence to date
to suggest an increased risk of cutaneous or
visceral cancer. The European Agency for the
Evaluation of Medicinal Products has not rec-
ommended any change in labelling or approv-
al of these topical agents, and a task force of
References
1 Contreras Ruiz J, Kerdel FA. Tacrolimus (FK-506)
In: Millikan LE, ed. Drug Therapy in Dermatology.
1st ed. New York, NY: Marcel Dekkar, Inc;
2004:161-170.
2 Ruzicka T, Bieber T, Schpf E, et al. A short-term
trial of tacrolimus ointment for atopic dermatitis.
N Engl J Med. 1997;337:816821.
3 Toutous-Trellu L, Abraham S, Pechere M, et al.
Topical tacrolimus for effective treatment of
eosinophilic folliculitis associated with human
January February 2008
Ta c r o l i m u s i n D e r m a t o l o g y : P a r t I
Table. Tacrolimus: Drugs that May Alter Tacrolimus Metabolism1,32
Parameter Drugs
Increase of tac- Anticonvulsants: carbamazepine, phenobarbital, phenytoin
rolimus levels Antibiotics: rifampicin, rifabutin
Decrease of tac- Antifungal: clotrimazole, ketoconazole, fluconazole, itraconazole
rolimus levels Ca++ channel blockers: diltiazem, nifedipine, nicardipine,
verapamil
Macrolides: erythromycin, clarithromycin, troleandomycin
Miscellaneous: cyclosporin A, danazol, bromocriptine, cimeti-
dine, methylprednisolone, protease inhibitors
the American Academy of Allergy Asthma
and Immunology did not support the black
box warning as lymphoma is associated with
high-dose systemic therapy, the reported cases
are not consistent with lymphoma observed.
There may still be clinical situations where
such off-label treatment is seen as a lesser risk
than available alternatives such as oral admin-
istration of an immunosuppressant, and lim-
ited data on safety are emerging.
Dosages
Oral tacrolimus has been used in psoriasis in
the dosage of 0.1 mg/kg/body weight/d. The
plasma levels effective in inducing and main-
taining remission range from 0.5 mg to 1.4
ng/mL.43,44 The topical route is a preferred
choice; however, due to the benign nature of
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confine its use only in transplant patients.
Topically, tacrolimus has been used in 0.03%
to 0.1% ointment. In pediatric patients aged
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6 Brill TJ, Elshorst-Schmidt T, Valesky EM, et al.
Successful treatment of acrodermatitis continua
29
SKINmed: Dermatology for the Clinician (ISSN 1540-9740) is published bimonthly (Jan., March, May, July, Sept., Nov.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401,
Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy,
recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not
necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at BHarkinson@bos.blackwellpublishing.com or 781-388-8511.
Ta c r o l i m u s i n D e r m a t o l o g y : P a r t I
of Hallopeau with sequential combination of cal-
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January February 2008