Pharmacokinetic considerations in the camel (Camelus dromedarius): A review

ISSN 0742s8413/96/$15.00 I’ll SO742-8413(96)00120-X

Camp. Biochem. Physiol. Vol. 115C, No. 1, pp. 1-9, 1996 Copyright 0 1996 Elsevier Smnce hc.

ELSEVIER

Pharmacokinetic Considerations in the Camel (Camelus dromedarius): A Review B. H. AL,* M. Oukessout and A. K. Bash” *DESERT AND MARINE ENVIRONMENTRESEARCHCENTRE, UNIVERSITYOF THE UAE, Aox 17777, AL-AIN, UNITED ARAB EMIRATESAND *DEPARTMENT OF PHYSIOLOGYANII THERAPEUTICS, HASSAN II AGRONOMIC AND VETERINARYINSTITIJTE,RI’ 6202, RABAT, MOROCCO

P.0.

ABSTRACT. matory

In this article

agents

in camels

discussed. Copyright

been

the pharmacokinetic

has been 0

KEY WORDS. Camels,

reviewed.

profile

The

effect

Scww

1996 Elxvier

pharmacokinetics,

of several

antibacterial,

of dehydration

antiparasitic

on the kinetics

Inc. COMP BIOCHEMPHYSIOLllX;l:l-9,

antibacterial

agents,

antiinflammatory

and antiinflam-

of these

drugs

has also

1996.

agents,

antiparasitic

agents,

dehydration

different

INTRODUCTION The Arabian domestic

camel

animal

pastoral

societies

as a source

and for draught used in sport

(Camelus

dromedarius)

in arid and semi-arid of meat,

and transport.

races,

is an important

zones.

It is used in

hair, hides

and milk,

In the Gulf countries

and in other

countries

it is

it is a popular

zoo animal. Although search

more

recently

a minor

attention

(43,48,52,51,54),

species

Most of the research assumed,

without

and kinetics

to camel

re-

the camel is still currently

on the camel

production

albeit

given

in terms of pharmacological

ology, anatomy dynamics

has been

research

is concentrated

and diseases

scientific

(48,51).

(3,4).

in physiIt is often

basis, that the pharmaco-

of therapeutic

agents

in the camel

are not different from that of other large domestic animals, such as equine and bovine animals. In most cases, drug manufacturers

give no specific

Therefore,

recommendations

the doses used clinically

ally extrapolated

(on

mended

for other

because

toxic

a mg/kg

large animals.

or even

fatal

camels given certain drugs at doses harmless to other species (4).

of the fact that camels logical

and biochemical

this species

(32,44,45),

disposition

of drugs

possess

doses

This is not without

reactions

Pharmacokinetics describe ment of a drug into, around

from

sometimes which

This has been

are usually raised

where

water is scarce.

to dehydration

for relatively

(53). In view of the physiological

ical changes

that

accompany

that the disposition dratlon.

of the desert,

are well adapted

dehydration,

and biochemit is expected

of drugs may also be affected

In this article

the effect

by dehy-

of dehydration

on some

drugs will be reviewed. Pharmacokinetic

studies

can help in selecting view of the termining control

(and

other

dose regimens

use of camels

animals)

and can, in

in racing,

aid in de-

that can be useful for anti-doping

(26). The present

comment from

increased

in camels

appropriate

base parameters

article

on the pharmacokinetic

will gather

together

data in camels

and

reported

1980 to 1996.

ANTIBACTERIAL Tetracyclines

danger

Oukessou

occur

in

are apparently

anatomical,

that are peculiar

it is reasonable

to assume

may also be, more

that

to the

or less,

that

the pharmacokinetics

of oxytetracycline

after intravenous

(i.v.)

(OTC)

of a long-actin camels

administration

and

of OTC

(5 mg/kg) the mean residence time (MRT) was 77.0 & 2.8 hr, and steady-state volume distribution (V,,) was 75.3 2 23.2 ml/kg/hr. (10 mg/kg),

After

intramuscular

maximum

concentration

+ 0.44 pglml)

(i.m.) (C,,,,)

administration of OTC

(3.49

was seen after 7.3 ? 3.5 hr, the mean

sys-

temic availability was near 100X, and serum concentration >0.5 ,ug/ml was maintained for about 72 hr. Plasma

Address reprint requests to: R. H. Ali, Desert and Marine Environment Research Centre, Univekty of rhe UAE, P.0. Box 17777, Al-Ain, United Arab Emirates. Received 7 June 1995; accepted 14 June 1996.

AGENTS

(41) studied

ing formulation found

physio-

characteristics in camels

long periods

animals.

of drugs. Camels

conditions

animals

recom-

are usu-

the time-course of the moveand out of the body. In view certain

in the harsh These

large domestic

with a number

for the camel.

in this species

basis)

from other

confirmed

OTC

concentration

of 0.5 pguglml has been

sug-

gested to be effective against a wide spectrum of bacteria. It was concluded that the long-acting OTC preparation may be therapeutically found

that

useful.

the highest

Earlier, serum

in camels,

concentration

El Gendi after

(20)

i.m. ad-

2

B. A. Ali et al.

ministration

of OTC

at a dose of 3 mg/kg was reached

0.74 hr and that the distribution (t,,J

and elimination

were 0.17 hr and 7.0 hr, respectively.

that camels tribution

behave

similarly

and elimination.

believed

OTC

with little metabolism Z-2.5

mainly

or tubular

of hydration times

It was concluded

in terms of OTC

This was surprising

is eliminated

ma1 conditions about

to cattle

because

by glomerular secretion,

filtration

than

doses as low 1 mg/kg their

This,

to their

in addition

The

use in camels uneconomical tioning

that

stricted

to gram-negative

nor-

rate

is

cows (55).

newer

agents

was studied

obtained

results showed

0.6 IU/tnl

penicillin

(6000

after a single i.m. injection that the absorption

IU/kg)

(20). The

was rapid with

seen after 0.5 hr and the tiir of elimination

hr. The pharmacokinetics kg) was compared

of benzylpenicillin

in camels

0.6

(10,000

IU/

and sheep after i.v. administra-

tion (32). The tljr of elimination

and volume

at steady state (V,,) of the drug were similar

in both species.

The

was about

total

body clearance

the value obtained

in sheep.

dosage

regimen

longer

MRT and higher

ferences

Consequently,

plasma

could be explained plasma

that in camels

will result

level in camels.

These

flow in sheep

dif-

of benzyl-

filtration

(28)

is more

rate and

than

double

(22). Also, the MRT of benzylpenicillin

twice as long in camels

in

as in sheep.

This indicates

was

that the

in the body is much

in the camel.

these drugs are not commonly

cokinetics

of gentamicin,

ported These lowered

differences

dogs,

sheep,

to be longer guinea

ability

re-

(50).

on the basis of the (3) as the

(50).

inhibitory

above

tljr of the drug (3.1 i

concentrations

not

been

that

of mi-

are suscep-

determined

(1).

a level of 12 pug/ml is toxic

It is known

hepatic

that

the

is increased

diseases

seem to be justified,

as there

tolerance,

in

data has been obtained

(5,ll).

likelihood

of

in subjects

with

For all the

reasons

in camels

does not

the use of aminoglycosides

on the kinetics,

amino-

a dose of 2.75 mg/kg of gen-

nephrotoxicity

are relatively

insufficient

data

and efficacy of these drugs in this

species.

Sulphonamides Sulphadimidine

kinetics

in camels

et al. (58),

and El Sheikh

to kinetics

in sheep

slowest

in camels

3 hr) was found

(49). However,

(58).

were studied

et al. (21),

and goats.

and fastest ranged

It was further

dimidine

The

by Younan

and were compared plasma

clearance

was

in goats. The t,/: in camels was

from 8.7 to 16.5 hr, and the CLR

metabolism metabolic gested

pathway

bacterials

the

presence

(2).

These

values reported

in the camel was sug-

in camels

results

of

of an alterative of sulfa-

after iv. and oral

showed

that

the

main

were in the same range of magniin cows (33).

of some

in camels

of sulphapathway

the pharmacokinetics

was studied

pharmacokinetic A summary

and

recently,

methoxypyridazine

goats, birds and man

the acetylation

for sulphadimidine

(58). More

administration

in cattle, that

over the hydroxylation

in camels,

tude as those

to pro-

found

predominates

water

pharmacokinetic

is given

in Table

variables

of anti-

1.

(see below).

In another experiment by the same group (1) tobramycin (1.3 mg/kg) kinetics was studied in healthy camels, and the of kanamycin

and/or

cited

than

This gives a C,,;,, of 11 pug/ml in plasma.

camels.

In the latter

to the unique

12 hr was suggested levels

that

in the body. The dif-

in the camel

and safe plastna

than

pigs and man

to be related

mechanisms

have

t,,: in cam-

of the camel

are not metabolized

study a dose of 8.5 mg/kg every duce effective

Kanamycin

could not be explained

were suggested

conservation

used, the pharmaand kanamycin

(1,49,50,60).

drug metabolizing

aminoglycosides ferences

tobramycin

2 0.28 hr) was found

in horses,

renal

are

and nega-

effects.

man and rat (25). Pharmacokinetic healthy

aztreonam

of camel origin which

was lower than that reported

in camels

and

more expensive

have

however,

aminoglycoside

Some

7.4 hr, in sheep 4.7 hr, and in goats 2.77 hr. The elimination

Although

els (3.02

in camels.

It is known,

t,!; (in 3 camels)

Aminoglycosides

been studied

the minimum

is re-

infections.

gram positive

no nephrotoxic

from isolates

in humans

on the basis of the renal func-

The glomerular

mean time passed by the drug molecule longer

half

using the same

species

camels and sheep in elimination

tion of the two species. the renal

in camels

in the two ruminant

between

penicillin

(CL,)

susceptible

and not much

and have

monitoring.

unsafe. It is worth men-

as cephalosporins

to aminoglycosides

from

of distribution

and/or

Wasfi et al. (50) recommended tamicin

drug

high cost, may make their

life-threatening

against

croorganism tible

initial

use of aminoglycosides

such

equi-effective

In camels,

of sodium

in camels

the

tive organisms

Pencillin)

pharmacokinetics

use may require

dis-

glycosides, Pencillin S (Ben&

can cause some signs of nephrotoxic-

ity. In addition,

it is

filtration,

and under

glomerular

lower in camels

after

half lives

to be similar

to that

a dose rate of 2.5 mg/kg

ad-

ministered at 12 hr intervals was recommended for tobramycin (1). It was reported that significant hepatic or renal adverse effects were not found after tobramycin or kanamytin administration (1,49). However, aminoglycosides are antibiotics with a low margin of safety, and are considered obligatory nephrotoxicants (13). In animals and humans

ANTIPARASITIC Triclabendazole The

pharmacokinetics

AGENTS of the anti-trematodal

drug tricla-

bendazole (10 mg/kg, orally) was compared in camels and sheep (38). The parent drug was not detected in the plasma of both species due to hepatic first pass effect. There was a significant difference between the two species with respect to triclabendazole metabolites. Triclabendazole sulphoxide concentration in camels was found to be half rhat in sheep.

6000

Penicillin G Tohramycin Kanamycin Gentamicin Streptomycin Oxytetracycline Oxytetracycline Sulphadimdine Sulphadimidine Sulfamethoxypyridazine Tylosin (hydrated camels) Tylosin (dehydrated camels) Chloramphenicol (hydrated camels) Chloramphenicol (dehydrated camels Enrofloxacin (dehydrated camels) Enrofloxacin (hydrated camels)

iv.

i.m.

2.5 mg/kg

i.m.

50 mg/kg i.m.

i.m.

50 mg/kg

2.5 mg/kg

i.\

10 lug/kg

i.u/kg i.m. 1.3 mg/kg i.v. 6 mg/kg i.v. 3 mg/kg i.v. 10 mg/kg i.m. 3 mg/kg i.m. 5 mg/kg i.v. 100 mg/kg i.v. 50 mg/kg i.v. 100 mg/kg iv. 10 mg/kg i.v.

1000 i.u/kg

Dose/route

Benzyl penicillin

Drug

TABLE 1. A partial list of pharmacokinetic

1.09 3.15 3.03 2.92 8.22 7.0 7.7 7.4 13.2 9.5 0.91

0.81 -c t i-c -+ t ++ 2 -c c

0.05 0.12 0.28 0.12 0.24 0.41 0.08 1.6 2.4 0.6 0.13

?I 0.05

t,/z (h)

3880

i

412

68.8 34 75.7 40 2222 39.73

_

t

3.6

? 41.2

t 0.16 * 0.09 2 0.09

1.22 0.34 0.66 0.62 2393

? +2 i i

706.1 394 730 470 11930

2 0.28

0.9 i- 0.04 1.21 ? 0.11 1.05 -+ 0.08

4.87

CL* (mllminlkg)

228 +- 9.4 304.4 ? 17.1 260.6 2 12.8

151 ? 0.01

(m>kg)

data of antibacterial drugs in camels

15936.7

72.3 2 9.8 2598.6 i 3625 1329 2 156 1293.6 3108.0

20.79 2 114 (iu-min/ml)

AUC ,ug.hlml

2.85

1.44

2.2

3.8

7.81 + 0.11 1.5 + 0.1

0.6 2 0.01

? 0.01

24 24

0.5

56

56

61

6:

41 21 58

20 1 49 50 20 20

1.0

1.40 -c 0.01 1.10 -c 0.05

0.53

37

Ref.

w

4

B. A. Ali et al.

This

could

absorption

be explained

by a reduction

from the digestive

in triclabendazole

lower than those reported

tract in the camel as reported

for other drugs (39) and/or

that the camel has lower hepatic

metabolizing

in sheep,

activity

than

sults (3). These

findings

ommendations

for camels.

confirming

earlier

reached cattle

re-

also stress the need for specific

rec-

pharmacokinetics

and the prodrug formations camels sheep,

netobimin

Compared

it appeared

of both

than

bimin

was higher

camels

in camels

age, albendazole

lsometamidium

of 9-10

chloride

has been

dos-

which

is

found

to in

is not readily

rapidly

a plasma com-

results differ

These

within

differences

to the method

normal

24 hr, 2

could

be as-

of the drug

suggests

to metabolize

for the susceptibility doses

of

of isometamidium

It does not seem to be re-

behaviour

protein

and cattle.

The kinetic

of flunixin

The results indicated blood

in the camel a single iv. in-

that flunixin

was maintained

above

is similar

to that in horses

Flunixin

disposition to that in

by the kidney,

of the drug in camels

may be related

when

to the relatively

the slower

compared

to cows

low glomerular

flow in camels

con-

0.75 ,ug/

differs from that in cows, but is similar is eliminated

drug

and used in horses

(3), following

from that in cows (10,46).

As flunixin

clearance

binding.

antiinflammatory

disposition

ml for about 6 hr. This duration

horses.

in camels in the hump

DRUGS

by Oukessou

in camel

be

data of antiparasitic

has been widely studied

(1.1 mg/kg).

would

postulated

2.

nonsteroidal

which

in camels

in tissues and milk, in camels

The authors

in Table

doses.

and other

of ivermectin

of plasma

is a potent

but different

camels

filtration

(22) compared

to that

in cows (35). It was concluded

that using the same dosage

regimen

and cattle

lower

of flunixin

in camels

pharmacological

effectiveness

would

result

in

in camels

than

in

cattle.

of the drug in this

the drug may be transformed, in that are responsible for the tox-

Phenylbutazone

unstated

(PBZ)

drug’s absorption were lower and longer, respectively, those reported for cattle and sheep. The absorption

than tljz in

longer than that reported (2.68 ng/ml) considerably

abstract)

were compared

after i.v. and oral administration

oral administration,

The pharmacokinetics of ivermectin was studied in 3 camels injected S.C. (0.2 mg/kg) (12). The rate and extent of the

of PBZ at a dose of 4.4 mg/kg

in the published

els and sheep

Ivermectin

(1.19 days) was ten-fold and the C,,,, in camels

species.

concentration

is given

The pharmacokinetics

for cattle,

periods

of some pharmacokinetic

was investigated

that anthelmin-

from the drug’s sequestration

(NSAID),

jection

residues

withdrawal

in camels

paradox

in divided

between

that ivermectin

fat, or its high degree

Flunixin

This

they are given

differences

may have resulted

However,

efficacy against

in terms of the longer duration

from that in other

A summary

species.

in the camel to lower concentra-

when

rate and renal plasma

of measurement,

icitv.

camels

increases

centration

(29), or pigs (30), in which

apparent.

It is possible that into metabolite(s)

that,

and disappeared

48 hr (7). These

The reason

lated to the pharmacokinetic

showed

of 0.2 mg/kg would

in other

since it has been shown

that the low plasma

it has been found

of the pigs, goats, and cattle with

in camels

and endoparasites.

of the parasites

tic efficacy

different is

trypanosomes

in the limit of detection

experiments,

to toxicity

species. camels,

ecto-

tions of ivermectin,

species

than

by the authors

and consequently,

bioavailabil-

the drug reached

from the circulation

the drug more rapidly. chloride

in

of neto-

30 min after administration.

declined

to differences

or to the ability

of the camel

The pharmacokinetic

In this respect

in camels

mg/kg,

pg/ml

hr, and 24 hr, respectively.

camels

various

in the camel

in goats (6), cattle

in the various

like that

as a solution

drug which

however,

the drug disappeared cribed

more

while after netobimin

already

from the blood within

from those

and the disposition

were

and safe against

The concentration pletely

and

and toxic (7,8). A study of the pharmacoki-

concentration

times longer

The above pharmacokinetic

that this dose has excellent

ANTIINFLAMMATORY Flunixin

when given i.v. at 0.5-1.0

was three

than in molecule

it is well known was explained

and C,,., was

intact

in camels

Chloride

of isometamidium

for the

be less effective

agents

animals,

and sheep,

taken

species.

by the abomasum.

effective

to be ineffective netics

time

the body (MRT)

of exposure

in 10

in cattle

the bioavailability

of particles,

is an antitrypanocidal

domestic

work

(19). The higher

is produced

absorbed

be both

biotrans-

was studied

that of albendazole.

to sheep

orally)

may be due to the fact that albendazole

given as a suspension

This

whose

metabolites)

In camels

than

were similar

better

(anthelmintics

that the metabolism

in cattle.

ity of netobimin

(10 mg/kg,

to previous

anthelmintics

sheep

through

The

than in other ruminant

most

of albendazole

lead to identical

(19).

or sheep.

for cattle

three times slower in camels

results may suggest that an S.C. injection

Netobimin and Albendazole The

approximately

the absorption

(dose

in cam-

(39). After

of PBZ was slower

and

lower in the camel than in sheep. Systemic availability was approximately 23.8% in camels and 55% in sheep. Following i.v. administration, both CLr, and Vss of PBZ were higher in camels than in sheep. These differences were attributed to a lower degree of PBZ binding to plasma proteins in the camel. Indeed, for PBZ concentrations varying from

Pharmacokinetics

in Camels

TABLE 2. A partial list of pharmacokinetic

data of antiparasitic agents in camels

0.5 or 1 mg/kg

Isometamidium chloride Triclabendazole* (T) T. sulphoxide T. sulphone Netobimin* (N) N sulphoxide N sulphone Albendazole”

b&%

(m&W

04

T

C

AUC

t112 Dose/route

Drx

G

Ref.

-

7

9.8 _t 0.2

(i.v.)

10 mg/kg (P.0.) 20.7 t 1.6 25.1 ? 2.1

4.54 2 1.25 2.40 -t 0.85

294.8 5 69.2 152.7 ? 51.2

0.5 2 0.1 0.5 -c 0.1

38

15.8 mg/kg (P.0.f -

(A)

71.7 36.4

2.59 1.34

20 76

19

32.9 21.9

1.42 0.95

20 70

19

10 mg/kg (PO.)

A sulphoxide A sulphone Ivermeccin

0.2 me/kg

2.68

66.30 + 11.7 ng. day/ml

412.8

(S.C.)

-c 0.32

103.2

31.0

?

12

ng/ml

Values recorded are means + s.e.m. (n = 3-10 camels). *Parent drug. Pharmacokinettc data are reported for the metaholites. p.0. = orally, i.v. = intravenously, 5.c. = subcutaneously.

5 to

3 to

100 lug/ml,

18.4%

(Oukessou,

the

fraction

unbound

in camels compared unpublished

data).

lite of PBZ (oxphenbutazone) in plasma

of both species.

large quantities ment

with

dosage regimen in reduced

of this

PBZ (31).

active

of PBZ recommended

effectiveness.

observed

0.174

hr, and in other

in other

and Zine(27). For

similar results were obwork was 0.162

parameters.

large differFor example,

and Zine-Filali

(39) was 27.9

(27) it was 17.2 hr. The

differences

laboratory

is not clear

and inter-animal

tljz in the

but may be due to inter-

differences,

breed

differences,

causes.

Antipyrine

into

total

plasma

administration

(40). Following

Its

after i.v. and i.m.

i.v. administration

(2.2 mg/

kg), the CLR was 0.597 ml/min/kg and the elimination tl/l 5.19 hr. These values are different from those reported in cows (1.60 ml/min/kg and 2.67 hr). These differences between

camels

and cows could be attributed

effects

TXBz levels

in

of several

ANTIPYRINE

body

used as a marker for xenobi-

(47). It is completely

inactivation.

water

with

negligible

It has been shown

such as sheep,

goats and Wistar

has been subsequently the United

camels

Arab

confirmed

by the antipyrine

antipyrine

(25 mg/kg)

disposition

followed goats

tiiz was longest

and clearance goats. Thus,

of phase

or

I and

in other

species

by 3). This (18) and

in piitro results

test in an experiment

was injected

by sheep,

to tissue

in Saudi Arabia

to that

antipyrine

slowest

(21).

sess lower drug metabolizing ability than confirmed both in vitro and in uiwo.

The

followed

that camels other

sheep

elimination

in the camel,

the suggestion

and its

in desert

in the same manner that

were where

i.v. in camels,

and compared treated

that

rats (reviewed

(4). These

of this work indicated then

enzymes than

confirmed

Emirates

binding

from

distributed

that the basal activities

of the drug metabolizing

II are lower in Sudanese

cleared

It is rapidly

species

poswas

to differences

in ketoprofen metabolism and/or excretion. Following injection at the same dose, C,,,, in camels (14.7 pg/ml) double profen

ability

proteins.

Ketoprofen is a NSAID widely used in human

medicine.

NSAIDs.

OF

the body by hepatic

results

in camels

serum

and other

is a drug commonly

otic metabolizing

and Nubian

were studied

plasma

ecosanoids).

to measure

ketoprofen

PHARMACOKINETICS

Ke toprofen

pharmacokinetics

cyclooxygenase-derived

are in progress given

to correlate

pharmacological

the

for sheep would result

However,

of

to their

treat-

work was 22.1 hr and in the later 12.5 hr. The cause

of these or other

work

in camels

and extended

l/kg.

MRT in the work of Oukesson former

following

the Vd in the former

For example,

and in the latter, were

Studies

are needed

of NSAID

inhibition

camels

The work of Oukesson parameters,

pharmacokinetic

(i.e.,

in trace amounts

that

investigations

concentrations

the horse produces

metabolite

It was concluded

certain

ences

metabo-

was present

confirmed

l/kg,

hydroxylated

Interestingly,

Further

from

in sheep

The

Filali (39) was recently tained.

of PBZ varies

to 0.8-6.7%

that in cows (7.1 pg/ml), resulting in a higher bioavailability in the former species.

i.m. was keto-

EFFECT ON

DRUG

OF

WATER DISPOSITION

DEPRIVATION IN

CAMELS

Most of the pharmacokinetic data reported in camels were derived from animals watered ad &turn. However. in its

6

B. A. Ali et al.

native

arid habitat,

scarcity

of water,

the camel

is usually

and this species

confronted

is often

allowed

water once every 4 or more days. Dehydration changes

in basic physiological

and may influence water deprivation investigated (1456).

for several

absorption pected

into

hepatic

treating

account

loss in body weight organs

these processes

Vss were noted

the delay in Tylosin

the ex-

Tylosin

disposition

was markedly

As the liver and kidand excretion

that dehydration

may in-

Dehydration

of data

of

of the drug at doses of 10 and 20, respectively,

were significantly administration

reduced

(57). The folfrom dehy-

AUC

respectively. was three

pared to normally

pared in normal

antibiotic

and water-deprived

camels

found that a 7 day water deprivation or elimination

tions were noted

eliminated

Its disposition

Significant

in both the rate and the extent

tion from the i.m. injection

the plasma

time

two times

drated

(AUC),

camels.

were about

This reduction

in gentamicin

was attributed

to reduced

i.m. injection

site. It is interesting

presence caused

of both

diuretic

a reduction

mer

that

of gentamicin

(34)

have

recently

and a high such

nephrotoxicity

treatment

( 17). However,

tration

of absorp-

concentration bioavailability at the that

the

rate of fluid loading could Obatomi

in rats. It reduce

the

and Plum-

very similar.

func-

It is concluded

that

the to be

camel. cam-

for tylosin adminis-

ENF administration tion

the turn-

tion.

tliz shorter,

however,

to dehydrated than

dose was

V4

absorption

NFN

(24). After NFN treatment, and dehydrated

were significantly in watered

during

tamicin

were

measured

not distinguish

were

camels

mean serum drug and the elimina-

camels.

Interestingly,

se-

of NFN although

the

to those

of the latter.

camels

the 4 hr following

higher,

This was explained

of ENF or to its limited

had a more rapid passage

over of cells and enzymes excreted into the urine. In camels, however, it is not known whether nephrotoxicity (due to gencamels.

camels

rum ENF levels were similar complete

(EFN) (2.5 mg/kg) and norwere injected i.m. into normal

in watered

In contrast

concentrations

former’s

would occur in dehydrated

rate

are reduced

camels.

(10 mg/kg)

that the drug could mastitis. It is worth

overdose)

may be due

elimination

seen in the water-deprived

enrofloxacin

(NFN)

and 14 days dehydrated

gen-

and increasing

there

that iv. is the route of choice

drug concentration

water

by altering

effects

by i.m. route appears

for the dehydrated

quinolones

floxacin

in rats both

that

liver and lung).

time

Fluoroquinolones The

in dehy-

here

i.m. the

camels when com-

These

(in which

dose of 20 mg/kg

to ill dehydrated

for 24 hr could potentiate

reported

loading and water deprivation tamicin

either

blood circulation to recall

camels.

The low i.m. availability els implies

and water-deprived

was injected

into tissues and slower camel

iv.

reduc-

lower

in serum levels of gentamicin

was thus suggested toxicity

peripheral

insufficient

It was

site. The C,,,:,,, the time to reach

C,,,,,, it,,,;,,), and the area under curve

(59,60).

did not influence

of gentamicin.

ex-

was com-

tylosin

in water-deprived

watered

of kidney,

recommended

distribution

When

about five times higher

tions

Sentamicin

After

times lower, and the mean absorption

in the dehydrated

by the kidney.

deprivation.

tl/z were 55 min and 91 mm,

and Vss 12 l/kg and 3.9 1 /kg in normal

to less distribution

is an aminoglycoside

by water

the elimination

camels,

rate and

parame-

from i.v. and i.m. ad-

compart-

reduced

obtained

ministration

by 14 days wa-

pharmacokinetic

also leads

central

camels.

unchanged

influenced

rate of elimination)

to the

rate

at the doses

no sign of toxicity.

ters (including

from the muscles

clusively

(56). The antibiotic

affect both

water

a 14 day water dep-

a slower elimination

and can severely

extent

Gentamicin

following

(61). Th e major

( 1554).

is a brief description

used produced

reduced

iv. administration

ter deprivation

in significantly

drated

After

chloramphenicol(50

from the i.m. injection

examining

by dehydration

ment of the body resulting lowing

site were significantly rivation.

and OTC,

rate and extent

days causes

in the camel.

of drug absorption

for gentamicin

absorption

for antipyrine

when

of metabolism

of body

mg/kg)

for 7-14

most drugs, it would be expected to redistribution

of

As reported

and higher

to optimize

Dehydration

(53)

Effects

Chloramphenicol

in camels were

sick animals,

in order

and renal functions

fluence

that

of drugs induced

effect.

neys are the main

and

concluded

and when

therapeutic

a 15-25%

of the camel

in this species.

antibacterials

and excretion

must be taken

may lead to

on drug pharmacokinetics

It was generally

drug efficacy,

functions

drug kinetics

with

to ingest

by the

tissue distribu-

into milk, suggesting

be useful in the systemic treatment of mentioning that the fluoroyuinolones

microbiologically. between

The

method

used does

enrofloxacin

and its active

meta-

was reported

to be slower

when

bolic ciprofloxacin. Oxytetracycline Yagil et al. (57) studied OTC disposition in normal and 12 days dehydrated camels following i.v., i.m., and S.C. administration. Water deprivation was found to significantly reduce the Vss, urinary recovery, and bioavailability of OTC. When using a long-acting formulation of OTC, reduction in bioavailability was only observed for the S.C. injection.

Antipyrine Antipyrine

elimination

camels were deprived of water for 10 days (14). This was suggested to be due to diminished enzymatic activity and/ or changes in water compartments as indicated by the sig-

nificantly

7

in Camels

Pharmacokinetics

different

Vss of antipyrine

in the

drugs, and may therefore

dehydrated

ules in dehydrated

camel.

An important CONCLUSION It would

appear,

frotn the results

macokinetics

of several

drated

is different

camel

drugs

in the

from that

mals. The basis of this species may be multifactorial. Pharmacokinetic the

liver

and

a relatively

higher

larger species. chemical

Camels

to xenobiotics,

to them.

than

most other

animals,

possible

be that,

the animal

thereof)

may be deficient

bility was tested

and confirmed

in the liver, kidney

sheep,

species.

in camels that

the

cantly

were

drug

is metabolised

42.7 min; in goats 22 min). was the sulphate, The different other ences

extent

dotnestic

influence

while

could

disposition

be noted

affect drug kinetics

differences

healthy

animals

dard hygienic

factor

section

conditions,

in camels

causing

may differ-

in sheep

factors

known

treatment

to

with

etc.) and other factors such were not involved

in the

as all animals

used were

more or less similar

and stan-

and were provided

where

that

species

on phenylbutazone).

above;

under

conditions,

(6).

and the

is phenylbutazone

health

reviewed

ud libidium (except

be another

(e.g. diet, concomittant

kept

(t,,? in camel

in camels

of drugs,

and general

species

to a signifi-

in goats

that environmental

other drugs, housing as age, gender

the

it was found

binding

of this

(see earlier

It should

in dif-

this fact. When

The main metabolite

of protein

(15). An example

and camels

pathways

data from studies

in goats it was the glucuronide

animals

the

mucosa

The same drug may

and eliminated than

(or

This possi-

of drug metab-

paracetamol,

in camels

may

enzymes

and duodenal

metabolic

with

to An-

difference

or lacking.

corroborates

injected

lesser extent

(53) compared

we have obtained

and goats which

two species

in their re-

15% are fatal.

for a number

via different

Recently

and bio-

losses of body water

goats and rats (3,42).

he biotransformed ferent

than

drug tnetabolizing

olizing

of camels,

have

capacity

of drugs given

for the species

certain

the higher

generally

may be reflected

losses over

explanation

enzymes

species,

of

to basic

physiological

tolerate

food and water

mentioned).

The above results stress the need to study the pharmacokinetics of any particular drug in the target species itself, and to minimize

dependence

on extrapolation

of dosage reg-

imens from one species to another. It should also be emphasized that dehydration, which is a distinct possibility in camels raised significantly

naturally

in

pastoral

nomadic

alter the pharmacokinetic

The camel

countries

individual

of drugs in camels in meat

camel

is slowly becoming Therefore,

drugs need to be determined

liver

of drugs and other

is eaten

recognised a commodity withdrawal in treated

un-

as a farm on the times for camels.

drug concentra-

species

body weight

where

in camels,

isoenzymes

rate of the animals.

are related

camels

25% of their

In some

in many countries.

and in the disposition

For example,

greater

tissues.

residues

and camel milk is fast becoming

these

which

and the xenobiotic

market

and

have peculiar

milk,

edible

dosage sched-

is the passage

animal

biotransformation

characteristics

sponse

other

drug

into

studied

but

is not certain,

influence

smaller

has thus far not been

of the drugs in ques-

to the functions

rate. Therefore,

aspect in the disposition

that

cooked.

domestic

are related

(23). The smaller

its metabolic

and dehy-

modified

ani-

difference

that

tissues

and the kidneys,

metabolism

hydrated

of the metabolic

processes

in blood

that the phar-

of other

The disposition

tion may be a function tions

presented,

necessitate

camels.

societies,

properties

may

of certain

Thanks to Mrs. Yasmeen B&jut S&em for patiently typing the manuscript. 13. H. A. acknowledges the help of May B Baker (U. K.) the Unielersity of Khartoum, and the U.A.E. Uniwersity in supporting some of the ulork cited in this review.

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