Effects of Obesity on pharmacokinetics
1
Review
‫ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
Effects of Obesity on Pharmacokinetics
Hanadi S. Al- Addam
Abstract
Obesity is a worldwide problem, with major health, social and
Economic implications. The adaptation of drug dosages to obese
Patients are a subject of concern, particularly for drugs with
narrow therapeutic index. The main factors that affect tissue
distribution of drugs are body composition, regional blood flow
and affinity of drug for plasma proteins and/or tissue components.
This review analyses recent publications on several classes of
drugs: antibacterial, anticancer drugs, psychotropic drugs,
anticonvulsants, and drugs commonly used in the management of
obesity. The dosage of these drugs should be based on the ideal
body weight (IBW). However, some of these drugs (e.g.,
antibacterial and some anticancer drugs) are partly distributed in
adipose tissues, and their dosage is based on IBW plus a
percentage of the patient’s excess body weight.
Our present knowledge of the influence of obesity on drug
pharmacokinetics is limited. Drugs with small therapeutic index
should be used prudently and the dosage adjusted with the help of
drug plasma concentrations.
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Introduction
Obesity is considered a worldwide
concern, and in 1998, the World Health
Organization (WHO) published a report on
preventing and managing the global
epidemic. Obesity is a disease characterized
as a condition resulting from the excess
accumulation of body fat. As consequence,
obese
individuals
generally
require
intervention that is more therapeutic earlier
in life than non-obese individuals do. A very
important consideration for pharmacological
treatment of obese individuals is the possible
discrepancies between obese and non-obese
individuals in pharmacokinetic and/or
pharmacodynamic activities of drug.
The
international
recommended
classification of obesity recently published
by the WHO]1[ is based on the body mass
index (BMI), calculated as bodyweight (in
kg) divided by the square of the height in
meters. Overweight is defined as a BMI ≥25
to 29.9 kg/m2 and obesity as a BMI
≥30kg/m2. Obesity is divided into 3 classes:
moderate (BMI 30.0 to 34.9), sever (BMI
35.0 to 39.9) and morbid (BMI ≥ 40.0).
To present a clear overview,
analysis of pharmacokinetic information is
preceded
by
factors
affecting
pharmacokinetics
in
obesity.
The
implications for therapy with each of the
drug classes studied are considered.
Factors Affect Pharmacokinetics in
obese:
Obesity and Drug Absorption: The effect of
obesity on absorption and overall
bioavailability is poorly understood. Overall,
Effects of Obesity on pharmacokinetics
studies indicate no significant difference in
absorption between obese and lean subjects.
Obesity and Drug Distribution:
the volume of distribution of a drug is
dependent on a number of factors including
tissue size, tissue permeability, plasma
protein binding, and the affinity of drugs for
a tissue compartment.]2[ These factors can
be affected by the physical and chemical
properties of a drug in addition to the
presence of many disease states. Obesity is a
disease state associated with changes in
plasma protein binding constituents.]3,4[ and
increases in adipose tissue mass and lean
body mass,]5[ organ mass,]6,7[ cardiac
output,]8[ cardiac size and blood volume, and
splanchnic blood flow relative to normalweight individuals.
A general trend has been observed for
predicting changes in volume of distribution
in obese subjects. Increasingly lipophilic
substances, based upon lipid partitioning
coefficients
(LPC).
Are
generally
increasingly affected by obesity. Less
lipophilic compounds, with lower LPCs,
generally have a little to no change in
volume of distribution with obesity. There
are exceptions to this generalization :
cyclosporine, a highly lipophilic compound
with a relatively large volume of
distribution, has been shown in separate
experiments to have comparable absolute
volumes of distribution (Vdss) in both and
normal weight individuals.]9,10[
Plasma protein binding is an important
determinant of a drug pharmacokinetics.
Changes in the concentrations of plasma
binding protein or alterations in the affinity
of plasma protein for substrate could affect
the movement of drug into tissue
compartments. The major plasma proteins
are albumin, primarily responsible for
binding acidic drugs, α1-acid glycoprotein
(AAG), primarily responsible for binding
basic drugs, and lipoproteins. Studies have
shown that drugs primarily bound by
albumin show no significant changes in
protein binding in obese individuals.
Concentrations of AAG were more recently
shown to be slightly higher in obese
2
individuals than in normal-bodyweight
individuals, it should be emphasized that
the amount of a drug in the plasma depends
on the balance between the affinities of the
drug for plasma protein and tissue binding
cannot be measure directly in the clinical
setting. Due to higher triglyceride and
cholesterol levels common in obesity,
lipoprotein levels may be elevated in obese
individual; however the ramifications of
elevated lipoprotein levels has been poorly
studied and is not well understood to date.
The clearance of drugs can also be
affected by obesity, though increases in
clearance do not necessarily reflect changes
in half-life of a drug. The half-life of a drug
can be related to both volume of distribution
and clearance through the following
relationship:
t1 / 2  Vd 0.693
CL
The half-life of a drug may increase
without changes in clearance. Whenever the
volume of distribution in obese got increase.
Obesity and Drug Clearance:
Changes in Metabolic Enzymes in Obese Humans: The
liver of obese individuals frequently suffer
from fatty infiltration, one form of which is
nonalcoholic steatohepatitis.]11[ These lesion
could significantly influence the metabolic
activity of the liver. It is difficult to measure
the hepatic metabolism of drugs in humans.
There is no clear correlation between routine
liver function tests and the capacity of the
liver to metabolize drugs, but some
chemicals can be used as markers to assess
enzyme activities. Antipyrine has been used
as a marker of hepatic oxidative metabolism
in obese and normal individual; the systemic
clearance remained unchanged in the obese
group, suggesting that the hepatic oxidative
metabolism of drugs is not modified in
obesity.]12[
The 6-hydroxylation of chlorzoxazone has
been used as a probe the activity of hepatic
cytochrome P450(CYP) 2E1, which is
Effects of Obesity on pharmacokinetics
involved in the activation of carcinogens and
metabolism of drugs such as enflurane.]13[
Obesity resulted in a significant increase in
the clearance of chlorzoxazone as well as
increase formation clearance of the
hydroxylated metabolite. The authors
concluded that obese individual might be
increased risk of CYP2E1-mediated toxicity
of environmental agents.
The formation of N-methyl-erythromycin
has bee shown to provide a general marker
for cytochrome P450 3A activity in
humans,]14,15[ it was found negative
correlation existed between percent IBW
and N-methyl-erythromycin production.
This finding suggests that specific CYP3A
isoforms may be decreased in obesity.
However, the diversity of data obtained
from these studies underlines the difficulty
of obtaining a clear overview of drug
hepatic metabolism in obesity.
Another interesting consideration in
determining the metabolic activity of obese
individuals is considering changes in
metabolism in tissues other than the liver;
especially, due to the significant increase in
adipose tissue in obese individuals, changes
in metabolism within adipose tissue could be
significant. Further evidence suggests that
adipose tissue may play a role in the
increased clearance of prednisolone in obese
men.]16[ the inter-conversion of prednisolone
and prednisone is dependent on 11hydroxysteroide dehydrogenase, an enzyme
present in adipose tissue may provide an
alternative
site
off
clearance
for
prednisolone.
Changes in Renal Function in Obese
Humans:
Elimination of .drug through the kidney can
be accounted for by glomerular filtration,
tubular secretion, and tubular reabsorption;
however, articles on drug kinetics have
provided differing data on renal function in
obese individuals. Glomerular filtration is
more easily assessed than tubular function: it
is usually assessed by the creatinine
clearance (CLcr). Davis et al, shown
increases in glomerular filtration, measured
3
using creatinine clearance, in obese women
as compared to normal weight women.
Studies on ciprofloxacin,]17[
showed no
significant difference in CLcr between obese
individual and those with normal weight. In
contrast, a study on vancomycin reported a
significant increase in CLcr in morbidly
obese patients. ]18[ One possible explanation
for these different might be due to the
difference in extent of obesity and/or
associated renal pathology.
Tubular function (tubular secretion, and
tubular reabsorption) in the kidney is often
difficult to ascertain; thus, conclusions
regarding tubular function are often indirect.
Renal clearance of lithium primarily
involves glomerular filtration and tubular
reabsorption,]19[ consequently, the increase
in the renal clearance of lithium with no
increase in glomerular filtration,]20[ supports
decrease tubular reabsorption in obese
individuals.
Obesity and Drug Pharmacodynamics:
It is important to note that, with the plethora
of probable genetic and nutritional changes
associated with obesity, changes in receptor
expression or affinity for ligand could be
altered
resulting
in
differential
pharmacotherapeutic effects in obese
individuals as compared to lean individuals.
Pharmacotherapeutic Toxicity in Obesity:
The toxicity of substances can change with
obesity. With possible increases in
metabolism such as with CYP system.
Changes in the clearance, volume of
distribution,
bioavailability,
or
pharmacodynamics may affect the toxic
potential of a drug. Additionally, changes
In excretion, mechanism can alter the
toxicity of a compound by either increasing
exposure through decreased clearance or
vice-versa. The best approach for
pharmacotherapeutics in obese individuals
is to use previous knowledge and
conservative. Careful monitoring of the
obese
patient
is
necessary
when
Effects of Obesity on pharmacokinetics
4
administering drugs with a small therapeutic
index.
Effects
of
Obesity
on
pharmacokinetics of Drug Classes
the
1. Anti-infectives
1.1 Antibacterials
A series of pharmacokinetic studies were
done
with
moderately
lipophilic
antibacterials to optimized dosages in obese
individuals (table 1). An initial study after a
single administration of vancomycin showed
that the volume of distribution at steady
state (Vss) and CL were significantly higher,
and elimination half-life (t1/2 β) shorter. In
six morbidly obese patients than four nonobese individuals. It was concluded that
TBW should be used to determine
vancomycin dosage.]23[
Regression analysis revealed that TBW
and the percentage over LBW were
significant predictors of Vd . TBW was
predictive for total CL, and percentage over
LBW was a predictor of t1/2 β . Thus, TBW
appears to be better for calculating the initial
dose of vancomycin. Further dosages should
be guided by serum concentrations of the
drug.
The principle pharmacokinetic change in
obese patients was a clear increase in the CL
of vancomycin, which was positively
correlated with TBW. However, the values
were similar in obese and normal
bodyweight individuals when TBW was
used to normalize CL. ]21[
The Vss of ciprofloxacin was significantly
larger (by 23%) in obese individuals than
controls, but it was lower when normalized
to the total TBW. These findings indicate
that the antibacterial is distributed less in
adipose tissue than in other tissue. To
normalized obese Vss/kg to the controls,
45% of excess bodyweight (TBW-IBW)
must be added to the IBW of obese
individuals. The authors concluded that the
ciprofloxacin dosage should be based on the
IBW plus 45% of the excess body weight.]19[
The initial doses of aminoglycosides are
usually based on CLcr , most frequently
evaluated by the Cockroft-Gault equation1
taking into account the serum creatinine,
age, TBW and gender.]25[ The calculation
in obese patients leads to the overestimation
of CLcr
when TBW is used, and
underestimation when IBW is used.
Salazar and Corcoran developed another
equation based on the fat-free body Mass.]23[
Table 1 Pharmacokinetic parameters for antibacterials administered to obese and non-obese individual
Vd(L)
Drug
control
obese
Vd(L/kg TBW)
control
obese
Cl[L/h(ml/min)]
control
obese
t1/2 β(h)
control
obese
Recommendations
for
dosage
in
obese patients
Reference
Dose based on TBW, 18
as Vd and CL are
correlated with TBW
Daily dose/kg TBW 21
46
52
0.68
0.32*** 4.62(77)
11.8(197)*
7.2
3.3
similar to controls if
patient has normal
renal function
Calculation on IBW+ 17
269*
3.06
2.46*** 44.6(744) 53.8(897)*
4.0
4.2
Ciprofloxacin 219
45%
of
excess
bodyweight
Initial dose based on 22
16.7
18.2
4.01(66.9) 4.63(77.2)
3.3
3.1
Gentamycin
calculation of CLcr by
Cockroft equation with
IBW+0.4×(TBW-IBW)
CL= total body clearance; CLcr= creatinine clearance; IBW= ideal body weight; t1/2 β = terminal elimination half-life; TBW= total body weight; Vd=apparent
volume of distribution; *p<0.05;**p<0.01;***p<0.001.
1 CLcr= (140-age) × TBW/(A) × serum creatinine where age is in year, TBW is in Kg, and A=72 for men and 85 for women.
Vancomycin
28.9
43.0*
0.39
0.26*
4.85(80.8)
11.25(187.5)*
4.7
3.2**
Effects of Obesity on pharmacokinetics
Regression analysis indicated that the
Cockroft equation using weight as
IBW+0.4× (TBW-IBW) was the best of the
methods tested for calculating CLcr ,and thus
predicting Gentamycin pharmacokinetic
values.
1.2 Antifungal Agents
No pharmacokinetic study or guideline for
drug administration is available for this drug
group in obese patients. The currently
recommended treatment for Candida albicans
in patients with invasive disease is peak
serum
concentrations
greater
than
25mg/L.]25[ Thus, a higher dosage of
fluconazole was recommended for obese
patients.
2. Anticancer Drugs
Many anticancer drugs are relatively lipid
insoluble and may be poorly distributed in
adipose tissue. Their elimination may also
be altered in obese patients.
The pharmacokinetics of ifosfamide were
studied in 16 patients with bronchial
carcinoma.]26[ There was a positive
correlation between the Vd in the terminal
phase and the percentage of IBW, implying
that drug can be distributed in body fat.
Doxorubicin undergoes extensive hepatic
metabolism by aldoreductases that convert
the drug to doxorubicinol, which also
possesses
cytotoxic
properties.
The
pharmacokinetics were investigated in 21
adults with cancer, 7 of whom where obese
and seven severely obese.]27[ Obesity reduce
the CL of doxorubicin by inhibiting the
aldoketoreductases. However, the number of
patients was considered too small to propose
specific dosage guidelines.
Carboplatin is mainly eliminated via the
kidney. Bènèzet et al.]28[ studied the
accuracy of a formula for predicting CL
from patients-specific variables (serum
creatinine, bodyweight, age and gender) in
25 obese patients. CL over-predicted by
more than 20% for seven patients using the
TBW, and IBW led to un-prediction. The
5
best predictor was the mean value between
IBW and TBW[i.e., IBW+0.512× (TBWIBW)]; the percentage error was -22% to +
22%.
Most studies were done on a small number
of patients with a
particular type of
malignancy and who were treated with
specific chemotherapy regimens. Therefore,
the conclusions drawn by the authors are
cautious and mention the importance of
determining target plasma concentrations.
3. Drugs Used for Diseases of
the Central Nervous System
Only seven studies have investigated the
effects of obesity on the disposition of
central nervous system drugs.
3.1 Psychotropic Drugs
The efficacy of lithium in patients with
bipolar illness and its narrow therapeutic
window warrant consideration in obesity.
Studies on obese and normal body weight
individuals showed that Vss of lithium was
significantly correlated with IBW and fatfree-mass, and that Vss/kg was significantly
smaller in obese individuals. The CL of
lithium was significantly greater in the obese
individuals than in control group, although
CLcr had similar values in the two groups.]20 [
The results of this study suggest that the
loading dose for obese patients should be
based on IBW, and that a large maintenance
dosage is required to obtain an adequate
serum concentration in obese patients than
in lean patients.
3.2 Anticonvulsants
The loading doses of phenytoin required
for obese, control individuals were
determined after a single intravenous
infusion. [29] The t1/2 β of phenytoin was
significantly prolonged in the obese group,
and the metabolic CL tended to be
increased. Vd was positively correlated with
the percentage of IBW. The authors
concluded that phenytoin-loading dose
Effects of Obesity on pharmacokinetics
6
should be calculated based on IBW plus the
product of 1.33 times the excess bodyweight
over IBW.
4.Dugs Used in Anesthesiology
Few studies have investigated the effects
of obesity on the disposition of anesthetics
(table 2) .
IBW) and matched control patients. Vd and
t1/2 β were significantly increased in obese
patients in the sufentanil study.]31[ The Vd
was correlated positively with the degree of
obesity. This indicates that the drug was
distributed at least as extensively in the
excess body mass as in the lean tissues, and
that the loading dose should account for
total body mass.
4.3 Neuromuscular Blockers
4.1 General Anesthetics
The great lipophilicity of propofol and the
rather long duration of infusion used to
maintain general anesthesia are rational for
pharmacokinetic studies in morbidly obese
patients.]29[ Comparison with non- obese
controls showed that the CL and Vss of
propofol was significantly correlated with
TBW in the obese group, so that the values
of t1/2 β in non-obese and obese individuals
were similar. These pharmacokinetic data
suggest that the maintenance dosage of
propofol for
obese patients
may,
theoretically, be established on the same
basis as for lean patients, taking into account
the TBW.
4.2 Opioids
The systemic Opioids analgesics, fentanyl
congeners such as sufentanil is used in
anesthesiology. Because of their high lipid
solubility, their pharmacokinetics have been
studied in very obese (>60 to 80% over
A study on 9 obese and 9 non-obese
surgical patients receiving vecuronium
0.1mg/kg TBW showed that the Vss , CL and
t1/2 β were similar for both group.]32[ The
main difference was in the duration of
action, which was prolonged in obese
patients because of the excess dose
administered as a result of the drug being
administered on the basis of TBW.
Therefore, IBW should be used to calculate
doses of vecuronium in obese patients.
Conclusion
Regardless of the importance of published
studies on pharmacokinetics in obesity, they
have limitation. The number of patients and
interindividual variations hamper the
assessment of the results, and may lead to
Table 2 Pharmacokinetics of drugs used in anesthesiology in obese and non-obese patients
Vd(L)
Vd(L/kg TBW)
Cl[L/h(ml/min)]
t1/2 β(h)
Recommendations
Drug
control obese control obese control
obese
control obese for dosage in
Reference
obese patients
Propofol
13.0
17.9
2.09
1.8
1.70(28.3)
1.46(24.3)
4.1
4.05
MD based on TBW
30
LD based on TBW
31
,MD reduced
**
Dosage
calculated
on
44.7
0.99
0.47
19.5
15.6
2.2
2.0
Vecuronium 59.0
32
IBW basis
CL= total body clearance; CLcr= creatinine clearance; IBW= ideal body weight; LD= loading dose; MD=maintenance dosage;t1/2 β = terminal elimination halflife; TBW= total body weight; Vd=apparent volume of distribution; *p<0.05;**p<0.01;.
Sufentanil
346
547*
4.8
5.8
1.51(25.2)
1.25(20.8)
2.2
3.4*
Effects of Obesity on pharmacokinetics
differences between studies. It is important
to bear in mind that each drug may behave
differently, and that our present knowledge
of the influence of obesity on
pharmacokinetics is limited.
A safe therapeutic protocol for obese
individuals should be based upon existing
therapeutic information as well as careful
monitoring
of
the
patient
during
pharmacologic intervention.
7
14.
15.
16.
17.
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‫‪Pharmacokinetics and pharmacodynamics of‬‬
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