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Current Drug Metabolism, 2018, 19, 960-969

REVIEW
ARTICLE
ISSN: 1389-2002
eISSN: 1875-5453

Current
Drug
Hypoxia Plays a Key Role in the Pharmacokinetic Changes of Drugs Metabolism
Impact
Factor:
2.655

at High Altitude The international

journal for timely

in-depth reviews

on Drug Metabolism

BENTHAM
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Xuejiao Zhou1, Yongqiong Nian2, Yijie Qiao3, Meng Yang2, Yuanyao Xin2 and Xiangyang Li1,*
1
State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, China; 2Department of Resources of Biology,
College of Eco-Environmental Engineering, Qinghai University, Xining, China; 3Department of Pharmacy, Medical College, Qing-
hai University, Xining, China
Abstract: Background: Hypoxia can alter the Pharmacokinetic (PK) characteristics of drugs, thereby affecting drug
absorption, distribution, metabolism, and excretion. Environmental characteristics at high altitude include but are not
limited to hypobaric hypoxia, low temperature, high solar radiation, and arid climate, all of which can adversely
affect normal bodily functions. Therefore, it is important to study the pharmacokinetic changes of drugs at high altitude.
Method: A systematic review of published studies was carried out to investigate the effects of hypoxia on the meta-
bolic characteristics of some drugs and the activity and expression of drug-metabolizing enzymes in high-altitude
hypoxic environments, and discussed the relevant mechanisms.
ARTICLE HISTORY Results: The metabolism of most drugs decreases in high-altitude hypoxia, whereas Mean Residence Time (MRT),
Received: January 02, 2018 Half Time (T1/2), and Area Under the Curve (AUC) increase and Clearance (CL) decrease in this environment. The
Revised: March 08, 2018 effect of hypoxia on CYP450 enzymes in animals is still a subject of debate. With the exception of CYP2C11 and
Accepted: March 19, 2018 CYP2C22, the widespread belief is that high-altitude hypoxia decreased the activity and expression of CYP1A1,
DOI: CYP1A2, CYP2E1, and CYP3A1, and increased those of CYP3A6 and CYP2D1 in rats. The changes in the activity
10.2174/1389200219666180529112913 and expression of drug metabolizing enzymes are consistent with the changes in pharmacokinetics of some enzyme
substrates in the high-altitude hypoxia environment.
Conclusion: The findings of this review have indicated that hypoxia may play a key role in the PK changes of drugs
Current Drug Metabolism

at high altitude. It is suggested that patient living at or traveling to high altitude should be closely monitored, and the
dosages of some drugs metabolized should be reduced.
Keywords: High altitude, hypoxia, pharmacokinetics, drug metabolism, drug-metabolizing enzyme, mechanism.
1. INTRODUCTION
Plateaus are large areas of land that usually exceed 1,000 m,
and are characterized by steep slopes, vast area, and wide terrain. It
is generally recognized that particular physiological responses oc-
cur at above 1,500 m in altitude. Plateau conditions are character-
ized by hypoxia, low pressure, low temperature, strong wind, and
dry air, all of which can adversely affect normal bodily functions.
High-altitude hypoxia is classified into light hypoxia (1,500-2,500
m), moderate hypoxia (2,500-4,500 m), and severe hypoxia (4,500-
5,500 m) according to sea level height. The higher the altitude, the
lower the atmospheric pressure and available oxygen. The decrease
in partial pressure of oxygen in the atmosphere at high altitude,
resulted in decreased oxygen dispersed into the blood via pulmo-
nary alveoli, as well as a decrease in arterial partial pressure and
saturation of oxygen, leading to hypoxemia and histanoxia [1].
Hypoxia-induced fluctuations in organism function, metabolism,
and structure are the pathological basis of disease at high altitude.
High-altitude hypoxic environments significantly affect the
circulatory, nervous, and endocrine systems, as well as metabolism,
which in turn cause changes in bodily functions such as metabolism
and growth. This leads to altitude sickness including acute altitude
stress, pulmonary edema, encephalopathy, chronic polycythemia,
and cardiovascular disease [2, 3]. Hypoxia causes a range of effects
on bodily functions and metabolism, and the degree and conse-
quence of which are determined by its speed of entry into the pla-
teau, residence time at high altitude, and body metabolic status. A
slow adjustment to high altitude is typically followed by compensa-
tory reactions, whereas a rapid adjustment gives rise to metabolic
impairment and systemic disease [4, 5].
Studies of high-altitude hypoxia have focused on prevention,
nutrition, and adaption [6, 7]. However, since the 1980s, close
*Address correspondence to this author at the State Key Laboratory of Pla-
teau Ecology and agriculture, Qinghai University, Xining 810016, China.
Tel: (86-971)536 2083. Fax: (86-971)536 2383. E-mail: qhmclxy@163.com
attention has also been paid to the effects of hypoxia on drug me-
tabolism, which are mostly physiological but can also be pathologi-
cal. Both of these effects influence drug absorption, distribution,
metabolism, and excretion, leading to changes in the pharmacoki-
netic (PK) characteristics of drugs [8-10]. Human activities at high
altitude have increased in recent years; thus, rational drug use in
hypoxic conditions has been the subject of debate.
This review summarized the effects of high-altitude hypoxia on
drug metabolism, elaborated on the metabolic characteristics of
some drugs and the activity and expression of drug-metabolizing
enzymes in this environment, and investigated the relevant mecha-
nisms, with the goal of providing information about rational drug
use at high altitude.
2. DRUG PHARMACOKINETICS UNDER HYPOXIA
People traveling to high altitudes for sport, as tourists or for
military and other reasons are usually healthy and fit, but some-
times use drugs for common ailments like influenza, acute, and
chronic high-altitude sickness. Lower oxygen levels at high altitude
may compromise the metabolism of drugs. High-altitude hypoxia
affects drug PK, which may influence treatment decisions as drug
metabolism in vivo requires oxygen. Thus, when the hepatic meta-
bolic capacity of the liver is limited in hypoxic conditions, drug
biotransformation and clearance are modified. Powell et al. [11]
found that patients with the chronic obstructive pulmonary disease,
pulmonary edema, pulmonary cardiopathy, or cardiac failure main-
tained a low level of systemic clearance (CL), with a reduction of
30–60%. These diseases are all hypoxia-related; hence, we specu-
lated that decreases in theophylline CL are due to low oxygen lev-
els. These findings were subsequently confirmed, and the CL of
theophylline was shown to decrease by 25.7% in rabbits under
acute hypoxia [12, 13]. Du Souich [14] found that acute hypoxia did
not alter diltiazem disposition; however, the CL and Volume of
Distribution (Vd) were significantly decreased in dogs subjected to
a fraction of inspired oxygen (FiO2) of 8% for 120 h compared with
dogs breathing 21% FiO2.

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Hypoxia Plays a Key Role in the Pharmacokinetic Changes of Drugs at High Altitude Current Drug Metabolism, 2018, Vol. 19, No. 11 961

Acute hypoxia increased the area under the curve (AUC), mean
residence time (MRT), half-life (T1/2), and peak concentration
(Cmax) of propranolol in rats after exposure to an altitude of 4,010
m, but apparent clearance (CL/F) and Vd were significantly de-
creased [15]. High-altitude hypoxia also altered metoprolol disposi-
tion, and the AUC, Vd, and C max were significantly decreased, but
the MRT, CL/F, and T1/2 were significantly increased in rats after
exposure to an altitude of 4,010 m [16]. When rats ascended to
4,300 m, the AUC, MRT, and Cmax of amoxicillin significantly
increased, but the CL/F was significantly reduced [17]. Anjana et
al. [18] found that the T1/2 of gentamicin, acetlysalicylic acid, aceta-
zolamide, and phenobarbitone was increased in rabbits through
simulations of acute hypoxia, which was equivalent to 4,572 m in
altitude, whereas the elimination rate constant (Ke) decreased for
each drug. The MRT and T1/2 of ibuprofen in rats were significantly
increased by 42% and 51%, respectively, at an altitude equivalent
to 7,620 m above sea level [19]. Du Souich [20] studied the effects
of hypercapnia and/or hypoxemia on the kinetics and concentra-
tions of phenytoin in the cerebrospinal fluid of conscious rabbits
and found that the CL of phenytoin decreased by 36.9% and the
AUC increased by 67.6% in hypoxemic rabbits.
Due to differences in drug-metabolizing enzymes, metabolic
pathways, and drug metabolites between animals and humans, incon-
sistent results can be obtained when studying metabolism in a high-
altitude hypoxic environment. Some drugs decrease CL and others
increase CL; in fact, even the same drug can behave differently in
conditions of acute and chronic hypoxia. After volunteers from the
plain ascended to 4,500 m, the CL of theophylline and verapamil was
unchanged, suggesting that acute hypoxia had no effect on either drug
[21]. However, our group found significant changes in the disposition
of sulfamethoxazole in healthy male subjects after acute or chronic
exposure to an altitude of 3,780 m compared to those residing at an
altitude of 400 m. The T1/2 was 11.5% and 19.9% higher in the acute
and chronic exposure groups, respectively, compared with the low
altitude group. The CL/F was 17.8% and 8.9% lower in the acute and
chronic exposure groups, respectively, compared with the low alti-
tude group [8]. Arancibia et al [9, 22] studied the PK of furosemide
and prednisolone in volunteers from the plain, who had ascended to
3600 m and lived there for 6 months. The data indicated that for both
acute and chronic hypoxia, the Cmax of furosemide decreased and the
T1/2 and CL/F increased. The MRT, AUC, and Vd for furosemide
under acute hypoxia were reduced, but the MRT, AUC, and Vd for
chronic hypoxia were increased. Acute and chronic high-altitude
hypoxia increased the AUC of prednisolone by 12.8% and 13.5% and
the Cmax by 16.9% and 14.1%, respectively. On the other hand, acute
and chronic high-altitude hypoxia decreased the Vd by 20.4% and
15.6% and the CL/F by 25.2% and 15.6%, respectively. A study on
lithium carbonate demonstrated that the T1/2 increased by 64.1% and
111.4% in volunteers after acute and chronic exposure to high alti-
tude, respectively, compared to volunteers residing at low altitude. It
was also found that the Vd increased by 18.9% and 35.8% and the
MRT increased by 79.3% and 139.6% in acute and chronic hypoxia
groups, respectively. On the other hand, acute and chronic high- alti-
tude hypoxia decreased CL/F by 24.3% and 37.3%, respectively [23].
A study that evaluated the effects of high altitude on meperidine
demonstrated that the CL/F was significantly lower and the T1/2 and
MRT were significantly higher at high altitudes than at sea level [24].
One clinical study suggested that, in addition to age, sex, diet, fitness
level, the length and degree of hypoxia also contribute to high-
altitude hypoxia-induced drug metabolic changes [10].
Racial differences can influence the safety, efficacy, dose, and
dosage regimen of drugs, and in high-altitude hypoxic environ-
ments, additional differences can influence these drug characteris-
tics. Our study showed that the AUC of sulfamethoxazole was sig-
nificantly lower in native Tibetan than in native Han subjects living
at high altitude, but other PK parameters were not significantly
different between the two groups [25, 26]. The PK parameters of
lidocaine hydrochloride were significantly changed in native Han
and Tibetan subjects living at high altitude compared to Han sub-
jects living at low altitude. The T1/2, Vd, and AUC were higher in
the two high-altitude groups than in the low altitude group. How-
ever, there was no significant difference between native Han and
Tibetan subjects living at high altitude [27].
In brief, the metabolism of most drugs decreases in high-
altitude hypoxia, whereas the MRT, T1/2, and AUC increase and the
Ke and CL decrease in this environment. Table 1 shows the
changes in PK of different drugs at hypoxia.

Table 1. Changes in pharmacokinetics of different drugs at hypoxia.

Drug; Dosing
Species Model; Method Used Effects References
Route

Theophylline; acute exposure to air (con-

CL decreased from 1.52 ± 0.05 ml/min/kg in control to 1.13 ± 0.13 in hy-
trol) or to a high CO2 and/or
Rabbit Intravenous percapnia, 1.09 ± 0.09 in hypoxemia, and 1.02 ± 0.02 in hypoxemia com- [13]
low O2 atmosphere for 570
injection bined with hypercapnia.
min; HPLC.

Diltiazem; acute or chronic exposure to Acute hypoxia did not alter diltiazem disposition; chronic hypoxia reduced
Dog Intravenous a FiO2 of 8% for 1 h or 120 diltiazem CL from 64 ± 3 to 51 ± 5 ml/ min/kg, and Vd decreased from 11.4 [14]
injection h; HPLC. ± 1.2 to 9.1 ± 0.3 L.

AUC increased from 11.17 ± 1.38 μg·h/L to 60.61 ± 6.31 after acute expo-
Propranolol; acute exposure to high
sure to high altitude; T1/2 increased from 0.67 ± 0.11 h to 1.09 ± 1.53; MRT
altitude (4,010 m) from low
Rat Oral administra- increased from 0.92 ± 0.10 h to 1.44 ± 0.24; CL/F decreased from 141.49 ± [15]
altitude (50 m); LC-
tion 17.30 L/h/kg to 27.06 ± 3.69; Vd decreased from 131.44 ± 11.05 L to 40.82
MS/MS.
± 4.00; Cmax increased from 10.61 ± 0.93 μg/L to 48.06 ± 11.91.

AUC decreased from 6.94 ± 0.79 μg·h/ml to 5.87 ± 1.01 after acute expo-
Metoprolol; acute exposure to high
sure to high altitude; T1/2 increased from 1.25 ± 0.33 h to 2.97 ± 1.53; MRT
altitude (4,010 m) from low
Rat Oral administra- increased from 2.14 ± 0.11 h to 3.16 ± 0.32; CL/F increased from 0.56 ± [16]
altitude (50 m); LC-
tion 0.06 L/h/kg to 1.75 ± 0.28; Vd decreased from 1.00 ± 0.29 L to 0.67 ± 0.11;
MS/MS.
Cmax decreased from 2.49 ± 0.26 μg/ml to 1.60 ± 0.31.

Table (1) contd….

962 Current Drug Metabolism, 2018, Vol. 19, No. 11 Zhou et al.

Drug; Dosing
Species Model; Method Used Effects References
Route

Amoxicillin; acute exposure to high AUC increased from 11.62 ± 1.07 μg·h/ml to 47.878 ± 9.42 after acute expo-
altitude (4,300 m) from low sure to high altitude; T1/2 increased from 1.12 ± 0.12 h to 1.31 ± 0.23; MRT
Rat Oral administra- [17]
altitude (50 m); LC- increased from 1.51 ± 0.12 h to 2.54 ± 0.44; CL/F decreased from 1.02 ± 0.09
tion MS/MS. L/h/kg to 0.26 ± 0.05; Vd decreased from 1.64 ± 0.20 L to 0.47 ± 0.08.

exposure to hypobaric hy-

Gentamicin; poxia at 42.9 mm Hg pres- T1/2 increased from 1.80 ± 0.12 h to 1.11 ± 0.65; Ke decreased from 0.909 ±
Rabbit intraperitoneal sure equivalent to 4,572 m 0.051 to 0.389 ± 0.041; Vd increased from 163.9 ± 13.9 ml/ kg to 241.4 ± [18]
injection altitude for 5 h/day for 7 12.4; CL decreased from 93.3 ±10.9ml/kg/h to 83.9 ± 6.2.
days; HPLC.

Acetlysalicylic exposure to hypobaric hy-

poxia at 429 mm Hg pres- T1/2 increased from 5.69 ± 1.02 h to 7.63 ± 0.84; Ke decreased from 0.144 ±
acid;
Rabbit sure equivalent to 4,572 m 0.032 to 0.095 ± 0.01; Vd decreased from 1071.1 ± 125.1 ml/ kg to 806.1 ± [18]
intraperitoneal 122.1; CL decreased from 155.2 ± 39.4 ml/kg/h to 72.3 ± 7.0.
altitude for 5 h/day for 7
injection
days; HPLC.

exposure to hypobaric hy-

Acetazolamide; poxia at 429 mm Hg pres-
T1/2 increased by 28%; Ke decreased from 0.720 ± 0.188 to 0.527 ± 0.028;
Rabbit intraperitoneal sure equivalent to 4,572 m [18]
Vd increased; CL increased.
injection altitude for 5 h/day for 7
days; HPLC.

exposure to hypobaric hy-

Pentobarbital; poxia at 429 mm Hg pres- T1/2 increased from 7.28 ± 3.33 h to 8.01 ± 2.40; Vd decreased from 950.1 ±
Rabbit intraperitoneal sure equivalent to 4,572 m 178.5 ml/kg to 760.8 ± 238.4; CL decreased from 96.7 ± 27.2 ml/kg/h to [18]
injection altitude for 5 h/day for 7 66.6 ± 10.9.
days; HPLC.

exposure to simulated
Ibuprofen; altitude of 7,620 m for 6 and
Rat T1/2 and MRT increase by 42% and 51% respectively. [19]
Oral administration 24 h in a decompression
chamber; HPLC.

Phenytoin;
exposure to hypoxia at 48 CL decreased from 4.20 ± 0.55 ml/kg/min to 2.65 ± 0.44; AUC increase
Rabbit Intravenous injec- [20]
mm Hg pressure; HPLC. from 2575 ± 319 μg·min/ml to 4316 ± 740.
tion

acute exposure to hypoxia

Theophylline; (12% oxygen correspond-
Human Intravenous injec- ing to an altitude of 4,500 m Acute hypoxia did not alter the pharmacokinetics of theophylline. [21]
tion above sea level); LC-
MS/MS.

acute exposure to hypoxia

Verapamil; (12% oxygen correspond-
Human Intravenous injec- ing to an altitude of 4,500 m Acute hypoxia did not alter the pharmacokinetics of verapamil. [21]
tion above sea level); LC-
MS/MS.

acute high-altitude hypoxia: T1/2 increased from 9.30 ± 1.11 h to 10.37 ±

0.88; MRT increased from 12.06 ± 0.94 h to 13.15 ± 0.67; CL/F decreased
Sulfamethoxa- acute and chronic exposure from 1.01 ± 0.22 L/kg/h to 0.83 ± 0.13; AUC increased from 1202.5 ±
zole; to high altitude (3,800 m) 238.3 μg·h/ml to 1416.3 ± 202.6.
Human [8]
Oral administra- from low altitude (400 m) chronic high-altitude hypoxia: T1/2 increased from 9.30 ± 1.11 h to 11.15 ±
tion for 16 h and 1 year; HPLC. 1.53; MRT increased from 12.06 ± 0.94 h to 13.00 ± 1.01; CL/F decreased
from 1.01 ± 0.22 L/kg/h to 0.92 ± 0.22; AUC increased from 1202.5 ±
238.3 μg·h/ml to 1298.5 ± 256.0.

Table (1) contd….

Hypoxia Plays a Key Role in the Pharmacokinetic Changes of Drugs at High Altitude Current Drug Metabolism, 2018, Vol. 19, No. 11 963

Drug; Dosing
Species Model; Method Used Effects References
Route

acute high-altitude hypoxia: Cmax decreased from 3.93 ± 1.39 μmol/l to 3.54
± 1.35; T1/2 increased from 0.90 ± 0.20 h to 1.13 ± 0.47; CL/F increased
from 0.18 ± 0.04 L/kg/h to 0.20 ± 0.05; MRT decreased from 10.65 ± 4.44
acute and chronic exposure h to 9.62 ± 4.08; AUC decreased from 10.18 ± 2.39 μmol·h/l to 9.23 ± 1.91;
Furosemide;
to high altitude (3,600 m) Vd decreased from 5.05 ± 1.89 L/kg to 4.60 ± 1.01.
Human Oral administra- [22]
from sea level for 15 h and chronic high-altitude hypoxia: Cmax decreased from 3.93 ± 1.39 μmol/l to
tion
6 months; HPLC. 3.70 ± 1.82; T1/2 increased from 0.90 ± 0.20 h to 1.32 ± 0.52; CL/F in-
creased from 0.18 ± 0.04 L/kg/h to 0.19 ± 0.11; MRT increased from 10.65
± 4.44 h to 13.89 ± 10.37; AUC increased from 10.18 ± 2.39 μmol·h/l to
11.22 ± 4.52; Vd increased from 5.05 ± 1.89 L/kg to 5.18 ± 2.27.

acute high-altitude hypoxia: AUC increased from 3.12 ± 0.55 μg·h/ml to

3.52 ± 0.32; Cmax increased from 0.71 ± 0.11 μg/ml to 0.83 ± 0.09; CL/F
Prednisolone; acute and chronic exposure decreased from 440.84 ± 82.88 ml/kg/min to 381.21 ±35.08; Vd decreased
Oral administra- to high altitude (3,600 m) from 1.24 ± 0.27 L/kg to 1.03 ± 0.07.
Human [9]
tion from sea level for 15 h and chronic high-altitude hypoxia: AUC increased from 3.12 ± 0.55 μg·h/ml to
6 months; HPLC. 3.54 ± 0.45; Cmax increased from 0.71 ± 0.11 μg/ml to 0.81 ± 0.06; CL/F
decreased from 440.84 ±82.88 ml/kg/min to 381.42 ± 43.94; Vd decreased
from 1.24 ± 0.27 L/kg to 0.99 ± 0.13.

acute high-altitude hypoxia: T1/2 increased from 9.86 ± 2.21 h to 16.24 ±

acute and chronic exposure
Lithium carbon- to high altitude (4,360 m)
ate; from low altitude (600 m)
Human
Oral administra- for 15 h and 10 months;
tion Atomic absorption
spectrophotometry.
5.64; MRT increased from 10.84 ± 2.68 h to 19.44 ± 7.30; Vd increased
from 0.539 ± 0.033 L/kg to 0.641 ± 0.092; CL/F decreased from 0.659 ±
0.154 ml/kg/min to 0.499 ± 0.160.
[23]
chronic high-altitude hypoxia: T1/2 increased from 9.86 ± 2.21 h to 20.84 ±
3.05; MRT increased from 10.84 ± 2.68 h to 25.97 ± 5.11; Vd increased
from 0.539 ± 0.033 L/kg to 0.732 ± 0.130; CL/F decreased from 0.659 ±
0.154 ml/kg/min to 0.413 ± 0.088.

acute high-altitude hypoxia: T1/2 increased from 3.95 ± 0.62 h to 5.09 ±

acute and chronic exposure 1.08; MRT increased from 6.03 ± 0.92 h to 7.75 ± 1.64; CL/F decreased
Meperidine; to high altitude (4,360 m)
from 16.19 ± 3.74 ml/kg/min to 13.05 ± 1.74.
Human intramuscular from sea level for 7 days [24]
and 10 months; Gas chro- chronic high-altitude hypoxia: T1/2 increased from 3.95 ± 0.62 h to 4.80 ±
injection
0.93; MRT increased from 6.03 ± 0.92 h to 7.48 ± 1.29; CL/F decreased
matography.
from 16.19 ± 3.74 ml/kg/min to 12.10 ± 2.28.

Chinese Han volunteers
living at low altitude (400
Lidocaine;
m) and in native Han and
Human Oral administra-
Tibetan Chinese volunteers
tion
living at high altitude (2,200
-4,500 m); HPLC.
native Han volunteers: T1/2 increased from 1.88 ± 0.32 h to 2.44 ± 0.52; Vd
increased from 3.82 ± 1.01 L/kg to 4.49 ± 0.90; AUC increased from 6.75 ±
1.23 μg·h/ml to 7.08 ± 1.32; CL/F decreased from 1.40 ± 0.29 L/kg/h to
1.30 ± 0.27.
[27]
native Tibetan volunteers: T1/2 increased from 1.88 ± 0.32 h to 2.44 ± 0.69;
Vd increased from 3.82 ± 1.01 L/kg to 4.31 ± 1.48; AUC increased from
6.75 ± 1.23 μg·h/ml to 7.43 ± 1.86; CL/F decreased from 1.40 ± 0.29 L/kg/h
to 1.24 ± 0.34.

drug metabolism, is mainly metabolized by CYP1A. Studies on the

3. THE ACTIVITY AND EXPRESSION OF DRUG-
METABOLIZING ENZYMES UNDER HYPOXIA
3.1. Cytochrome P450
Cytochrome P450 (CYP450) enzymes are components of an
oxidase system encoded by a large gene family. Its main subtypes
include CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9,
CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. More than
90% of drugs are metabolized by CYP1A2, CYP2C9, CYP2C19,
CYP2D6, CYP2E1, and CYP3A4. Among them, CYP3A4 is the
body’s most important drug-metabolizing enzyme, biotransforming
more than 50% of common drugs [28, 29]. Theophylline, one of the
earliest studied drugs for understanding hypoxia-induced changes in
effects of hypoxia on drug-metabolizing enzymes begin with an
understanding of the CYP450 enzyme system. Proulx & Du Souich
[30] found that the CYP450 concentration decreased while the ac-
tivity remained unchanged in rabbits after acute hypoxia for 8 h, but
both the concentration and activity decreased after acute hypoxia
for 24 h, indicating that the effects of hypoxia on CYP450 enzyme
activity were time-dependent. Kurdi et al [31] simulated high-
altitude hypoxia with a hypobaric chamber, and found that the ac-
tivity and expression of CYP450 from rabbits clearly changed after
acute hypoxia for 48 h. CYP1A1 activity significantly decreased,
the protein expression of CYP1A1 and CYP1A2 decreased by 20%,
and that of CYP3A6 increased by 70% [31]. Under the same ex-
964 Current Drug Metabolism, 2018, Vol. 19, No. 11 Zhou et al.

perimental conditions, Fradette et al. [32, 33] found that acute hy-
poxia downregulated CYP1A1, CYP1A2, CYP2B4, CYP2C5, and
CYP2C16, and upregulated CYP3A6 in rabbit liver.
We investigated the effects of acute and chronic hypoxia on the
activity and expression of CYP1A2, CYP2D1, CYP2C11,
CYP2C22, and N-acetyltransferase 2 (NAT2) in rats, a high-
altitude environment after either acute or chronic exposure to an
altitude of 3,780 m compared to 400 m. This research group simu-
lated a real-life environment and showed that acute or chronic ex-
posure to high-altitude hypoxia led to a decrease in CYP1A2 activ-
ity and expression. Specifically, at 2,800 m, CYP1A2 activity
dropped by 62.3% and 60.8%, protein expression decreased by
60.4% and 62.0%, and mRNA expression decreased by 51.1% and
32.9% during acute and chronic exposure, respectively. At 4,300 m,
CYP1A2 activity decreased by 60.8% and 53.8% after acute or
chronic exposure to high altitude, protein expression decreased by
65.8% and 64.8%, and mRNA expression decreased by 37.2% and
30.7% [34]. A study on CYP2D1 showed that at altitudes of 2,800
m and 4,300 m, both the activity and expression of CYP2D1 in-
creased in rats in chronic hypoxia, whereas CYP2D1 remained
unchanged in acute hypoxia. Similar observations were made for
CYP2E1 and CYP3A1 in rats, which remained unchanged in acute
hypoxia, but significantly decreased in chronic hypoxia. Specifi-
cally, at 2,800 m, chronic hypoxia decreased the activity, protein
expression, and mRNA expression of CYP2E1 by 60.2%, 33.9%,
and 56.0%, respectively, and by 44.2%, 35.5% and 52.0%, respec-
tively at 4,300 m. Chronic hypoxia decreased the activity, protein
expression, and mRNA expression of CYP3A1 by 43.2%, 39.7%
and 31.1% in rats, respectively at 2,800 m, and by 50.1%, 27.5%,
and 31.7%, respectively at 4,300 m [34, 35]. The expression of
CYP2C11 and CYP2C22 was not affected by hypoxia in rats,
whereas the activity of CYP2C22 slightly increased to 117.6%
when exposed to acute hypoxia of 4,300 m [34, 36]. Studies on
CYP2D1, CYP2E1, and CYP3A1 have shown that chronic hypoxia
at high altitude plays a key role in enzyme activity and expression.
The aforementioned results demonstrate that the impact of hypoxia
on CYP450 enzymes in animals is still a subject of debate. With the
exception of CYP2C11 and CYP2C22, the widespread belief is that
high-altitude hypoxia decreased the activity and expression of
CYP1A1, CYP1A2, CYP2E1, and CYP3A1, and increased those of
CYP3A6 and CYP2D1 in rats (Table 2).

Table 2. Changes in the activity and expression of drug metabolizing enzymes at hypoxia.

Drug Metabo-
Species Model; Method Used Effects References
lism Enzymes

acute exposure to a FiO2 of 12%

After 8 h of hypoxia, total amount but not the activity of cytochrome
for 8 h or 12 h. Dithionite-
Rabbit CYP450 P450 was decreased; after 24 h of hypoxia, both the amount and the [30]
reduced carbon monoxide dif-
activity of cytochrome P450 were decreased.
ference spectrum.

Rabbit CYP1A1 CYP1A1 protein expression decreased by about 20%.

acute exposure to a FiO2 of 10%
Rabbit CYP1A2 CYP1A2 protein expression decreased by about 20%. [31]
for 24 h. Western blot.
Rabbit CYP3A6 CYP3A6 protein expression increased by about 70%.

Rabbit CYP1A1 CYP1A1 protein expression decreased by 37%.

Rabbit CYP1A2 CYP1A2 protein expression decreased by 40%.

Rabbit CYP2B4 acute exposure to a FiO2 of 8% CYP2B4 protein expression decreased by 55%. [32]
Rabbit CYP2C5 for 48 h. Western blot. CYP2C5 protein expression decreased by 75%.

Rabbit CYP2C16 CYP2C16 protein expression decreased by 82%.

Rabbit CYP3A6 CYP3A6 protein expression increased by 71%.

acute exposure to middle alti-
tude of 2,800 m from low alti-
tude of 400 m for 1 day (AMH);
Rat CYP1A2
chronic exposure to middle
altitude of 2,800 m from low
altitude of 400 m for 30 days
(CMH); acute exposure to high
altitude of 4,300 m from low
Rat CYP2D1 altitude of 400 m for 1 day
(AHH); chronic exposure to
high altitude of 4,300 m from
low altitude of 400 m for 30
Rat CYP2C11
days (CHH). HPLC; ELISA;
real-time PCR.
Rat CYP2C22
CYP1A2 activity decreased by 62.3%, 60.8%, 60.8% and 53.8% in
the AMH, CMH, AHH and CHH groups, respectively; CYP1A2
protein expression decreased by 60.4%, 62.0%, 65.8% and 64.8% in
the AMH, CMH, AHH and CHH groups, respectively; CYP1A2
mRNA expression was decreased 51.1%, 32.9%, 37.2% and 30.7% in
the AMH, CMH, AHH and CHH groups, respectively.
CYP2D1 activity increased by 86.2% and 176.1% in the CMH and [34]
CHH groups, respectively; CYP2D1 protein expression increased by
20.3% and 23.5% in the CMH and CHH groups, respectively;
CYP2D1 mRNA expression increased by 34.7% in the CHH groups.
hypoxia did not affect the activity, protein and mRNA expression of
CYP2C11.
CYP2C22 activity increased by 117.6% in the AHH group.

Table (2) contd….

Hypoxia Plays a Key Role in the Pharmacokinetic Changes of Drugs at High Altitude Current Drug Metabolism, 2018, Vol. 19, No. 11 965

Drug Metabo-
Species Model; Method Used Effects References
lism Enzymes

acute exposure to middle alti-
tude of 2,800 m from low alti-
Rat CYP2E1
tude of 400 m for 1 day (AMH);
chronic exposure to middle
altitude of 2,800 m from low
altitude of 400 m for 30 days
Rat CYP3A1 (CMH); acute exposure to high
altitude of 4,300 m from low
altitude of 400 m for 1 day
(AHH); chronic exposure to
high altitude of 4,300 m from
Rat NAT2 low altitude of 400 m for 30
days (CHH). HPLC; ELISA;
real-time PCR.
CYP2E1 activity decreased by 60.2% and 44.2% in CMH and CHH,
respectively; CYP2E1 protein expression decreased by 33.9% and
35.5% in CMH and CHH, respectively. CYP2E1 mRNA expression
decreased by 56.0% and 52.0% in CMH and CHH, respectively.
[35]
CYP3A1 activity decreased by 43.2% and 50.1% in CMH and CHH,
respectively; CYP3A1 protein expression decreased by 39.7% and
27.5% in CMH and CHH, respectively; CYP3A1 mRNA expression
decreased by 31.1% and 31.7% in CMH and CHH, respectively.
NAT2 activity decreased by 23.1% and 28.6% in AMH and AHH,
respectively; NAT2 expression decreased by 55.8% and 19.5% in [34]
AMH and AHH, respectively.

exposure to high altitude of

Rat NAT2 4,600 m from low altitude of NAT2 activity decreased by 38.7%. [10, 38]
400 m for 7 days. HPLC.

exposure to acute hypobaric GST activity decreased by 15% and 23% after 6 h and 24 h of acute
Rat GST [19]
hypoxia for 6 h and 24 h at a hypoxia, respectively.
simulated altitude of 7,620 m.
Rat UGT Fluorimeter. Acute hypoxia did not affect the activity of UGT. [19, 39]

Human CYP1A2 Hypoxia did not affect the activity of CYP1A2.

Human CYP2C19 exposure to acute hypoxia for 7 Hypoxia did not affect the activity of CYP2C19.
days at 4559 m above sea level. [37]
Human CYP2D6 HPLC. a small decrease in the activity of CYP2D6.

Human CYP3A4 a small decrease in the activity of CYP3A4.

There are differences in certain enzymes between humans and
animals. Jurgens et al. [37] found that the activities of CYP2D6 and
CYP3A4 slowed down after plain volunteers went to 4,559 m pla-
teau and quickened after they returned to a flat area. The activities
of CYP1A2 and CYP2C19 remained stable throughout this experi-
ment.
3.2. Other Drug-Metabolizing Enzymes
Studies on the effects of high-altitude hypoxia on CYP450 en-
zymes and other drug-metabolizing enzymes have only been re-
ported in recent years. It has been demonstrated that NAT2 activity
in rats decreased by 38.7% after they quickly ascended to 4,600 m
from 400 m [10, 38]. Subsequent studies further demonstrated that
acute high-altitude hypoxia significantly reduces the activity and
expression of NAT2 in rats, whereas chronic hypoxia does not have
these effects. The activity and mRNA expression of NAT2 in rats
under acute hypoxia at 2,800 m decreased by 23.1% and 55.8%,
respectively, and by 28.6% and 19.5%, respectively at 4,300 m
[34]. Shefali et al. [19] simulated a 7,620 m plateau with low cabin
pressure and found that the activity of glutathione s-transferase
(GST) in rats after 6 h and 24 h of acute hypoxia dropped by 15%
and 23%, respectively. Under hypoxia, the activity of UDP-
glucuronsyltransferase (UGT) remains unchanged [19, 39].
The changes in the activity and expression of drug metabolizing
enzymes are consistent with the changes in the pharmacokinetics of
some enzyme substrates in the high-altitude hypoxia environment.
For example, hypoxia reduces the activity and expression of
CYP1A2, CYP2B6, CYP2C11, CYP2C22, and NAT2, and the
metabolism of their substrates theophylline, phenytoin, ibuprofen,
and sulfamethoxazole is slow, suggesting that the dosage of these
drugs should be reduced in the high-altitude hypoxia environment
[40].
Table 2 shows the changes in the activity and expression of
drug-metabolizing enzymes at hypoxia.
4. REGULATION OF CYTOKINES AND NUCLEAR RE-
CEPTORS ON DRUG-METABOLIZING ENZYMES IN HY-
POXIA
Studies on the mechanisms underlying the influence of hypoxia
on drug metabolism are undergoing. High altitude hypoxia can lead
to a broad range of physiological changes, leading to the changes in
the ADME process of drugs. It was previously believed that hy-
poxia caused blood redistribution in organs, resulting in a decrease
in hepatic blood flow and inability of the liver to properly break
down and utilize drugs, thereby slowing down drug CL [41]. Du
Souich et al. [42] found that the CL of lidocaine metabolites de-
creased in dogs under acute and chronic hypoxia without changes in
hepatic and kidney blood flow, indicating the lack of a causal rela-
tionship between them in hypoxia. Red blood cells, hemoglobin,
hematocrit and so on are changed in the high altitude hypoxia envi-
ronment, and changes in blood cells are closely related to emplace-
ment time and altitude. It has been claimed that red blood cells are
increased after exposure to high altitude. Li et al. [8] and Arancibia
et al. [9] found that the hematocrit was significantly increased in
healthy subjects after chronic exposure to high altitude, and the
binding of drug to red blood cells was significantly higher in the
chronic exposure group than in the low altitude group. The in-
creased binding in the chronic exposure group might be explained
by the increased hematocrit levels. The increased binding to red
blood cells may also explain the lower clearance observed in the
966 Current Drug Metabolism, 2018, Vol. 19, No. 11
groups exposed to a high altitude. Currently, many mechanistic
studies are focused on the effects of hypoxia on cytokines and nu-
clear receptors.
4.1. Cytokines
The effects of hypoxia are similar to those of acute inflamma-
tory reactions, except that the inflammatory response causes down-
regulation of CYP3A whereas hypoxia causes upregulation [43]. In
rabbits with inflammation, researchers found that interleukin 6 (IL-
6) was the blood modifier for the decrease in CYP450 enzyme ac-
tivity. IL-1, Tumor Necrosis Factor (TNF), and Interferon  (IFN-
) function in weak analogous manners [44-46]. Hypoxia promotes
the release of cytokines IL-1, TNF, IFN, Erythropoietin (EPO),
and hypoxia-inducible factor 1 (HIF-1) [47-49], and activates the
protein tyrosine kinase (PTK), protein kinase C (PKC), and mito-
gen-activated protein kinase (MAPK) signal transduction pathways.
Hypoxia activates HIF-1 and activator protein-1 (AP-1), and their
translocation to the nucleus and regulates CYP450 enzyme activity
and expression [33, 50]. One study showed that after 24 h of serum
incubation, rabbits in acute hypoxia showed a decrease in CYP1A1
and CYP1A2 activity and expression, and an increase in the activity
and expression of CYP3A6. When antibodies against IFN- and IL-
1 were added to the incubation system, the downregulation of
CYP1A1 and CYP1A2 was suppressed, indicating that IL-1, IL-
2, and IFN- regulate their downregulation. The up-regulation of
CYP3A6 is influenced by EPO [32]. In addition, hypoxia activates
the binding of HIF-1 to the CYP3A6 oligonucleotide probe and
regulates its activity [33]. Hypoxia improves blood circulation and
cell metabolism through the regulation of various genes such as
HIF-1 [51, 52]. HIF-1 consists of
and  subunits, the latter of
which is the aryl hydrocarbon receptor nuclear translocator, which
is unaffected by hypoxia. This subunit forms a dimer with the Aryl
Hydrocarbon Receptor (AhR), and translocate to the nucleus where
it combines and activates its corresponding target genes [41]. The
downregulation of CYP1A1 and CYP1A2 in hypoxia is related to
HIF-1
expression. The expression level of HIF-1
is too low to
detect in aerobic conditions but rapidly increases in hypoxia, after
which it forms a dimer with HIF-1, inhibiting formation of the
HIF-1/AhR dimer. AhR is constitutively active in the body, and
CYP1A1 and CPY1A2 are constitutively expressed. HIF-1 is acti-
vated in hypoxia, inhibiting formation of the HIF-1/AhR het-
erodimer and CYP1A expression [50, 53]. The ARD1 of mammals
can help HIF-1
acetylation and degradation, but is inhibited in
O2
PXR
ROI
CAR
HIF-1
DNA
mRNA
CYP450
Fig. (1). The regulatory mechanisms underlying the drug metabolism of serum cytokines and nuclear receptor in hypoxia.
Zhou et al.
hypoxia, which allows its stabilization [54]. Fisher et al. [55] re-
vealed that the level of human ARD1 protein does not decrease in
hypoxia, nor does HIF-1
acetylation. It remains unknown if these
studies can explain the differences between human and animal drug
metabolism in hypoxia. Rahman & Thomas [56] postulated that the
downregulation of CYP1A expression is related to IL-1 and nitric
oxide accumulation. Moreover, regulation of hypoxia is related to
the activation of P-glycoprotein and AP-1 [33].
4.2. Nuclear Receptor
There have been significant improvements in our understanding
of how exogenous compounds affect CYP450-dependent metabo-
lism. Breakthrough discovery was achieved about the inducement
mechanism of exogenous compounds on liver CYP450 isozyme
expression, which confirmed the role of three main receptors in the
nuclear receptor superfamily: Pregnane X Receptor (PXR), Consti-
tutive Androstane Receptor (CAR), and the peroxisome prolifera-
tor-activated receptor (PPAR). Studies have shown that PXR is a
key inducer of CYP3A expression, whereas CAR mainly regulates
the transcription of CYP2B, CYP1A, and CYP3A [57, 58]. Gene
knockdown studies have demonstrated that PXR and CAR regulate
CYP2C9, CYP2C19, and CYP2C18 expression [59, 60]. In addi-
tion, most phase II UGT1A drug-metabolizing enzymes are regu-
lated by PXR, with the exception of UGT1A1, which is co-
regulated by PXR and CAR [61]. Hypoxia can decrease the expres-
sion of PXR and CAR, thereby further regulating CYP450 activity
and expression [62, 63]. Fig. (1) shows the regulatory mechanisms
underlying the drug metabolism of serum cytokines and nuclear
receptor in hypoxia. Additional studies are needed to determine the
mechanisms underlying the effects of hypoxia on drugs metabo-
lized by CYP1A1, CYP1A2, and CYP3A6, among others.
CONCLUSION AND FUTURE OUTLOOKS
Several previous studies have indicated that hypoxia plays a
key role in the PK changes of drugs at high altitude. The metabo-
lism of most drugs decreases in high-altitude hypoxia, with the
MRT, T1/2, and AUC increase and the Ke and CL decrease. These
findings may have important clinical implications. It is suggested
that patient living at or traveling to high altitude should be closely
monitored, and the dosages of some drugs metabolized by
CYP1A1, CYP1A2, CYP2E1 or CYP3A1 should be reduced.
Travel to high altitude can lead to medical problems, from the
mild symptoms of acute mountain sickness to the potentially fatal
IL-1β IL-2β IFN-γ
PTK
PKC MAPKs
AP-1
Hypoxia Plays a Key Role in the Pharmacokinetic Changes of Drugs at High Altitude
high altitude pulmonary edema or cerebral edema. High altitude
hypoxia not only affects the 140 million people living at high alti-
tude, it also affects an increasing number of people traveling to high
altitude. In recent years, human plateau activity has become in-
creasingly frequent. Crowds exposed to highland develop acute
hypoxia and sometimes even altitude illness. Due to high-altitude
emergency situations, and high-altitude military training, and popu-
lations living at high altitude, there has been a gradual focus to-
wards understanding drug metabolism at high altitude. High altitude
medicine has been developing rapidly, and many research institu-
tions of the high altitude disease have been set up. Although the
prevention and treatment of high altitude illness at high altitude has
made great progress, the clinical rational use and the efficacy of
drugs has not yet caused enough attention, so it will become very
important to establish the subject of high altitude pharmacy and the
research institute of drugs in the plateau area.
How hypoxia influences drug metabolism is a new direction of
high altitude medicine and drug metabolism research; specifically,
the characteristics and mechanisms of drug-metabolizing enzymes
in these environments, as well as rationale drug use [64, 65]. This
review primarily focused on studies on acute hypoxia and the
CYP450 enzyme system, most of which adopted a low-pressure
oxygen cabin to stimulate the plateau environment. These types of
studies are not similar enough to the real highland environment and
cannot give a comprehensive assessment of the effects of hypoxia
on drug PK in those conditions. Thus, although certain findings on
the effects of plateau hypoxia on drug metabolism by the CYP450
enzyme and related drugs have been validated, overall investiga-
tions are still in the exploratory stage.
Preliminary studies have focused on mammals like rats and
rabbits, but the drug metabolism of these animals differs from hu-
mans. Therefore, studies in humans should be performed to investi-
gate the effects and mechanism of high-altitude hypoxia. In addi-
tion, studies should be conducted in people native to high altitude,
as that 38 million worldwide live in that environment. Furthermore,
many ethnic minorities live in plateaus, for example, Tibetan, Hui,
Tu, Salar, and Mongol nationalities reside in the Qinghai-Tibet
Plateau. Differences in metabolism among these nationalities
should be taken into consideration. Models of acute hypoxia in-
duced by chemical methods or low-pressure cabin can only stimu-
late hypoxia, and not hypothermia, intense radiation, or dry climate,
nor is it a real atmosphere. When someone enters the plateau envi-
ronment, it takes a long time to develop hypoxia; this type of re-
striction makes chronic hypoxia difficult to simulate experimen-
tally. However, an adaptive process cannot be represented in an
experimental model of hypoxia. According to the literature reports
and our research, it is generally believed that hypoxia above 2,500
m altitude will affect the pharmacokinetics of drugs. Therefore, the
real plateau environment (2,500 m) should be used as the ex-
perimental site to overcome limitations of the simulated environ-
ment, and factors such as hypoxia, low pressure, strong radiation,
and cold should be taken into account when investigating changes
in drug metabolism at high altitude.
Aminophylline, dexamethasone, furosemide, and acetazolamide
have been commonly used for the treatment of acute high-altitude
disease, and their pharmacokinetics in high-altitude environments
were previously reported. We should also lay emphasis on cardio-
vascular drugs that prevent chronic plateau disease on their meta-
bolic kinetics study at high altitude in hypoxia, which would offer
references for plateau rational drug use. The study of activity and
expression of drug metabolism enzyme focuses on CYP450 enzyme
system. In addition, there should be more research on other
CYP450 enzymes and phase II metabolism enzymes like NAT2,
UGT, and UST, as current studies seem to mostly focus on cytokine
regulation. A comprehensive understanding is needed of the pathol-
ogy, cytobiology and molecular biology of the mechanisms under-
lying drug metabolism in high-altitude hypoxic environments.
Current Drug Metabolism, 2018, Vol. 19, No. 11 967
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
This article is original, has been written by the stated authors
who are all aware of its content and approve its submission. It has
not been published previously, it is not under consideration for
publication elsewhere, no conflict of interest exists. The article will
not be published elsewhere in the same form, in any language,
without the written consent of the publisher.
ACKNOWLEDGEMENTS
This study was supported by the National Natural Science Fund
of China (No. 81760673 and 81460568), and the National Natural
Science Fund of Qinghai province (No.2016-ZJ-902). We thank
LetPub (www.letpub.com) for their linguistic assistance during the
preparation of this manuscript.
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