Clin Pharmacokinet 2011; 50 (5): 281-294

REVIEW ARTICLE 0312-5963/11/0005-0281/$49.95/0

ª 2011 Adis Data Information BV. All rights reserved.

Duloxetine
Clinical Pharmacokinetics and Drug Interactions
Mary Pat Knadler, Evelyn Lobo, Jill Chappell and Richard Bergstrom
Eli Lilly and Company, Indianapolis, Indiana, USA

Contents

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
1. Mechanism of Action and Therapeutic Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
2. Clinical Pharmacokinetics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
2.1 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
2.2 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284
2.3 Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
2.4 Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
3. Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
3.1 Sex and Smoking Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
3.2 Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
3.3 Ethnicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
3.4 Hepatic Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
3.5 Renal Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
3.6 Lactation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
4. Drug Interaction Evaluations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
4.1 In Vitro Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
4.1.1 Cytochrome P450 (CYP) Inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
4.1.2 CYP Induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
5. Clinical Pharmacokinetic Drug Interaction Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
5.1 Potential for Other Drugs to Affect Duloxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
5.1.1 Agents Affecting Gastric pH and Activated Charcoal. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
5.1.2 Effect of CYP2D6 Inhibition/Genetic Polymorphism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
5.1.3 Effect of CYP1A2 Inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
5.1.4 Effect of CYP1A2 Inhibition and CYP2D6 Genotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
5.2 Potential for Duloxetine to Affect Other Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
5.2.1 Effects on CYP2D6 Substrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
5.2.2 Effects on CYP1A2 Substrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
5.3 Pharmacodynamic Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
5.3.1 Benzodiazepines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
5.3.2 Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
5.3.3 Anticoagulant Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
5.3.4 Serotonin Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292

Abstract Duloxetine, a potent reuptake inhibitor of serotonin (5-HT) and norepinephrine, is effective for the
treatment of major depressive disorder, diabetic neuropathic pain, stress urinary incontinence, generalized
anxiety disorder and fibromyalgia. Duloxetine achieves a maximum plasma concentration (Cmax) of ap-
proximately 47 ng/mL (40 mg twice-daily dosing) to 110 ng/mL (80 mg twice-daily dosing) approximately
282 Knadler et al.

6 hours after dosing. The elimination half-life of duloxetine is approximately 10–12 hours and the volume of
distribution is approximately 1640 L. The goal of this paper is to provide a review of the literature on
intrinsic and extrinsic factors that may impact the pharmacokinetics of duloxetine with a focus on con-
comitant medications and their clinical implications. Patient demographic characteristics found to influence
the pharmacokinetics of duloxetine include sex, smoking status, age, ethnicity, cytochrome P450 (CYP) 2D6
genotype, hepatic function and renal function. Of these, only impaired hepatic function or severely impaired
renal function warrant specific warnings or dose recommendations. Pharmacokinetic results from drug
interaction studies show that activated charcoal decreases duloxetine exposure, and that CYP1A2 inhibition
increases duloxetine exposure to a clinically significant degree. Specifically, following oral administration in
the presence of fluvoxamine, the area under the plasma concentration-time curve and Cmax of duloxetine
significantly increased by 460% (90% CI 359, 584) and 141% (90% CI 93, 200), respectively. In addition,
smoking is associated with a 30% decrease in duloxetine concentration. The exposure of duloxetine with
CYP2D6 inhibitors or in CYP2D6 poor metabolizers is increased to a lesser extent than that observed with
CYP1A2 inhibition and does not require a dose adjustment. In addition, duloxetine increases the exposure
of drugs that are metabolized by CYP2D6, but not CYP1A2. Pharmacodynamic study results indicate that
duloxetine may enhance the effects of benzodiazepines, but not alcohol or warfarin. An increase in gastric
pH produced by histamine H2-receptor antagonists or antacids did not impact the absorption of duloxetine.
While duloxetine is generally well tolerated, it is important to be knowledgeable about the potential for
pharmacokinetic interactions between duloxetine and drugs that inhibit CYP1A2 or drugs that are meta-
bolized by CYP2D6 enzymes.

1. Mechanism of Action and Therapeutic Use 2. Clinical Pharmacokinetics

Duloxetine (Cymbalta), administered as duloxetine hy- 2.1 Absorption

drochloride – or (+)-(S)-N-methyl-g-(1-naphthyloxy)-2-thio-
phenepropylamine hydrochloride – (see figure 1), is a potent
inhibitor of serotonin (5-HT) and norepinephrine reuptake.[1-5]
Compared with its effects on 5-HT and norepinephrine reup-
take, duloxetine weakly inhibits dopamine reuptake and has
low binding affinity for other neurotransmitter receptors, in-
cluding adrenergic, muscarinic (nonselective) and histamine
H1 receptors; dopamine D2 receptors; 5-HT1A, 5-HT1D and
5-HT2C receptors; and opioid receptors.[1,2,6] Duloxetine is used
clinically in many countries to treat disorders related to nor-
epinephrine and 5-HT, such as depression,[7-13] diabetic neu-
ropathic pain,[14,15] generalized anxiety disorder[16-19] and
fibromyalgia.[20] In Europe, duloxetine is also used to treat
stress urinary incontinence.[21,22] The safety of duloxetine
has been extensively evaluated in a large number of patients
across indications.[6,23] To understand the potential for drug
interactions and whether dose adjustments are appropriate
for a specific patient with any of these indications, it is im-
portant to consider the intrinsic and extrinsic factors that
influence the pharmacokinetics or pharmacodynamics of du-
loxetine. The goal of this paper is to provide a review of the
Duloxetine is acid labile, requiring the development of a
formulation that utilizes enteric-coated pellets to protect
duloxetine from degradation in the acidic environment of the
stomach. The delayed-release formulation prevents dissolu-
tion in acidic conditions (pH <5.5) such as those in the stomach
but allows for immediate release and rapid absorption at the
pH in the small intestine. Following oral administration, du-
loxetine is well absorbed with a median time to maximum
plasma concentration (tmax) of 6 hours after dosing. The ab-
solute oral bioavailability averaged 50%, ranging from 30% to
80%, after a 60 mg single dose in one study[2] and averaged 43%,
ranging from 19% to 71%, in another study.[24] Population
pharmacokinetic results in patients indicate that the rate of
absorption is rapid (absorption rate constant 0.168 h-1) once
dissolution occurs in the intestine.[25] The elimination half-life
(t½) of duloxetine is approximately 10–12 hours and therefore
steady state occurs within 3 days. Plasma concentrations gen-
erally range from 24.6 ng/mL to 110 ng/mL depending on the
dose and dosing regimen (tables I and II and figures 2 and
3).[24,26-29] A single dose of 60 mg of duloxetine produced a


literature on factors that may impact the pharmacokinetics of mean area under the plasma concentration-time curve (AUC)
duloxetine with a focus on the clinical implications of these from time zero to infinity (AUC1) of 591 ng h/mL (table I)
factors. and 40 or 60 mg twice-daily dosing provided a mean steady-

ª 2011 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2011; 50 (5)
Duloxetine Pharmacokinetics and Drug Interactions 283

Glucuronide
conjugate of 4-hydroxy duloxetine

Other pathways OH

N CH3
H
S
Major 4-Hydroxy duloxetine

CYP1A2
CYP2D6
O OH
OH
OH
* N CH3
H
S Major
Duloxetine
CYP1A2
CYP2D6 O O

N CH3 N CH3
H H
S S
5-Hydroxy or
Catechol duloxetine
6-hydroxy duloxetine

CH3
O

OH

N CH3
H
Sulfate and glucuronide conjugates
of 5-hydroxy-6-methoxy duloxetine S

5-Hydroxy-6-methoxy duloxetine

Fig. 1. Metabolism pathways and cytochrome P450 enzymes (CYPs) involved in the major oxidation steps of duloxetine biotransformation. The asterisk
indicates the position of the radiolabel in the material used for the distribution study. The bracketed compound is postulated, but has not been isolated.

state AUC (AUCt,ss) of 412 or 1050 ng h/mL (table II), re-

spectively.
 time and in the presence of food, especially fats. Decreased
motility may also prolong exposure of a drug to intraluminal and
Food and time of day impact duloxetine absorption, with food gut-wall degradation or metabolic processes, thus decreasing the
and bedtime administration delaying tmax by 4 hours. This finding extent of absorption. However, food had no significant effect on
is consistent with a decrease in gastrointestinal motility at bed- duloxetine maximum plasma concentration (Cmax) and reduced

ª 2011 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2011; 50 (5)
284 Knadler et al.

Table I. Summary of pharmacokinetic parameters of duloxetine and its two major metabolites following a single oral dose of 40 mg or 60 mg of duloxetine[24,26,27]
Parameter Duloxetine 40 mga Duloxetine 60 mga

duloxetine duloxetine glucuronide conjugate of sulfate conjugate of

(n = 24) (n = 50) 4-hydroxy duloxetine 5-hydroxy-6-methoxy duloxetine
(n = 26) (n = 26)
Cmax (ng/mL) 24.6 [50.8] 40.1 [47.5] 402 [47.6] 258 [49.1]
tmax (h)b 6.00 [0.99–10.01] 6.00 [2–6.03] 5.51 [3–8] 5 [3–8]
t½ (h)c 11.8 [8.04–17.5] 10.2 [6.96–14.9] 11.6 [9.06–17.1] 10.1 [6.46–13.2]


AUC1 (ng h/mL) 422 [50.5] 591 [55.6] 6830 [46.6] 3290 [42.4]
CL/F (L/h) 94.8 [50.5] 101 [55.6] NA NA
Vss/F (L) 1800 [51.2] 1620 [45.8] NA NA
Metabolite/parent drug ratiod NA NA 6.88 3.83
a Values are expressed as geometric mean [CV%] unless specified otherwise.
b Median [range].
c Geometric mean [range].
d Metabolite/parent drug ratio = AUC1,metabolite/AUC1,duloxetine.
AUC1 = area under the plasma concentration-time curve from time zero to infinity; CL/F = apparent clearance after oral administration; Cmax = maximum plasma
drug concentration; CV = coefficient of variation; NA = not applicable; t½ = elimination half-life; tmax = time to reach Cmax; Vss/F = volume of distribution at steady
state after oral administration.

AUC1 and t½ by only 11% and 18%, respectively. Bedtime ad-
ministration had no effect on t½ and reduced duloxetine Cmax
and AUC1 by 29% and 18%, respectively.[30] Because the effects
of food and bedtime administration are relatively small and
clinically insignificant, dose adjustments or time-of-day restric-
tions are not required. Patients may be instructed to take du-
loxetine with or without food and in the morning or at bedtime.
2.2 Distribution
Duloxetine is extensively distributed throughout the body,
as indicated by a large mean apparent steady-state volume of
distribution of 1620–1800 L (table I).[31] Protein binding was
assessed as a factor that may impact duloxetine distribution.
Results from in vitro studies showed that more than 90% of

Table II. Summary of pharmacokinetic parameters of duloxetine and its two major metabolites following twice-daily oral dosing of 40 mg or 60 mg of duloxetine[26,28,29]
Parameter Duloxetine 40 mga Duloxetine 60 mga

duloxetine duloxetine glucuronide conjugate of sulfate conjugate of

(n = 14) (n = 36) 4-hydroxy duloxetine 5-hydroxy-6-methoxy duloxetine
(n = 22) (n = 22)
Cmin,ss (ng/mL) 22.9 [73.0] 66.3 [75.7] 353 [55.0] 185 [31.0]
Cmax,ss (ng/mL) 47.8 [58.6] 110 [66.7] 568 [43.1] 336 [28.5]
Cav,ss (ng/mL) 34.3 [58.5] 87.7 [69.4] 467 [46.2] 259 [26.6]
tmax,ss (h)b 6 [2–9] 6 [3–8] 6.00 [4–8] 6.00 [4–8]


AUCt,ss (ng h/mL) 412 [58.5] 1050 [69.4] 5600 [46.2] 3110 [26.6]
CLss/F (L/h) 97.1 [58.5] 57.0 [69.4] NA NA
Metabolite/parent drug ratioc NA NA 3.17 2.04
a Values are expressed as geometric mean [CV%] unless specified otherwise.
b Median [range].
c Metabolite/parent drug ratio = AUCt,ss,metabolite/AUCt,ss,duloxetine.
AUCs,ss = area under the plasma concentration-time curve during one dosing interval at steady state; Cav,ss = average plasma concentration at steady state;
CLss/F = apparent clearance at steady state after oral administration; Cmax,ss = maximum plasma concentration at steady state; Cmin,ss = minimum plasma
concentration at steady state; CV = coefficient of variation; NA = not applicable; tmax,ss = time to reach Cmax at steady state.

ª 2011 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2011; 50 (5)
Duloxetine Pharmacokinetics and Drug Interactions
Duloxetine after duloxetine 60 mg sd (n = 18)
Glucuronide conjugate of 4-hydroxy duloxetine
after duloxetine 60 mg sd (n = 14)
Sulfate conjugate of 5-hydroxy-6-methoxy duloxetine
after duloxetine 60 mg sd (n = 14)
Duloxetine after duloxetine 40 mg sd (n = 16)
1000
Plasma concentration (ng/mL)
100
10
1 metabolites to membranes expressing cloned human 5-HT and
0.1
0 12 24 36 48 60
Time (h)
Fig. 2. Mean plasma concentration-time profiles of duloxetine and its two major
metabolites after a single oral dose (sd) of duloxetine 60 mg or 40 mg.[24,26]
duloxetine is protein bound in human plasma.[2] The binding
occurs primarily to albumin and a1-acid glycoprotein.[32] The
percent bound was independent of duloxetine concentration
across the concentration range associated with therapeutic use.
While displacement from protein binding sites could potentially
impact distribution of drugs when two highly protein-bound
drugs are co-administered, data across a wide spectrum of
drugs suggest that changes in protein binding would not result
in a clinically significant drug interaction.[33,34]
Duloxetine has been shown to distribute into the brains of
both rats and humans. In rats administered a 20 mg/kg dose of
duloxetine, the concentrations in the cerebral cortex were
higher than those in plasma.[2] The plasma protein binding in
rats is similarly high as in humans. In a study of healthy male
subjects administered single doses of 5–60 mg of duloxetine or
60 mg repeat doses, 5-HT transporter occupancy in the thala-
mus was studied using positron emission tomography.[35] Based
on these data, doses of 40 mg and higher of duloxetine resulted
in 80% occupancy, thus demonstrating that duloxetine is dis-
tributed into brain areas.
2.3 Metabolism
Duloxetine undergoes extensive metabolism into a complex
array of metabolites. Importantly, the major biotransforma-
tion pathways involve oxidation in the naphthyl ring followed
by further oxidation, methylation and conjugation. After a
single oral dose of 14C-duloxetine, the relative AUC of parent
ª 2011 Adis Data Information BV. All rights reserved.
285
drug accounts for approximately 3% of the circulating radio-
activity and approximately 9% of the radioactivity based upon
Cmax. The two major circulating metabolites of duloxetine
are the glucuronide conjugate of 4-hydroxy duloxetine and
the sulfate conjugate of 5-hydroxy-6-methoxy duloxetine
(figure 1).[36] The metabolic ratio (metabolite concentration/
duloxetine concentration) for the glucuronide conjugate of
4-hydroxy duloxetine averaged across studies ranges from 3.2
to 6.9 and the metabolic ratio for the sulfate conjugate of
5-hydroxy-6-methoxy duloxetine averaged across studies ranges
from approximately 2.0 to 3.8 (tables I and II). Binding of these
norepinephrine transporters produced inhibition constant (Ki)
values >10 000 nmol/L for both receptors while the Ki for du-
loxetine was 0.8 nmol/L for 5-HT binding and 7.45 nmol/L for
72
norepinephrine binding.[37] The low binding of the glucuronide
conjugate of 4-hydroxy duloxetine and the sulfate conjugate of
5-hydroxy-6-methoxy duloxetine lead to a conclusion that
these compounds are pharmacologically inactive metabolites.
Studies were performed to determine the cytochrome P450
(CYP) enzymes responsible for the biotransformation of du-
loxetine to 4-, 5- and 6-hydroxy duloxetine.[38] The studies
correlated the formation of these metabolites with markers of
CYP enzymes in a human liver microsome bank, assessed
which complementary DNA (cDNA)-expressed CYPs formed
the metabolites and utilized CYP inhibitors to determine which
CYP enzymes were responsible for the initial oxidation step.[24]
Duloxetine after duloxetine 60 mg bid (n = 36)
Glucuronide conjugate of 4-hydroxy duloxetine
after duloxetine 60 mg bid (n = 22)
Sulfate conjugate of 5-hydroxy-6-methoxy duloxetine
after duloxetine 60 mg bid (n = 22)
Duloxetine after duloxetine 40 mg bid (n = 14)
1000
Plasma concentration (ng/mL)
100
10
1
0 3 6 9 12
Time (h)
Fig. 3. Mean plasma concentration-time profiles of duloxetine and its two
major metabolites at steady state during twice-daily (bid) oral dosing of
duloxetine 40 mg or 60 mg.[26,28,29]
Clin Pharmacokinet 2011; 50 (5)
286
The rates of formation from the in vitro studies indicated that
4-hydroxy and 5-hydroxy duloxetine, but not 6-hydroxy du-
loxetine, define the metabolic clearance of duloxetine. These
findings for 4-hydroxy and 5-hydroxy duloxetine were corro-
borated by experiments using microsomes that express specific
CYP enzymes. cDNA-expressed CYP2D6 and CYP1A2
formed 4-hydroxy duloxetine, and CYP2D6, CYP1A2 and
CYP2C9 (at a relatively slow rate) formed 5-hydroxy dulox-
etine. CYP2D6 was identified as a low-affinity enzyme
(Michaelis-Menten constant [Km] 1 mmol/L) responsible for the
formation of both 4-hydroxy and 5-hydroxy duloxetine.
CYP1A2 was identified as a moderate-affinity enzyme (Km
20 mmol/L). Therefore the in vitro data indicate both enzymes
would be likely to participate in the biotransformation of du-
loxetine to 4-hydroxy and 5-hydroxy duloxetine, but in vivo
clinical studies using potent CYP2D6[29] and CYP1A2 in-
hibitors[24] (described below) reveal that CYP1A2 is the more
important enzyme. In vitro data indicate that the role of other
CYP enzymes is small and these enzymes would not be expected
to contribute to the in vivo metabolism of duloxetine.
2.4 Elimination
Duloxetine oral clearance (CL/F) following a single 60 mg
dose was 101 L/h, which decreased to 57 L/h following 60 mg
twice-daily dosing at steady state, but was 97.1 L/h after 40 mg
twice-daily dosing (tables I and II). Another report showed that
mean duloxetine CL/F was 114 L/h in healthy males[31] ad-
ministered multiple doses ranging from 20 mg to 40 mg. The
dose dependency in CL/F was observed in patients, where the
effect of doubling the duloxetine dose from 30 mg to 60 mg or
from 60 mg to 120 mg resulted in 2.3 and 2.6 times the average
concentration at steady state (Cav,ss), respectively.[25] Relative
to the high interindividual variability (~60%) in CL/F, the
magnitude of nonlinearity in duloxetine exposure with respect
to dose was considered to be minor and dose adjustments are
not warranted for patients on long-term therapy.
Following administration of 14C-labelled duloxetine, ap-
proximately 72% of the radioactivity was excreted in urine
principally as the glucuronide and/or sulfate conjugates of the
oxidative duloxetine metabolites. The relatively small amount
of radioactivity found in faeces as duloxetine (<5% of the dose)
was excreted by 96 hours after dosing. These results reflect the
substantially complete oral absorption of the dose. It is note-
worthy that the majority of faecal radioactivity was excreted
beyond simply gastrointestinal transit time, suggesting a role of
biliary excretion. The profile of faecal radioactivity showed that
in addition to duloxetine, 4-hydroxy duloxetine and a meta-
ª 2011 Adis Data Information BV. All rights reserved.
Knadler et al.
bolite that has not been characterized account for the majority
of faecal radioactivity.[36] No additional work was conducted to
identify the unknown metabolite because it was present in very
low levels (<5% of the dose) and faecal excretion is not a major
elimination pathway.[36]
3. Special Populations
3.1 Sex and Smoking Status
Population pharmacokinetic analyses of duloxetine con-
centrations in 594 patients with major depressive disorder
(n = 223), stress urinary incontinence (n = 128), diabetic neuro-
pathic pain (n = 112) or fibromyalgia (n = 131) show that sex
and smoking status impact duloxetine bioavailability.[25] The
effect of sex and smoking status on duloxetine exposure is
attributable to CYP1A2 metabolism since these factors affect
the expression and activity of CYP1A2.[39,40] CYP1A2 activity
in women is lower than in men and this decrement in CYP1A2
activity has an impact on the metabolism of duloxetine, re-
sulting in higher duloxetine systemic concentration in women
compared with men. Smoking increases the expression of
CYP1A2 and this increased expression is associated with a 30%
decrease in duloxetine concentration in smokers compared with
nonsmokers. The combined effect of sex and smoking status
typically results in duloxetine concentrations for a male smoker
that are 57% lower than the concentrations in a female non-
smoker. Another study revealed similar findings to the popu-
lation pharmacokinetic study with smokers showing lower
mean plasma duloxetine concentrations than nonsmokers.[41]
On a population basis the magnitude of change in duloxetine
concentrations due to sex and smoking status is notable, but in
individual patients these effects have a smaller impact than
the much larger random sources of variability (approximately
60% coefficient of variation) for clearance.[25] Consequently,
while the distributions of the pharmacokinetic parameters
and observed duloxetine concentrations broadly reflect sex
and smoking status differences, the large ranges for these val-
ues substantially overlap. Therefore, duloxetine pharmaco-
kinetics are remarkably similar between smokers and non-
smokers, and between males and females. That is, while sex
and smoking status have a consistent rank-order impact on
the typical (or average) pharmacokinetic parameter estimates
for each subgroup (average duloxetine concentrations in fe-
male nonsmoker > male nonsmoker > female smoker > male
smoker), differential dosing recommendations for individual
patients based solely on sex and smoking status are not
warranted.
Clin Pharmacokinet 2011; 50 (5)
Duloxetine Pharmacokinetics and Drug Interactions
3.2 Age
In elderly women (age 65–77 years), the rate of elimination of
duloxetine was slower than that in younger women (age 32–50
years).[42] Results based on the analysis of a large patient pop-
ulation also showed that age had a small effect on CL/F such
that duloxetine CL/F was lower among the older patients.
Relative to the Cav,ss for a 49-year-old patient (the median age),
the Cav,ss was 13% lower for a patient who was 29 years old (at
the 5th percentile of the age distribution) and Cav,ss was 17%
higher for a patient who was 69 years old (at the 95th percentile
of the age distribution).[25] While these findings indicate that
age has a small effect on duloxetine pharmacokinetics, the
magnitude of these pharmacokinetic differences across age is
not great enough to warrant a specific dosing recommendation
for the elderly.
3.3 Ethnicity
Single-dose pharmacokinetics in Caucasian and Japanese
subjects revealed that the mean duloxetine Cmax and AUC were
approximately 20% higher in Japanese subjects. This difference
is likely related to the 15% lower average bodyweight in Japa-
nese subjects[26] as bodyweight normalized exposures (Cmax,
AUC) were similar in Caucasians and Japanese subjects.
Conclusions could not be drawn from this study as to the effects
of factors other than bodyweight, such as CYP2D6 poor me-
tabolizer status or smoking status, because most subjects in
both groups were CYP2D6 extensive metabolizers and non-
smokers. Similar small pharmacokinetic differences were also
observed following multiple doses of duloxetine.[26] In Chinese
subjects, duloxetine pharmacokinetics were not statistically
significantly different from those reported previously in Cau-
casian and Japanese subjects.[43] Another study in Chinese
subjects found volume of distribution after oral administration
(Vd/F), tmax, Cmax and AUC in Chinese subjects to agree with
other published studies.[44]
Population pharmacokinetic analyses found that Hispanics
had double the Vd/F compared to non-Hispanics.[25] However,
the effect of ethnic origin on the Vd/F did not have an impact on
duloxetine Cav,ss. Therefore specific dosing recommendations
based on ethnicity are not warranted.[25]
3.4 Hepatic Impairment
Patients with clinically evident hepatic insufficiency exhibit a
substantial decrease in the ability to metabolize and eliminate
duloxetine. Following a single, 20 mg oral dose of duloxetine,
ª 2011 Adis Data Information BV. All rights reserved.
287
subjects with moderate hepatic impairment (Child-Pugh Class
B) had a mean plasma duloxetine exposure that was 5-fold
higher[32] and elimination took approximately 3 times longer
compared to age- and sex-matched healthy subjects, but Cmax
was unaffected.[45] Use of duloxetine in patients with hepatic
insufficiency is not ordinarily recommended.
3.5 Renal Impairment
Duloxetine and its metabolite concentrations were elevated
in subjects with end-stage renal disease (ESRD) requiring dia-
lysis. The Cmax and AUC of duloxetine after a single 60 mg dose
of duloxetine were approximately twice as high in subjects with
ESRD than in subjects with normal renal function.[46] Given
that the t½ was unaffected, the higher duloxetine exposure in
ESRD appears to be due to an increase in the oral bioavaila-
bility, allowing a larger portion of the drug to reach the systemic
circulation on first pass. More directly related to reduced renal
function, the AUCs of the major circulating metabolites,
4-hydroxy duloxetine glucuronide and 5-hydroxy-6-methoxy
duloxetine sulfate, were approximately 7- to 9-fold higher than
the metabolite exposure in control subjects with normal renal
function. The magnitude of these differences may potentially
increase upon multiple-dose administration because the con-
jugated metabolites of duloxetine are principally excreted in
urine.[36] Given the increase in the exposure of duloxetine and
metabolites, use of duloxetine is not ordinarily recommended
for patients with ESRD or for patients with severe renal impair-
ment (creatinine clearance [CLCR] <30 mL/min). Population
pharmacokinetic analyses show that patients with mild to moderate
degrees of renal dysfunction (CLCR between 30 and 80 mL/min)
have no significant difference in the clearance of duloxetine,
therefore a dose adjustment is unnecessary for these patients.[46]
3.6 Lactation
After giving multiple doses of 40 mg of duloxetine twice daily
to lactating women, approximately 7 mg/day (ranging from
4 to 15 mg/day) of duloxetine was secreted in their breast milk.
The estimated dose for an infant consuming breast milk is
2 mg/kg/day (ranging from 0.6 to 3 mg/kg/day), or approxi-
mately 0.14% of the maternal dose.[28] Although this amount of
duloxetine dosage for an infant is small, the safety of duloxetine
in infants has not been systematically investigated and is cur-
rently unknown. If duloxetine is prescribed for mothers who
may be nursing, the health care provider and the mother need to
assess the potential risks of exposing the infant to duloxetine
compared with the benefits of nursing.
Clin Pharmacokinet 2011; 50 (5)
288
4. Drug Interaction Evaluations
The evaluation of duloxetine drug interactions used a
systematic approach that integrated information about du-
loxetine physicochemical properties and data from in vitro en-
zyme studies and human clinical pharmacology studies.
Specific drug interaction studies were designed based upon the
known metabolic pathways and the metabolic impact of du-
loxetine. The drug interaction studies conducted in healthy
subjects evaluated both the potential for duloxetine to affect
other drugs and the potential for other drugs to affect dulox-
etine. The drugs chosen for the studies were selected because of
the impact on or sensitivity to specific CYP enzymes[47] rather
than the likelihood of their clinical use together with dulox-
etine. However, these specific probes provide a rigorous
evaluation of the potential for drug interactions and are re-
presentative for many other drugs that likewise have an impact
on, or are affected by, specific CYP enzymes. A key aspect of
this series of studies was to coordinate results from in vitro
enzyme studies with in vivo human clinical studies.
Specific interactions for duloxetine involving transporters
were not assessed in vitro or in vivo and no data on this topic
were found in the literature. Nonetheless, it is informative to
know that the equilibration of duloxetine between the blood
and brain of rats was rapid and reversible. In rats, duloxetine
concentrations were distinctly parallel between plasma and
brain across time.[2] These results indicate rapid equilibration of
duloxetine into and out of the brain and that this process most
likely occurs via passive diffusion which is thought to be the
predominant mechanism for duloxetine disposition. Therefore
transporter-based drug-drug interactions are considered un-
likely. Since duloxetine is cleared primarily by metabolism with
minimal renal excretion, an interaction with renal transporters
is also unlikely.
4.1 In Vitro Studies
4.1.1 Cytochrome P450 (CYP) Inhibition
In vitro studies conducted using human liver microsomes
assessed the potential for duloxetine to inhibit major CYP en-
zymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and
CYP3A4).[24,38] The lowest Ki value of 2.4 mmol/L was obtained
for the effect of duloxetine on CYP2D6 (table III), suggesting
the possibility that duloxetine may inhibit CYP2D6 activity.
This assessment used the established criteria[47] that CYP in-
hibition will likely make a substantial pharmacokinetic impact
if the Cmax/Ki ratio is >1, CYP inhibition will possibly make an
impact if the Cmax/Ki ratio is between 0.1 and 1, and a
ª 2011 Adis Data Information BV. All rights reserved.
Knadler et al.
Table III. In vitro cytochrome P450 (CYP) enzyme studies of the potential
inhibitory effect of duloxetine[24,38]
Enzyme Ki (mmol/L) Cmax/Ki a
CYP2D6 2.4 0.2
CYP1A2 17.7 <0.1
CYP3A 133 <0.1
CYP2C9 306 <0.1
CYP2C19 7.1 <0.1
CYP2C8 97 <0.1
a The Cmax value used was 0.48 mmol/L or 144 ng/mL after 60 mg twice-
daily dosing, the highest dose studied for efficacy.
Cmax = maximum plasma concentration; Ki = inhibition constant.
pharmacokinetic impact is unlikely if the Cmax/Ki ratio is <0.1.
For duloxetine, the Cmax/Ki ratio was 0.2 for CYP2D6 (table
III), predicting that duloxetine would potentially affect the
pharmacokinetics of drugs metabolized by CYP2D6. In vivo
studies were conducted with the known CYP2D6 substrates
desipramine, metoprolol and tolterodine (see below).
4.1.2 CYP Induction
The ability of duloxetine to induce the catalytic activities
associated with CYP1A2 and CYP3A was examined in primary
cultures of human hepatocytes. Primary cultures of human
hepatocytes were treated for 48 hours with duloxetine at con-
centrations ranging from 0.01 mmol/L to 100 mmol/L, and the
effects of treatment on catalytic activities associated with
CYP1A2 and CYP3A were compared to those activities in
vehicle-treated control cultures (0.1% dimethyl sulfoxide). There
was no significant induction of CYP1A2[24] or CYP3A[32,38] in
any of the three preparations of cultured human hepatocytes
examined; therefore it is unlikely that duloxetine induces these
enzymes when used clinically.
5. Clinical Pharmacokinetic Drug Interaction Studies
5.1 Potential for Other Drugs to Affect Duloxetine
5.1.1 Agents Affecting Gastric pH and Activated Charcoal
A gelatin capsule is used to contain an enteric-coated pellet
formulation of duloxetine hydrochloride.[32] The enteric-coated
pellets protect the acid-labile drug from normal acidic condi-
tions of the stomach and they immediately release duloxetine
hydrochloride for dissolution in the more alkaline conditions of
the small intestine. Each capsule contains a multitude of small
enteric-coated pellets that are dispersed in the gastrointestinal
tract, leading to a more consistent performance than the per-
Clin Pharmacokinet 2011; 50 (5)
Duloxetine Pharmacokinetics and Drug Interactions
formance that would be obtained with a monolithic enteric-
coated tablet. However, all enteric-coated formulations are
responsive to changes in gastrointestinal pH. Therefore specific
pharmacokinetic studies were conducted to assess the impact of
change in gastrointestinal pH on the duloxetine formulation.
Drugs like famotidine (an H2-receptor antagonist) or alumi-
nium hydroxide/magnesium hydroxide/simethicone (Mylanta;
an antacid) increase the pH in the gastrointestinal tract and are
likely to facilitate the release and early absorption of duloxetine
after oral administration. However, these drugs did not change
the pharmacokinetics of duloxetine, suggesting that the chan-
ges in gastrointestinal pH due to these drugs have no impact on
the rate or onset or extent of absorption. In contrast, activated
charcoal significantly decreased duloxetine Cmax by approxi-
mately 32% and AUC by approximately 35%, likely resulting
from the binding of duloxetine to the activated charcoal when
duloxetine was released into the gastrointestinal content. These
results indicate a potential benefit of using activated charcoal
early in the treatment of a duloxetine overdose to decrease the
amount of duloxetine that may be absorbed.[48]
5.1.2 Effect of CYP2D6 Inhibition/Genetic Polymorphism
The co-administration of duloxetine with paroxetine, a po-
tent CYP2D6 inhibitor, increased both the mean Cmax and
AUC of duloxetine by approximately 60%.[29] Although this
increase in exposure falls outside of the standard no-effect
boundary (0.8–1.25), the clinical relevance of the increased
concentration would depend on individual tolerance to du-
loxetine across a range of concentrations (i.e. the therapeutic
index of the drug). Therefore the effect of paroxetine on du-
loxetine concentrations seen in this study may not necessarily
be manifested by a significant change in tolerance. Further-
more, since CYP1A2 provides the primary pathway for du-
loxetine metabolism even though there is evidence of CYP2D6
metabolism for duloxetine, the effect of CYP2D6 inhibition
alone on duloxetine pharmacokinetics is considered to be less
important when compared with the much larger impact of
CYP1A2 inhibition (see below). Therefore a dose adjustment
does not appear to be necessary when duloxetine is co-
administered even with potent CYP2D6 inhibitors such as
paroxetine.
A commonly recognized polymorphism in drug metabolism
is the absence of CYP2D6 activity in a small segment of the
population. CYP2D6 poor metabolizers represent approxi-
mately 5–10% of the Caucasian population and they lack
CYP2D6 activity due to a variety of genetic mutations of the
gene responsible for the formation of this enzyme. This per-
centage differs among ethnic groups. Chinese subjects in a
ª 2011 Adis Data Information BV. All rights reserved.
289
duloxetine study who were identified as CYP2D6 intermediate
metabolizers had duloxetine exposures slightly higher (16%)
than the exposures in extensive metabolizers;[43] however, this
difference is not clinically meaningful. In another study with
Japanese and Caucasian subjects, four subjects were genotyped
as CYP2D6 poor metabolizers; two of the poor metabolizers
had duloxetine exposures 1- to 3-fold higher than other subjects
in the study who were not poor metabolizers and two poor
metabolizers had duloxetine exposures comparable to the other
subjects.[26] These results indicate that exposure cannot be
predicted by CYP2D6 metabolism status alone and factors such
as CYP1A2 activity predict exposure more substantially.[26]
Therefore in patients with a CYP2D6 poor metabolizer phe-
notype, a lower dose of duloxetine is not necessary.
5.1.3 Effect of CYP1A2 Inhibition
Duloxetine was administered both intravenously and orally
to healthy male CYP2D6 extensive metabolizers in the presence
and absence of the potent CYP1A2 inhibitor fluvoxamine.[24]
Following oral administration in the presence of fluvoxamine,
the AUC1 and Cmax of duloxetine significantly increased by
460% (90% CI 359, 584) and 141% (90% CI 93, 200), respect-
ively. In the presence of fluvoxamine, the oral bioavailability of
duloxetine increased from 42.8% to 81.9%. The magnitude of
increase in AUC and Cmax for duloxetine co-administered with
a potent CYP1A2 inhibitor compared with a potent CYP2D6
inhibitor suggests that CYP1A2 is the predominant enzyme
responsible for duloxetine metabolism. Therefore co-adminis-
tration of duloxetine with a potent CYP1A2 inhibitor (e.g.
fluvoxamine, some quinolone antibacterials) should be avoided
and is contraindicated in some labels such as the European
Union summary of product characteristics (SPC). No studies
have been reported in which duloxetine was administered at a
lower dose with a potent CYP1A2 inhibitor to assess if dose
adjustments of duloxetine in the presence of CYP1A2 inhibitors
could be safely administered.
5.1.4 Effect of CYP1A2 Inhibition and CYP2D6 Genotype
Duloxetine was given to CYP2D6 poor metabolizer subjects
along with the potent CYP1A2 inhibitor, fluvoxamine, to
evaluate the effect of inhibiting both CYP1A2 and CYP2D6.[49]
At steady state, there was a clinically significant increase in
duloxetine AUC (540%) and Cmax (471%) in the presence of
fluvoxamine (see figure 4). The magnitude of increase in du-
loxetine exposure is similar to that caused by CYP1A2 inhibi-
tion alone, reflecting the predominant role of CYP1A2 in
duloxetine metabolism. The effect of fluvoxamine on duloxetine
metabolism was similar but of smaller magnitude following
Clin Pharmacokinet 2011; 50 (5)
290
Duloxetine (n = 14)
Glucuronide conjugate of 4-hydroxy duloxetine (n = 14)
Sulfate conjugate of 5-hydroxy-6-methoxy duloxetine (n = 14)
800
Trough plasma concentration (ng/mL)
600
400
200
0 moderate inhibitor of CYP2D6.[49]
0 2 4 6
Fig. 4. Mean predose trough plasma concentrations of duloxetine and its
two major metabolites in healthy cytochrome P450 2D6 poor metabolizers
(n = 13–14) during twice-daily dosing of duloxetine 40 mg. Fluvoxamine was
given once daily in the evening: 50 mg on days 5 and 6, 100 mg on days 7
through 21.
intravenous administration, suggesting that fluvoxamine in-
hibition of CYP1A2 affects both the first-pass and systemic
metabolism of duloxetine. In addition, the study showed that
the steady-state Cmax and AUC values for the two major cir-
culating duloxetine metabolites were decreased by about 50%.
These results further emphasize that the co-administration of
duloxetine with a potent CYP1A2 inhibitor should be avoided.
However, the impact of this important CYP1A2 drug inter-
action is not substantially greater for patients also taking a
potent CYP2D6 inhibitor or for patients having the genetic
characteristics of a CYP2D6 poor metabolizer.
5.2 Potential for Duloxetine to Affect Other Drugs
5.2.1 Effects on CYP2D6 Substrates
The investigations of the effects of duloxetine on CYP2D6
metabolism produced varied outcomes. When given as 60 mg
twice-daily oral doses, duloxetine increased the mean AUC of
desipramine, a sensitive CYP2D6 substrate, by 192%.[29] Doses
of 30 mg twice daily increased the mean AUC of desipramine
122%.[50] Co-administration of 40 mg of duloxetine twice daily
with the CYP2D6 substrate tolterodine (2 mg twice daily) in-
creased tolterodine steady state AUC and Cmax by 71% and
64%, respectively, and prolonged tolterodine t½ by 14%. Du-
loxetine did not affect the Cmax or AUC of the active 5-hy-
droxylmethyl tolterodine metabolite,[51] which is consistent
with the established fact that this clinically important tolter-
odine metabolite is not a CYP2D6 substrate. Administration of
ª 2011 Adis Data Information BV. All rights reserved.
Knadler et al.
duloxetine with metoprolol, a CYP2D6 substrate, increased the
metoprolol Cmax and t½ and decreased its clearance, leading to
a 180% increase in metoprolol AUC.[52] This increase in AUC
was found to be greater than the increase in the AUC for me-
toprolol caused by escitalopram (89%) or sertraline (48% and
67%). However, the baseline metoprolol concentrations were
lower prior to dosing with duloxetine than with either escita-
lopram or sertraline, which may have resulted in the percent
change in metoprolol concentrations with duloxetine being
unusually high.[52] In general, escitalopram is considered a
weak inhibitor of CYP2D6, sertraline is considered a mild to
moderate inhibitor of CYP2D6 and duloxetine is considered a
8 10 12 14 16 18 20
Collectively, results from these drug interaction studies with
Time (d)
three CYP2D6 substrates (desipramine, tolterodine and me-
toprolol) indicate that duloxetine is a moderately potent in-
hibitor of CYP2D6. Therefore caution is advised when
duloxetine is co-administered with drugs that are extensively
metabolized by CYP2D6 and have a narrow therapeutic index,
including certain tricyclic antidepressants (e.g. nortriptyline,
amitriptyline and imipramine), phenothiazines and certain type
1C antiarrhythmics (e.g. propafenone and flecainide).
Atypical antipsychotics and antidepressant drugs such as
duloxetine are commonly co-administered.[53-55] Some of the
antipsychotic drugs such as risperidone and aripiprazole are
CYP2D6 substrates, so co-administration with duloxetine may
result in higher plasma concentrations of these antipsychotics,
but not for other antipsychotics such as olanzapine and que-
tiapine which are not CYP2D6 substrates.
5.2.2 Effects on CYP1A2 Substrates
The pharmacokinetics of theophylline, a CYP1A2 substrate,
were not significantly affected by duloxetine in either men or
women.[24] Further, duloxetine did not have any effect on the
urinary metabolite profiles of theophylline. As duloxetine does
not appear to be a clinically significant inhibitor or inducer
of CYP1A2, dose adjustment of CYP1A2 substrates is not
necessary when such drugs are co-administered with duloxetine.
5.3 Pharmacodynamic Interactions
The possibility for a potentially clinically relevant pharma-
codynamic interaction may be assessed by examining the
known pharmacology of each drug being considered for co-
administration. The adverse events reported at the highest rate
during duloxetine use are consistent with the known pharma-
cology of duloxetine rather than specific to an indication.[6]
Therefore the possibility for additive adverse effects warrants
Clin Pharmacokinet 2011; 50 (5)
Duloxetine Pharmacokinetics and Drug Interactions
caution when other drugs are co-administered with duloxetine.
Across indications, common adverse events reported with du-
loxetine use include nausea, headache, dry mouth, insomnia,
constipation, dizziness, fatigue, somnolence, diarrhoea and
hyperhidrosis.[6,32]
Consistent with its adrenergic pharmacology, duloxetine
produces modest increases in blood pressure and pulse rates[56]
that may be clinically important when duloxetine is used in
combination with another drug that produces similar effects.
Particularly important to consider in this regard are other
serotonergic drugs, which might potentiate a pharmacodyna-
mic interaction and serotonin syndrome, as described below.
Since there is a possibility for orthostatic effects with dulox-
etine,[6,56] caution is warranted for combined use of duloxetine
with agents, such as diuretics, that might exacerbate this effect
in some patients.
Electrocardiogram evaluations in clinical studies and a
thorough QT study at supratherapeutic dosages indicate that
duloxetine has no adverse effect on cardiac repolarization.[57,58]
Therefore it is unlikely that duloxetine would increase the risk
for torsades de pointes when used with a concomitant QT-
prolonging drug.
Because of the pharmacology of duloxetine as a central
nervous system (CNS)-acting drug, or because of concern
for a potential pharmacokinetic/pharmacodynamic interaction,
specific studies with benzodiazepines, alcohol and warfarin
have been conducted to evaluate a pharmacodynamic inter-
action with duloxetine.
5.3.1 Benzodiazepines
The potential for a pharmacodynamic interaction with
benzodiazepines was investigated using lorazepam, a drug that
is metabolized primarily via glucuronidation rather than via
CYPs. The primary finding of this investigation was increased
sedation on subjective and objective tests in subjects who re-
ceived co-administration of lorazepam and duloxetine.[59] Due
to the potential for increased CNS effects when duloxetine is
co-administered with other CNS-acting drugs such as the benzo-
diazepines, caution should be used when co-administering
duloxetine with other CNS-acting drugs.[32]
5.3.2 Alcohol
The pharmacodynamic effect of the combination of dulox-
etine and alcohol was assessed in male and female subjects
administered 60 mg of duloxetine alone, alcohol alone and
duloxetine with alcohol (blood alcohol level of approximately
0.1 g/dL).[60] Pharmacodynamic assessments included computer-
based performance tests and self-administered questionnaires.
ª 2011 Adis Data Information BV. All rights reserved.
291
Alcohol alone decreased performance on six of nine psycho-
metric tests and the addition of duloxetine did not exacerbate
the cognitive and psychomotor impairment produced by alco-
hol. Because it is possible that duloxetine and alcohol may in-
teract to cause liver injury or that duloxetine may aggravate
pre-existing liver disease, duloxetine should ordinarily not be
prescribed to patients with substantial alcohol use or evidence
of chronic liver disease.[32]
5.3.3 Anticoagulant Drugs
Recent reports have suggested an interaction between du-
loxetine and anticoagulant drugs, leading to unexpected al-
terations in the international normalized ratio (INR). In one
case, a 63-year-old woman on stable acenocoumarol therapy
experienced a decrease in INR values from 2.58 to 1.49 after
taking a single 60 mg dose of duloxetine.[61] The INR values
remained low for 3 weeks after discontinuation of duloxetine,
and then returned to baseline. In another report, a 44-year old
woman taking stable warfarin therapy experienced an increase
in INR after initiating daily therapy with duloxetine 30 mg and
the INR increased even further after warfarin was dis-
continued. Upon discontinuation of duloxetine, INR decreased
and warfarin treatment was reinstated.[62] Based on the differ-
ing metabolic pathways of duloxetine and warfarin (primarily
via CYP2C9), a pharmacokinetic interaction does not seem a
likely explanation for these changes in INR values.
Given the known effects of serotonin inhibitors on platelet
aggregation which could lead to an increased risk of bleeding[63]
and the involvement of serotonin in the mechanism of action
for duloxetine, a pharmacodynamic interaction between du-
loxetine and warfarin was considered possible prior to the
conduct of a drug interaction study to determine the impact of
duloxetine on INR. Duloxetine 60 mg/day or 120 mg/day was
co-administered daily with warfarin for 14 days to healthy
subjects who had a stable INR with an individualized dose of
warfarin (2–9 mg) prior to the combined dosing period. The
INR was determined daily during co-administration of duloxetine
and warfarin and duloxetine had no statistically or clinically
significant effect on the anticoagulant effects of warfarin.[64] In
addition, duloxetine did not affect the pharmacokinetics of
either R- or S-warfarin. Since study results show neither a
pharmacokinetic interaction nor a pharmacodynamic inter-
action between duloxetine and warfarin, a clear explanation of
the changes in INR in the two case reports cannot be made.
5.3.4 Serotonin Syndrome
The combined use of serotonergic drugs with duloxetine has
the potential for additive pharmacodynamic effects that could
Clin Pharmacokinet 2011; 50 (5)
292
lead to serotonin toxicities.[65] A case is reported of serotonin
syndrome in a patient on duloxetine treatment when linezolid,
an antibacterial that inhibits monoamine oxidase, was co-
administered.[66] While the patient was on multiple other
medications for treatment of sarcoma of the lower extremity,
the authors attributed the serotonin syndrome to linezolid due
to its inhibition of monoamine oxidase. In another case report,
a patient who had been on long-term treatment with moclo-
bemide (300–600 mg/day) discontinued moclobemide treat-
ment (600 mg/day) and began taking duloxetine (60 mg/day) the
next morning. Shortly after the first duloxetine dose, the patient
began to experience intense restlessness, generalized tremor,
dizziness, nausea, headache and tic-like facial movements. On
the second day of duloxetine dosing the patient experienced an
increase in blood pressure. The patient’s symptoms were gone
within 2 days following discontinuation of duloxetine.[67]
Duloxetine should not be co-administered with monoamine
oxidase inhibitors or other serotonergic drugs, including trip-
tans and drugs with secondary serotonergic properties such as
tramadol.[32] In addition, care should be taken in transitioning
patients from a selective serotonin reuptake inhibitor (SSRI)
or another selective serotonin and norepinephrine reuptake
inhibitor (SNRI) to duloxetine. Finally, because duloxetine is
approved for use in certain non-psychiatric indications such as
the treatment of stress urinary incontinence, it is important that
prescribers consider the patient’s medication profile which may
include monoamine oxidase inhibitor (MAOI), SSRI or SNRI
drugs.
6. Conclusions
Duloxetine is cleared primarily by metabolism via CYP1A2
and the resulting inactive metabolites are cleared after con-
jugation by renal excretion. Duloxetine is a moderately potent
inhibitor of CYP2D6, but does not significantly inhibit other
CYP enzymes. In comparison with SSRIs, duloxetine is a
weaker inhibitor of CYP2D6 than paroxetine and fluoxetine,
but a stronger inhibitor than escitalopram. Results from the
drug interaction studies that have been performed with du-
loxetine and information on the pharmacokinetic properties of
potential concomitant drugs may be used to inform clinical
judgement as to the potential for drug-drug interactions with
duloxetine.
Situations in which the pharmacokinetics of duloxetine are
altered to a clinically significant extent include the co-admin-
istration of duloxetine with potent CYP1A2 inhibitors, the
co-administration of CYP2D6 substrates that have a narrow
therapeutic index and the usage of duloxetine in patients with
ª 2011 Adis Data Information BV. All rights reserved.
Knadler et al.
severe renal disease or ESRD, or in patients with hepatic im-
pairment. The potential for pharmacodynamic interactions
with duloxetine include co-administration with benzodiazepines
and MAOIs.
Overall, interpatient variability in duloxetine pharmaco-
kinetics is high and a robust pharmacokinetic and pharmaco-
dynamic relationship has not been established that provides a
targeted concentration range associated with efficacy or mini-
mization of adverse events. Although some have suggested that
therapeutic drug monitoring can be conducted for dulox-
etine[68] in order to maximize therapeutic effects and minimize
side effects for an individual patient, dose adjustments should
principally be made on the basis of an individual patient’s
clinical response and known factors that impact duloxetine
concentrations. In cases where an individual patient is not re-
sponding to therapy, therapeutic drug monitoring may be
useful to identify a noncompliant patient from a nonresponder.
Acknowledgements
The authors acknowledge Ryan Wright’s contribution in providing
writing support for this manuscript.
This review was funded by Eli Lilly and Company (Indianapolis, IN,
USA), the manufacturer of duloxetine. All authors have read the manu-
script and conflict of interest statement and approved the version sub-
mitted for publication. All authors are current or former employees of Eli
Lilly and Company; Richard Bergstrom is retired from Eli Lilly and
Company and now works at Butler University College of Pharmacy (In-
dianapolis, IN, USA). All authors are stock owners in Eli Lilly and
Company and have participated in the development of duloxetine.
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Correspondence: Mary Pat Knadler, PhD, Eli Lilly and Company, Lilly
Corporate Center, Indianapolis, IN 46285, USA.
E-mail: Knadler_Mary_Pat@lilly.com
Clin Pharmacokinet 2011; 50 (5)