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Altitude-induced alterations in drug action and metabolism
Lüe Sciences Vol. 7, Part I, pp. 1163-1169, 1968 . Printed in Great Britain .
Pergamon Press
ALTITUDE-INDUCED ALTERATIONS IN DRUG ACTION AND METABOLISM James H . Merritt and Miguel A. Medina Pharmacology-Biochemistry Branch, Biosciences Division USAF School of Aerospace Medicine, Brooks AFB, Texas
(deceived 19 Aprü 1968; in final form 2 August 1968) It has been accepted for years, in a general way, decreased barometric pressure drug action is altered . digitalis for cats
that under conditions of Thus, the LD50 for
is smaller at altitude than at ground level
(1) .
Strychnine
is also more toxic to rats and ground squirrels at higher altitudes (2) and the LD50 for reserpine for mice is decreased by altitude morphine sulfate is
(3) .
In contrast,
less toxic to rats kept in an altitude chamber at
pressure but with ground
level equivalent pOZ (4) .
reduced
Chlorpromazine and meproba-
mate administered at altitude to mice caused a decrease in motor activity over that produced by either drugs or altitude alone (5) " was reduced in mice at altitude
(6) .
Hexobarbital sleep time
Most of these studies were concerned with
hypoxia and little weight was given to the effect of decreased pressure J'ér se . Furthermore,
in none of these experiments has any measurement of the rate
of metabolism or tissue concentrations of the drugs been performed .
We have
therefore examined the effect of altitude on the metabolism, brain levels, and duration of sleep time produced by hexobarbital .
The research reported in this USAF School of Aerospace Medicine, States Air Force, Brooks Air Force authorized to satisfy the needs of
paper was conducted by personnel of the Aerospace Medical Division, AFSC, United Further reproduction is Base, Texas . the U .S . Government .
The animals involved in this study were maintained In accordance with the "Guide for Laboratory Animal Facilities and Care" as published by the National Academy of Sciences--National Research Council .
1163
Vol . 7, No . 21
EFFECTS OF ALTITUDE
116 4
Methods and Materials Male mice of the C57 strain were used throughout . provided with water and Purina chow ad libitum. maintained at
Groups of animals were
18,000 feet in an altitude chamber for five days or at
ground level in a similar cage . shavings .
All animals were
All animals were kept on beds of pine
Ground control animals were taken up to 18,000 feet and immediately
brought down
in order to subJect them to the same stress as the altitude
animals in descending . the mice were
In one experiment carried out in a large chamber,
infected at altitude .
Immediately after removal from the altitude chamber, the animals were infected
intraperttoneally with 125 ng . hexobarbital/kg . and sleeping time
was then determined . the animal
Sleeping time was counted from time of infection until
righted itself three times in one minute .
Hexobarbital content in brain was determined 50 minutes after infection and at times of awakening by the method of Cooper and Brodie (7) .
Liver
microsomal metabolism of hexobarbital was assessed as described by Kato and Gillette
(8) .
Results
Table I summarizes the data obtained on sleeping time .
In each group
tested, sleeping time for the animals maintained at altitude was shorter than the comparison ground level controls . animals were
This was scan whether the
infected Immediately after removal from the chamber or whether
they were infected while at altitude .
Vol . 7, No . 21
EFFECTS OF ALTITUDE
1185
TABLE I Effect of Simulated Altitude (18,000 ft) on Hexobarbital Sleep Time Sleep Time
in Min . * S .E .
P
Ground
Altitude * 2 .0
(12)
68 .6 * 5 .9
(12)
< 0 .001
31 .8 * 2 .9
(20)
51 .2
* 4 .1
(19)
< 0 .001
* 3.8
(20)
85 .1
* 5 .8
(25)
< 0 .001
X65 .8 * 5 .2
(20)
*78 .2
* 3 .6
(24)
44 .5
55 .1
~InJected at altitude .
Data on hexobarbital
>`< 0 .05
Number of determinations
in parentheses .
Hexobarbital content
levels are shown in Table II .
in brain 50 minutes after injection of 125 mg ./kg . was found to be significantly
less
group .
In
in the altitude-exposed group when compared to the ground control this particular experiment all of the mice were asleep at
of sacrifice .
the time
When the hexobarbital content of brain was determined at the
time of awakening, there was no difference between the two groups .
TABLE II Effect of Simulated Altitude (18,000 ft) on Hexobarbital Levels in Mouse Brain ug . Hexobarbital/gm . Tissue
* S .E .
Ground
Altitude
P
50 min after inj
50 .3
* 3.1
(44)
59 .1
* 2 .9
(44)
< 0 .05
At awakening
17 .4 = 1 .6
(18)
15 .1
* 2 .1
(19)
N .S .
Number of determinations
in parentheses .
116 6
EFFECTS OF ALTITUDE
Metabolism of hexobarbital
Vol . 7, No . 21
by liver microsomes
Is shown in Table III .
The
data Indicate that the liver microsomes of altitude-exposed mice metabolize hexobarbital at a faster rate than the ground level controls .
TABLE III Effect of Simulated Altitude (1ô,000 ft) on _In Vitro Metabolism of Hexobarbital by Liver Microsomes Hexobarbital Metabolized (uM./gm . of liver/hr. t S .E .) Ground
3 .6 a 0 .4
(8)
Altitude
5 .0 t 0 .5
(8)
Number of determinations
P < 0.05
in parentheses .
Discussion The present study confirms alteration of drug action by altitude . this case, drug action altitude .
(hexobarbital sleep time)
In
is decreased as a result of
This decreased sleep time was found whether the mice were Injected
while at altitude or immediately after being brought down to ground
level .
The increased metabolism of hexobarbital by liver microsomes from the altitude animals, and the fact that the brain hexobarbital
levels in both
groups was the same at the time of awakening, would suggest that the decreased sleep time
is a result of an increased degradation of the drug .
The lower
hexobarbital content " in brain in altitude-exposed animals when both groups are assayed at the same time after infection also Infers a difference
in
metabolism . Our results also
indicate that the responsiveness of the receptor sites
is not affected by altitude since, although a difference exists
to sleeping
Yol . 7, No. 21
1187
EFFECTS OF ALTITUDE
time and in microsomal enryme activity between both groups, the hexobarbital content in brain on awakening was not altered . An explanation for the observed modification of drug action animals have simply been stressed by the altitude exposure . sleep time is decreased by the stress of hind
limb ligation
is
that the
Hexobarbital (9), and cold
stress has been shown to affect microsomal drug-metabolizing enzymes In the casa of cold stress
(10) .
in rats, however, hexobarbital metabolism Is
decreased . Another possibility is that hypoxia resulting from the altitude exposure could change the blood pH and so modify metabolism and excretion . respect, Christensen and Hastings
found no change in blood pH
27,000 feet, at which "break point" the rats become acldotic event, respiratory acidosis
In this
in rats up to (11) .
In any
increased the concentration of phenobarbltal
in
brain (12) . There is considerable evidence
in the literature that altitude produces
marked changes in body fluid compartments .
Studies with a variety of species
at various altitudes indicate that plasma volume decreases as a result of exposure to decreased atmospheric pressure
(13,
14, 15) "
Thus, it
possible that a portion of the alteration In sleep time observed experiments may be due to a difference
is also
in our
In the distribution of hexobarbital
in fluid compartments . Tha meager data available points to an effect on drug action as a result of decreased total pressure over and above the effect of hypoxia .
However,
in order to obtain information on the effect of altitude alone, additional studies on drug distribution and metabolism have to be undertaken total pressure is
lowered but p0 2 kept at ground level equivalent .
in which This begs
the question, of course, of what effect a lowering of partial pressures of other gases ; e.g ., nitrogen, from ground action .
level equivalent will have on drug
1168
EFFECTS OF ALTITUDE
Vol. 7, No . 21
Since the duration of aerospace operations has been and will be extended to days and even weeks,
it seems inevitable that drugs will be administered
to crew members under conditions of reduced pressure .
In addition, large
numbers of patients receiving potent drugs are currently being transported via aeromedical evacuation flights routinely at cabin altitudes above feet .
8,000
The studies reported here show that conditions of reduced barometric
pressure can alter drug action and metabolism .
These results may make it
necessary to re-examine the dosage of drugs administered to humans at altitude .
Summary Mice maintained at
18,000
feet for five days and then infected with
125
mg .
hexobarbital/kg . were found to have decreased sleeping time, smaller concentrations of brain hexobarbital
50
minutes after infection, and increased liver
microsomal metabolism of the drug compared to ground level controls . the same conditions, brain levels of hexobarbital same for both groups .
Under
in awakening mice was the
The significance of these observations
is discussed in
relation to changes in drug action at altitude .
References
97, 540 (1931) .
l.
D . L . Macht, J . Am . Physiol . Soc .
2.
A . W . Moore and J . C . Ward, J . Am . Pharm. Assoc . Scient . Ed .
24, 460 (1935) "
3.
I . P . Baumei, S . M. Robinson and W. F . Blatt,
56, 918 (1967) .
4.
A . J . Nedzel,, J . Aviat . Med .
5.
F . Sparuteri, Riv . Med. Aero .
6.
S . Robinson, W. Blatt, R . Schatz and R. Joy, Fed. Proc .
7.
J . R . Cooper and B. B . Brodie, J . Pharmacol . Exp . Therap .
8.
R . Kato and J . R. Gillette, J . Pharmacol . Exp . Therap .
9.
B . D . Rupe, W . F. Bousquet and T . 5 . Miya, Science
J . Pharm. Sci .
26, 164 (1955) " . 23, 397 (1960) " 27, 283 (1968) . 114, 409 (1955) "
150, 285 (1965) .
141, 1186 (1963) "
Vol . 7, No . 21
EFFECTS OF ALTITUDE
10 .
R . L . Furner and R . E . Stitzel,
Biochem. Pharmacol .
11 .
W . R . Christensen and A . B . Hastings, J . Aviat . Med .
12 .
W . J . Waddell and T . C . Butler, J . Clln . Invest .
13 .
K . R . Reissmann, Am . J . Physlol .
14 .
G . R . Fryers, Am . J . Physiol .
15 .
V . C . Ellis, S . Afr . J . Med . Sci .
167, 52 (1951) .
171, 459 (1952) . 18, 45 (1953) "
1169
17, 121 (1968) . 20, 221 (1949) .
36, 1217 (1957) "
Pergamon Press
ALTITUDE-INDUCED ALTERATIONS IN DRUG ACTION AND METABOLISM James H . Merritt and Miguel A. Medina Pharmacology-Biochemistry Branch, Biosciences Division USAF School of Aerospace Medicine, Brooks AFB, Texas
(deceived 19 Aprü 1968; in final form 2 August 1968) It has been accepted for years, in a general way, decreased barometric pressure drug action is altered . digitalis for cats
that under conditions of Thus, the LD50 for
is smaller at altitude than at ground level
(1) .
Strychnine
is also more toxic to rats and ground squirrels at higher altitudes (2) and the LD50 for reserpine for mice is decreased by altitude morphine sulfate is
(3) .
In contrast,
less toxic to rats kept in an altitude chamber at
pressure but with ground
level equivalent pOZ (4) .
reduced
Chlorpromazine and meproba-
mate administered at altitude to mice caused a decrease in motor activity over that produced by either drugs or altitude alone (5) " was reduced in mice at altitude
(6) .
Hexobarbital sleep time
Most of these studies were concerned with
hypoxia and little weight was given to the effect of decreased pressure J'ér se . Furthermore,
in none of these experiments has any measurement of the rate
of metabolism or tissue concentrations of the drugs been performed .
We have
therefore examined the effect of altitude on the metabolism, brain levels, and duration of sleep time produced by hexobarbital .
The research reported in this USAF School of Aerospace Medicine, States Air Force, Brooks Air Force authorized to satisfy the needs of
paper was conducted by personnel of the Aerospace Medical Division, AFSC, United Further reproduction is Base, Texas . the U .S . Government .
The animals involved in this study were maintained In accordance with the "Guide for Laboratory Animal Facilities and Care" as published by the National Academy of Sciences--National Research Council .
1163
Vol . 7, No . 21
EFFECTS OF ALTITUDE
116 4
Methods and Materials Male mice of the C57 strain were used throughout . provided with water and Purina chow ad libitum. maintained at
Groups of animals were
18,000 feet in an altitude chamber for five days or at
ground level in a similar cage . shavings .
All animals were
All animals were kept on beds of pine
Ground control animals were taken up to 18,000 feet and immediately
brought down
in order to subJect them to the same stress as the altitude
animals in descending . the mice were
In one experiment carried out in a large chamber,
infected at altitude .
Immediately after removal from the altitude chamber, the animals were infected
intraperttoneally with 125 ng . hexobarbital/kg . and sleeping time
was then determined . the animal
Sleeping time was counted from time of infection until
righted itself three times in one minute .
Hexobarbital content in brain was determined 50 minutes after infection and at times of awakening by the method of Cooper and Brodie (7) .
Liver
microsomal metabolism of hexobarbital was assessed as described by Kato and Gillette
(8) .
Results
Table I summarizes the data obtained on sleeping time .
In each group
tested, sleeping time for the animals maintained at altitude was shorter than the comparison ground level controls . animals were
This was scan whether the
infected Immediately after removal from the chamber or whether
they were infected while at altitude .
Vol . 7, No . 21
EFFECTS OF ALTITUDE
1185
TABLE I Effect of Simulated Altitude (18,000 ft) on Hexobarbital Sleep Time Sleep Time
in Min . * S .E .
P
Ground
Altitude * 2 .0
(12)
68 .6 * 5 .9
(12)
< 0 .001
31 .8 * 2 .9
(20)
51 .2
* 4 .1
(19)
< 0 .001
* 3.8
(20)
85 .1
* 5 .8
(25)
< 0 .001
X65 .8 * 5 .2
(20)
*78 .2
* 3 .6
(24)
44 .5
55 .1
~InJected at altitude .
Data on hexobarbital
>`< 0 .05
Number of determinations
in parentheses .
Hexobarbital content
levels are shown in Table II .
in brain 50 minutes after injection of 125 mg ./kg . was found to be significantly
less
group .
In
in the altitude-exposed group when compared to the ground control this particular experiment all of the mice were asleep at
of sacrifice .
the time
When the hexobarbital content of brain was determined at the
time of awakening, there was no difference between the two groups .
TABLE II Effect of Simulated Altitude (18,000 ft) on Hexobarbital Levels in Mouse Brain ug . Hexobarbital/gm . Tissue
* S .E .
Ground
Altitude
P
50 min after inj
50 .3
* 3.1
(44)
59 .1
* 2 .9
(44)
< 0 .05
At awakening
17 .4 = 1 .6
(18)
15 .1
* 2 .1
(19)
N .S .
Number of determinations
in parentheses .
116 6
EFFECTS OF ALTITUDE
Metabolism of hexobarbital
Vol . 7, No . 21
by liver microsomes
Is shown in Table III .
The
data Indicate that the liver microsomes of altitude-exposed mice metabolize hexobarbital at a faster rate than the ground level controls .
TABLE III Effect of Simulated Altitude (1ô,000 ft) on _In Vitro Metabolism of Hexobarbital by Liver Microsomes Hexobarbital Metabolized (uM./gm . of liver/hr. t S .E .) Ground
3 .6 a 0 .4
(8)
Altitude
5 .0 t 0 .5
(8)
Number of determinations
P < 0.05
in parentheses .
Discussion The present study confirms alteration of drug action by altitude . this case, drug action altitude .
(hexobarbital sleep time)
In
is decreased as a result of
This decreased sleep time was found whether the mice were Injected
while at altitude or immediately after being brought down to ground
level .
The increased metabolism of hexobarbital by liver microsomes from the altitude animals, and the fact that the brain hexobarbital
levels in both
groups was the same at the time of awakening, would suggest that the decreased sleep time
is a result of an increased degradation of the drug .
The lower
hexobarbital content " in brain in altitude-exposed animals when both groups are assayed at the same time after infection also Infers a difference
in
metabolism . Our results also
indicate that the responsiveness of the receptor sites
is not affected by altitude since, although a difference exists
to sleeping
Yol . 7, No. 21
1187
EFFECTS OF ALTITUDE
time and in microsomal enryme activity between both groups, the hexobarbital content in brain on awakening was not altered . An explanation for the observed modification of drug action animals have simply been stressed by the altitude exposure . sleep time is decreased by the stress of hind
limb ligation
is
that the
Hexobarbital (9), and cold
stress has been shown to affect microsomal drug-metabolizing enzymes In the casa of cold stress
(10) .
in rats, however, hexobarbital metabolism Is
decreased . Another possibility is that hypoxia resulting from the altitude exposure could change the blood pH and so modify metabolism and excretion . respect, Christensen and Hastings
found no change in blood pH
27,000 feet, at which "break point" the rats become acldotic event, respiratory acidosis
In this
in rats up to (11) .
In any
increased the concentration of phenobarbltal
in
brain (12) . There is considerable evidence
in the literature that altitude produces
marked changes in body fluid compartments .
Studies with a variety of species
at various altitudes indicate that plasma volume decreases as a result of exposure to decreased atmospheric pressure
(13,
14, 15) "
Thus, it
possible that a portion of the alteration In sleep time observed experiments may be due to a difference
is also
in our
In the distribution of hexobarbital
in fluid compartments . Tha meager data available points to an effect on drug action as a result of decreased total pressure over and above the effect of hypoxia .
However,
in order to obtain information on the effect of altitude alone, additional studies on drug distribution and metabolism have to be undertaken total pressure is
lowered but p0 2 kept at ground level equivalent .
in which This begs
the question, of course, of what effect a lowering of partial pressures of other gases ; e.g ., nitrogen, from ground action .
level equivalent will have on drug
1168
EFFECTS OF ALTITUDE
Vol. 7, No . 21
Since the duration of aerospace operations has been and will be extended to days and even weeks,
it seems inevitable that drugs will be administered
to crew members under conditions of reduced pressure .
In addition, large
numbers of patients receiving potent drugs are currently being transported via aeromedical evacuation flights routinely at cabin altitudes above feet .
8,000
The studies reported here show that conditions of reduced barometric
pressure can alter drug action and metabolism .
These results may make it
necessary to re-examine the dosage of drugs administered to humans at altitude .
Summary Mice maintained at
18,000
feet for five days and then infected with
125
mg .
hexobarbital/kg . were found to have decreased sleeping time, smaller concentrations of brain hexobarbital
50
minutes after infection, and increased liver
microsomal metabolism of the drug compared to ground level controls . the same conditions, brain levels of hexobarbital same for both groups .
Under
in awakening mice was the
The significance of these observations
is discussed in
relation to changes in drug action at altitude .
References
97, 540 (1931) .
l.
D . L . Macht, J . Am . Physiol . Soc .
2.
A . W . Moore and J . C . Ward, J . Am . Pharm. Assoc . Scient . Ed .
24, 460 (1935) "
3.
I . P . Baumei, S . M. Robinson and W. F . Blatt,
56, 918 (1967) .
4.
A . J . Nedzel,, J . Aviat . Med .
5.
F . Sparuteri, Riv . Med. Aero .
6.
S . Robinson, W. Blatt, R . Schatz and R. Joy, Fed. Proc .
7.
J . R . Cooper and B. B . Brodie, J . Pharmacol . Exp . Therap .
8.
R . Kato and J . R. Gillette, J . Pharmacol . Exp . Therap .
9.
B . D . Rupe, W . F. Bousquet and T . 5 . Miya, Science
J . Pharm. Sci .
26, 164 (1955) " . 23, 397 (1960) " 27, 283 (1968) . 114, 409 (1955) "
150, 285 (1965) .
141, 1186 (1963) "
Vol . 7, No . 21
EFFECTS OF ALTITUDE
10 .
R . L . Furner and R . E . Stitzel,
Biochem. Pharmacol .
11 .
W . R . Christensen and A . B . Hastings, J . Aviat . Med .
12 .
W . J . Waddell and T . C . Butler, J . Clln . Invest .
13 .
K . R . Reissmann, Am . J . Physlol .
14 .
G . R . Fryers, Am . J . Physiol .
15 .
V . C . Ellis, S . Afr . J . Med . Sci .
167, 52 (1951) .
171, 459 (1952) . 18, 45 (1953) "
1169
17, 121 (1968) . 20, 221 (1949) .
36, 1217 (1957) "