Review Paper

A Survey of the Literature (1995^1999) on the Kinetics ofDrugs in Camels (Camelus dromedarius)

A.A. Alquarawi and B.H. Ali*Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine,King Saud University, Buraydah, Saudi Arabia*Correspondence: POBox 10158 Buraydah, Al Gaseem 81999, Saudi Arabia

Alquarawi, A.A. and Ali, B.H., 2000. A survey of the literature (1995^1999) on the kinetics of drugs incamels (Camelus dromedarius).Veterinary Research Communications, 24(4), 245^260

ABSTRACT

Recent publications dealing mainly with the kinetics of antiparasitic and antibacterial agents, NSAIDs,and other drugs in camels are brie£y reviewed. The kinetic data for most of these drugs indicated thatthey have longer absorption and elimination half-lives and slower systemic clearance in the camelcompared to other animals. This corroborates earlier reports that suggested that the activities of drug-metabolizing enzymes and the capacity to biotransform and eliminate xenobiotics is lower in camelsthan in other ruminants. There is a clear need to establish basic kinetic data for the camel in order toavoid extrapolation of drug dosage regimens and withdrawal times from data for other animals, as thismay result in irrational use of drugs in camels.

Keywords: anthelmintic, antibiotic, camel, chemotherapy, enzymes, pharmacokinetics, xenobiotic

Abbreviations: AUC, area under the curve; Cmax, maximum concentration; CYP, cytochrome P450;DME, drug-metabolizing enzymes; i.m., intramuscular(ly); i.v., intravenous(ly); IVM, ivermectin;MRT, mean residence time; MXD, moxidectin; NSAID, nonsteroidal anti-in£ammatory drug; s.c.,subcutaneous(ly); SDM, sulphadimidine; SDZ, sulphadiazine; tmax, time to reach maximum concen-tration; t1

2b, half-life of elimination;Vd, volume of distribution

INTRODUCTION

The dromedary camel (Camelus dromedarius) is an economically important animal inpastoral societies in Africa and Asia, where it provides draught and transportation,and constitutes a signi¢cant source of meat, milk, hide and hair. In certain ArabianGulf countries it is widely used for racing. In the rest of the world it is a popular animalin zoos.

Until relatively recently, the camel was considered a minor species as far aspharmacological research is concerned (for reviews see Ali, 1988; Ali and Elsheikh,1992a,b; Ali and colleagues, 1996b). However, the last decade has witnessed a surge inpharmacological research in the camel, almost entirely in the ¢eld of pharmacoki-netics. This stemmed from the need to establish drug dosage regimens in the camel, as

Veterinary Research Communications, 24 (2000) 245^260# 2000 Kluwer Academic Publishers. Printed in the Netherlands

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in most cases drug manufacturers give no speci¢c dosage recommendations for thisspecies. In practice, the use of drugs in camels, including dosage regimens andwithdrawal times, has been mostly based on data obtained from other ruminants,mainly cattle. This approach may lead to irrational drug use in the camel, resulting intoxicity (Ali and Hassan, 1986) or decreased e¡ectiveness (Oukessou, 1994). As thecamel is increasingly used for sport as a racing animal, there is a clear need for kineticdata to support forensic pharmacology for application in antidoping control and inrecommending withholding periods for certain drugs before racing.

The anatomical, biochemical and physiological peculiarities that characterize thecamel and di¡erentiate it from other ruminants may in£uence the disposition of drugs,their pharmacodynamic activity and their residues in edible tissues (e.g. Kadir et al.,1997; Oukessou et al., 1999).

Studies on the pharmacology of certain drugs in the camel that have mostly beenpublished in the last ¢ve years will be reviewed brie£y. This should be of value toveterinarians, pharmacologists and others interested in camels in facilitating theadoption of a rational basis for the establishment of dosage schedules in this speciesthat will avoid or minimize the presence of drug and metabolite residues in the meatand milk of camels raised for human food, and in the blood and urine of racinganimals.

ANTIPARASITIC DRUGS

Avermectins

Because of its e¡ectiveness, broad-spectrum activity and relative ease of administra-tion, ivermectin (IVM) is currently the drug that is most widely used to control endo-and ectoparasites in the camel. The kinetics of IVM was ¢rst studied by Oukessou andcolleagues (1996) in three camels. The drug was injected subcutaneously at the doserecommended for cattle (0.2 mg/kg), and blood was collected from the animals for upto 90 days. The area under the curve (AUC), which is an indicator of extent ofabsorption less metabolism/excretion, and the observed peak plasma concentrations(Cmax) (3.24 ng/ml) were considerably lower in camels than those reported for cows(54.6 ng/ml) and sheep (30.8 ng/ml). The time need to reach Cmax in camels was longerthan in cows or sheep (Alvinerie et al., 1996; Marriner et al., 1987; McKellar andBenchaoui, 1996). The rate and extent of absorption of IVM were therefore consideredto be lower in camels than in other ruminants. The mean residence time (MRT), whichindicates the transit of the drug through the body, was about three times longer incamels than in cows or goats (Alvinerie et al., 1993). These kinetic data suggest that asubcutaneous (s.c.) dose of 0.2 mg/kg might not be as e¡ective in camels as it is in otherruminants (Lanusse et al., 1997). However, ¢eld results seem to suggest that the drug ise¡ective at this dose against most endo- and ecto-parasites of the camel. Oukessou andcolleagues (1996) explained this apparent paradox on the basis of longer exposure ofthe parasites to lower concentrations of IVM, as the e¤cacy of anthelmintics tends toincrease when they are delivered in divided doses. Although no experiments to

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determine the withdrawal time or tissue residues have been conducted, judging fromthe kinetic results, it may be postulated that the residues of IVM in edible tissues andthe necessary withdrawal times are di¡erent in camels from those in other species.

More recently, a comparative kinetic study of IVM and moxidectin (MXD), amacrolide lactone belonging to the avermectin family, has been conducted on the milkand plasma of camels (Oukessou and colleagues, 1999). These drugs are substantiallyexcreted via the mammary gland owing to their high lipophilicity. As in the previousstudy, the kinetic data obtained from camels were markedly di¡erent for both drugsfrom those in other ruminants (Marriner et al., 1987; McKellar and Benchaoui, 1996;Lanusse et al., 1997; Toutain et al., 1997). The AUCs of IVM for plasma and milk wereabout two-fold higher in goats (Alvinerie et al., 1993) than in camels. Similarly, theCmax values for plasma and milk were higher and occurred earlier in goats than incamels. The di¡erences were even more pronounced when camels were compared withcows. For example, the AUC and Cmax values for plasma were about 8 times higher indairy cows (Toutain et al., 1988) than in camels (Oukessou et al., 1999). In camels, as incows and goats, the IVM concentrations in the plasma closely paralleled those in milk.

As with IVM, the kinetic behaviour of MXD in camels was substantially di¡erentfrom that in cattle (Lanusse et al., 1997), but much less so in sheep (Alvinerie et al.,1998). In camels, the Cmax for MXD was about four-fold higher than for IVM(Oukessou et al., 1999). This is di¡erent from the situation in cattle, in which nosigni¢cant di¡erence in Cmax values of MXD and IVM was observed (Lanusse et al.,1997).

As far as we are aware, the metabolism of the avermectins has not yet been studiedin camels, although this aspect has been relatively well studied in other species (Steel,1993). Considering the di¡erences between camels and other species in the activity oftheir drug-metabolizing enzymes (Ali and Elsheikh, 1992a,b), it seems that there maybe di¡erences in the metabolism of avermectins between camels and other species.

Closantel and albendazole

Treatment of 75 camels infested with six di¡erent types of gastrointestinal parasiteswas attempted in Jordan using oral closantel (10 mg/kg) plus albendazole (5 mg/kg),either as a single dose or in two doses given two weeks apart (Al-Qudah et al., 1999).From faecal egg counts and generic identi¢cation of third-stage larvae, it was foundthat a single treatment with the drug combination reduced the egg counts by 100%,100%, 98% and 77% for Haemonchus longistipes, Ascaris spp., Monezia expansa andFasciola hepatica, respectively. Treatment with a second dose signi¢cantly raised thee¤cacy of the drugs. The treatment caused no adverse e¡ects on the camels, althoughthere had been some concern about the safety of closantel in animals. In overdose, thisdrug caused spongiform changes in the brain and retinal degeneration, hepatotoxicosisand myopathy in sheep, goats and dogs (see Al-Qudah et al., 1999, and referencestherein).We are not aware of any kinetic studies on closantel in the camel, but there hasbeen one study on the kinetics of albendazole in camels, which were given the drugorally at a dose of 10 mg/kg (Delatour et al., 1989). Compared to previous work in

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cattle and sheep, it appeared that the metabolism and disposition of the anthelminticwas more like that in sheep than in cattle. It would have been of interest if Al-Qudahand colleagues (1999) had conducted a kinetic study simultaneously with thetherapeutic trial in order to correlate the drug levels with the e¤cacy of the treatment.Kinetic studies in diseased animals may be clinically more relevant than thoseconducted in healthy subjects.

ANTIBACTERIAL DRUGS

Sulphonamides

Kumar and colleagues (1998) studied the kinetics of the broad-spectrum antibacterialagent sulphadiazine (SDZ), apparently for the ¢rst time. Comparisons of the data fromcamels with those reported from other species revealed a number of signi¢cantdi¡erences. For example, the elimination half-life of SDZ in camels was found to be23.1 h, two to four times longer than that reported for ewes, mares, pigs, cows andbu¡alo calves (see Kumar et al., 1998, and references therein). The volume ofdistribution of SDZ was signi¢cantly higher than that reported for ewes, mares andpigs, indicating that SDZ is more extensively distributed in the £uids and tissues ofcamels than it is in ewes, mares and pigs. Following oral administration of SDZ, theCmax and Tmax of the drug were signi¢cantly greater in camels than in other ruminants.The long absorption half-life, coupled with a high oral bioavailability (about 88%),indicated that SDZ was slowly but adequately absorbed after oral administration incamels. In view of the low drug-metabolizing enzyme activities (Ali and Elsheikh,1992a) and the slow water turnover (Yagil, 1985) in camels, a dosage interval of 48 hwas suggested for SDZ in this species in order to minimize possibility of toxicity(Kumar et al., 1998). In another study Kumar and colleagues (1999) studied thekinetics of sulphadimidine (SDM) (100 mg/kg, given i.v. and orally) in Indian camelsduring the hot summer season. SDM was found to be well-distributed in the body (Vd

= 0.86 L/kg), and was rapidly cleared from the body (Cl = 0.035 L/(h kg)). Theelimination half-life of the drug ranged from 14.2 to 20.6 h. Cmax after oraladministration (63.2 mg/ml) was achieved 24 h after administration. These results werebroadly similar to those obtained earlier by Younan and colleagues (1989) andElsheikh and colleagues (1991) in Sudanese camels. However, most of the pharmaco-kinetic parameters obtained from the camel were signi¢cantly di¡erent from thosereported for other ruminants. For example, the elimination half-life was longer andvolume of distribution for SDM was larger than that found in sheep, goats andbu¡aloes (Kumar et al., 1999). It was calculated that, to achieve and maintaintherapeutically satisfactory plasma concentrations of SDM of about 50 mg/ml, theoptimum oral or i.v. dosage regimen for camels would be 110 mg/kg as the primarydose and 69 mg/kg as the maintenance dose, to be repeated at 24 h intervals.

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Aminoglycosides

Although these drugs are not commonly used in camels, the kinetics of gentamicin,tobramycin and kanamycin have been studied and signi¢cant di¡erences in theirkinetics have been found between the camel and other species (see Ali et al., 1996b fora review). Considering that the various aminoglycosides have more or less similarkinetic properties, it is surprising that di¡erent dosage regimens have been suggestedfor the di¡erent aminoglycosides in camels. For example, for gentamicin a dose of 8.5m/kg every 12 h was suggested to produce e¡ective and `safe' plasma levels (Was¢ etal., 1992), whereas for tobramycin a dose of 2.5 mg/kg was recommended (Hadi et al.,1994). A dose of 2.75 mg/kg of gentamicin was calculated to give a maximum plasmaconcentration of 11 mg/ml (Was¢ et al., 1992). It is known, however, that a level of 12mg/ml in the plasma is toxic in humans and rats. Moreover, these data were taken fromhealthy animals, and it is known that the likelihood of aminoglycoside nephrotoxicityis increased in subjects with renal and/or hepatic disease. Recently, the kinetic pro¢leof amikacin was studied by the same group (Was¢ et al., 1999b). Kinetic resultsbroadly similar to those obtained with the other aminoglycosides were reported and atherapeutic dose of 10 mg/kg, given once daily, was suggested. However, according toWas¢ and colleagues (1999b), this dose should result in a maximum serum concentra-tion of about 40 mg/ml, 10^40 times the minimum inhibitory concentration of 1^4 mg/kg for many susceptible organisms. El Gendi and colleagues (1983) in Egypt were the¢rst to study the kinetics of streptomycin in camels. More recently, the kineticbehaviour of streptomycin in camels was re-investigated by Hadi and colleagues(1998) and results dissimilar to those obtained from the earlier study were reported.For example, in the former study, the tmax, absorption half-life and elimination half-lifewere 86, 492 and 11 min, respectively. The corresponding values from the latter studywere 30, 208 and 17 min, respectively. The reasons for these discrepancies are not clear,but they may be related to di¡erent methods of measurement of the antibiotic. Basedon their kinetic data, Hadi and colleagues (1998) recommended that a single dose of 10mg/kg administered at 8 h intervals should provide a steady-state concentration in theserum of 20 mg/ml. These authors also stated that a once-daily (single) dose ofstreptomycin of 12.5^25 mg/kg would result in a maximum concentration of 50^100mg/ml. A MIC for this antibiotic of 5^10 mg/ml for susceptible bacteria has beenreported. Judging from the above data, the use of aminoglycosides in camels does notseem to be justi¢ed, as there are insu¤cient data on their kinetics, e¡ectiveness orsafety. In addition, some newer agents such as the cephalosporins and aztreonam areequally e¡ective against susceptible organisms (Jawetz, 1995), are not much moreexpensive than the aminoglycosides, have no nephrotoxicity or ototoxicity, and have alesser incidence of development of bacterial resistance.

Benzylpenicillin sodium

Several authors have studied the kinetics of this antibiotic (see Ali et al., 1996b). Thein£uence of the site of injection on the absorption of benzylpenicillin sodium has been

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studied in four camels in Morocco (Oukessou, 1995). The sites used were subcutaneous(s.c.) and intramuscular (i.m.) in the neck, semitendinous, and gluteal muscles. The rateof absorption, as judged by t1

2and Tmax was, expectedly, slower with s.c. than with i.m.

injections. However the extent of absorption, as represented by the AUC, was similarwith the two routes of administration. The extent of absorption from the semitendinousmuscle was highest, and that from the neck was lowest. These results in camels wereslightly di¡erent from those reported from other species. For example, in cows andhorses, absorption was more marked when drugs were injected into the neck muscles(Rutgers et al., 1980; Firth et al., 1986). The clinical signi¢cance, if any, of the reportedsmall di¡erences between the sites of injection in the camel is doubtful. However,residues of the antibiotic may vary with the injection site.

Metronidazole

Metronidazole is an antibacterial and antiprotozoal agent that is commonly used inhumans and some domestic species. In addition, the drug is a well-known `probe' forstudying the metabolizing capacity of animals and humans, especially for drugs thatare mainly metabolized by oxidation (cytochrome P450). A comparative kinetic studyon this drug in camels, sheep and goats has been conducted (Ali et al., 1999). The studycon¢rmed the presence of signi¢cant kinetic di¡erences between camels and the othertwo species, as was observed earlier with the other `probe' drugs, indicating that camelshave the lowest, and goats the highest, drug-metabolizing capacity of the three species.A therapeutic i.m. dose of 10 mg/kg for goats and sheep, and 5 mg/kg for camels, to berepeated every 12 h, was suggested. Although nitro compounds may cause localirritation at the injection site, the metronidazole preparation used (Torgyl Forte,Rhone-Merieux, Harlow, UK) caused no overt adverse e¡ects in our animals.

ANTI-INFLAMMATORY, ANALGESIC AND ANTIPYRETIC DRUGS

This group of drugs is particularly important in draught and racing camels. However,no pharmacodynamic studies relating the kinetic data to the actions of the drugs asanalgesic, antipyretic or anti-in£ammatory agents have been conducted in any of thestudies reviewed below. This is a serious omission and warrants future attention. Thefollowing is an account of the studies carried out on this group, which are alsosummarized in Table I.

Ketoprofen

Oukessou and colleagues (1995), in Morocco, studied the kinetic behaviour ofketoprofen in camels. A con¢rmatory kinetic study with the same drug was recentlyconducted in the United Arab Emirates (Alkatheeri et al., 1999). Ketoprofen wasinjected i.v. or i.m. at a dose of 20 mg/kg. Some of the results from this study were, in

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TABLE IRecent pharmacokinetic data for some analgesic, antipyretic and anti-in£ammatory agents in camels (Camelus dromedarius)

MRT AUC Cmax Tmax ClDrug Dose/route (h) t1

2(h) (mg h/ml) (mg/ml) (h) (ml/(h kg) Reference

Ketoprofen 2 mg/kg, i.v. 2.36 4.16 33.3 44.7, i.v. ^ 60 Alkatheeri et al. (1999)2 mg/kg, i.m. 3.77 3.28 44.0 12.2, i.m. 1.5 60

Tolfenamic acid 2 mg/kg, i.v. ^ 5.76 ^ ^ ^ 109 Was¢ et al. (1998a)

Flunixin 1.1 mg/kg, i.v. 3.5 3.76 12.53 ^ ^ 89 Was¢ et al. (1998b)2.2 mg/kg, i.v. 4.2 4.08 26.10 ^ ^ 84

Phenylbutazone 4.4 mg/kg, i.v. 17.2 12.51 451 ^ ^ 10 Kadir et al. (1997)4.4 mg/kg, i.m. 21.7 15.57 469 1.34 1.18 ^

Phenylbutazone 4.5 mg/kg, i.v. 18.4 13.44 389.81 ^ ^ 12.63 Was¢ et al. (1997)

Paracetamol 5 mg/kg, i.v. 0.8 ^ 202.4 ^ ^ 0.35 Ali et al. (1996a)5 mg/kg, i.m. 1.3 ^ 371.8 4.05 23 ^

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general, similar to those of Oukessou and colleagues (1995). For example, the t12bwas

found by Alkatheeri and colleagues (1999) to be 4.2 h (i.v.) and 3.3 h (i.m.), comparedwith 5.2 h by Oukessou and colleagues (1995). Inter-laboratory and inter-animaldi¡erences in drug kinetics of this magnitude are not uncommon. The volume ofdistribution was similar in the two studies. However, marked di¡erences in the totalclearance of ketoprofen were noted in the two studies. The clearance in the study byAlkatheeri and colleagues (1999) was about 70% greater than that found by Oukessouand colleagues (1995). This di¡erence may be ascribed to environmental di¡erences, tostrain di¡erences, or to di¡erences in the analysis of data.

The contribution of renal clearance of free ketoprofen to total clearance was about1.5% in camels, suggesting that the drug is eliminated mostly by metabolism.Alkatheeri and colleagues (1999) detected a hydroxylated metabolite of ketoprofen inthe plasma and urine of camels.

Tolfenamic acid

The kinetics and metabolism of tolfenamic acid (2 mg/kg) was studied for the ¢rst timein camel serum and urine by Was¢ and colleagues (1998a). The elimination half-life ofthe drug was found to be 5.8 h, and the total body clearance 0.1 L/(h kg). The parentdrug and a hydroxylated metabolite therefrom were detected in urine for up to 5 and 7days, respectively. It was therefore recommended that the drug should be withheld forat least 8 days prior to racing. As with ketoprofen, it was concluded that camelseliminate tolfenamic acid mainly via metabolism rather than by urinary excretion anddo so more slowly than cattle. Therefore, the extrapolation of dosage from cattle tocamels appears inappropriate.

Flunixin

The kinetics of £unixin was ¢rst studied in camels by Oukessou (1994). More recently,Was¢ and colleagues (1998b) con¢rmed and extended those results by using £unixin attwo i.v. doses of 1.1 and 2.2 mg/kg. Some similarities and di¡erences were notedbetween camels and other species. For example, the elimination half-life was longer incamels than in cows, while the volume of distribution was similar to that in cows butmuch larger than that reported in equids. Was¢ and colleagues (1998b) detected thedrugs and its metabolites in urine, and concluded that £unixin may be eliminated bothby conjugation with glucuronic acid and, to a lesser extent, by oxidation prior toelimination. The parent drug and its metabolites were detected in urine up to 96 and 48h, respectively, after administration. Judging from the kinetic data, a dose of 2.2 mg/kgwas suggested as an e¡ective dose in camels. However, there is a clear need forpharmacodynamic and toxicological studies to con¢rm the e¤cacy and safety of thisdose, and to relate the pharmacokinetic parameters to the actions of the drug as ananalgesic and anti-in£ammatory agent. These studies should include the measurementof serum thromboxane B2 (Kadir et al., 1997) and the use of tissue cage models (Leesand Higgins, 1986).

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Phenylbutazone

Phenylbutazone is an important nonsteroidal anti-in£ammatory drug (NSAID) thathas been used in various animal species for about 40 years. Oukessou and Zine-Filali(1992) were the ¢rst to study the kinetics of phenylbutazone in camels. In a shortabstract, they reported that, after intravenous (i.v.) administration of an unstated dose,the drug had an elimination half-life of 22.1 h. This was higher than that found in sheepgiven the same dose. The systemic availability was about 24% in camels and 55% insheep. It was suggested that the binding of phenylbutazone to plasma proteins waslower in the camel than that in the sheep. Indeed, for phenylbutazone concentrationsranging from 5 to 100 mg/ml, the unbound fraction of phenylbutazone varied from 3%to 18% in camels, compared to 0.8% to 7% in sheep (M. Oukessou, personalcommunication, 1996). Subsequently, Kadir and colleagues (1997) conducted a two-period crossover experiment in six camels, which were given the drug at a dose of 4.4mg/kg (the dose recommended for cattle) by the i.v. and i.m. routes. The t1

2bof the drug

after i.v. and i.m. administration was 12.5 and 15.6 h, respectively, signi¢cantly lowerthan the 22.1 h reported by Oukessou and Zine-Filali (1992) for camels. In the absenceof knowledge of the dose used by the latter authors, it is di¤cult to speculate on thecause(s) of the di¡erences in the two reports, as the kinetics and metabolism of thisdrug may be dose-dependent.The phenylbutazone metabolite oxyphenbutazone was detected in very small

quantities following i.v. administration of the parent drug (Kadir et al., 1997), andwas generally undetectable after i.m. administration, indicating that it is unlikely tocontribute to the pharmacological action produced by phenylbutazone administration.These workers also obtained some evidence that phenylbutazone inhibited the ex vivosynthesis of serum thromboxane B2 for 24 h after i.v. dosing. Another report on thekinetics of phenylbutazone in camels, which appeared shortly after that of Kadir andcolleagues (1997) and in which a similar dose (4.5 mg/kg) was used, was that by Was¢and colleagues (1997). Similar total body clearance and half-lives were obtained in thetwo studies. Was¢ and colleagues (1997) also detected small but measurable amountsof oxyphenbutazone in plasma and urine. It is unlikely, however, that these have anye¡ective biological (anti-in£ammatory) signi¢cance. The plasma oxyphenbutazoneconcentration was also found to be low in cattle, but not in horses, receivingphenylbutazone (Lees and Higgins, 1986).

Paracetamol (acetaminophen)

The pharmacokinetics of the analgesic antipyretic drug paracetamol and of its sulphateand glucuronide conjugate metabolites were studied in camels, and for comparativepurposes in goats (Ali et al., 1996b). Large di¡erences in the plasma pharmacokineticswere found. The clearance of the parent drug was signi¢cantly slower (by abouttwofold) in camels. However, the extent of distribution was similar in the two species.The predominant metabolite of paracetamol in camels was the sulphate, while in goatsit was the glucuronide, indicating that the two species metabolize this drug via two

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di¡erent metabolic pathways. Ruminants generally have more active glucuronidationand sulphation processes for xenobiotics than do monogastric species. Camels areknown to have a lower glutathione S-transferase activity than goats (Ali and Elsheikh,1992a). The activity of this enzyme may be of importance in paracetamol overdosagein the camel, especially in the absence of a speci¢c dosage recommendation in thisspecies.

OTHER DRUGS

The kinetic studies of three unrelated drugs ^ furosemide (a diuretic), promethazine (anantihistaminic drug) and lidocaine (an antiarrthymic and local anaesthetic drug) ^ arediscussed in this section.

Furosemide

This is a high-ceiling diuretic that is commonly used in humans and domestic animals,including camels in our region. In addition to its use in the treatment of various formsof oedema, azoturia and space-¢lling lesions, it has been found to be particularly usefulin the prophylaxis of epistaxis in racing animals and in exercise-induced bronchocon-striction (Sweeney et al., 1990; Maxons et al., 1995). The former condition has beenreported in racing camels (Akbar et al., 1994) and it is conceivable that furosemide maybe used to treat this condition in camels. The drug has also been used illegally to diluteout doping agents in racing animals, and its use before racing is not allowed in somecountries. Ali and colleagues (1998) studied the kinetics of furosemide in camels, andalso reported on its dynamic e¡ect on plasma electrolyte concentrations (Ali et al.,1997). In a cross-over study, the diuretic was given i.v. and i.m. at a dose of 1.5 mg/kg.As in other species, there was considerable individual variability in the kineticparameters. The elimination half-life of the drug was considerably longer, the volumeof distribution was larger, and its clearance was slower than in horses, dogs, rats andhumans. The decreased clearance was ascribed to the lower glomerular ¢ltration rateand renal blood £ow in camels, and/or to their decreased ability to metabolize thedrug, including conversion involving phase II glucuronyltransferases to form acylglucuronides, the major metabolic route for furosemide. The presence of furosemideglucuronide was reported in human plasma but this metabolite was not found in camelplasma, probably because of the decreased capacity for drug metabolism in camels,and especially of the conversions involving phase II glucuronyltransferase (Ali andElsheikh, 1992a,b). Unlike in some other species, furosemide-induced diuresis did notresult in any signi¢cant changes in the blood electrolyte balance of camels (Ali et al.,1997), probably because of the ability of these animals to preserve blood homeostasisdespite severe loss of water, as in cases of severe exercise or dehydration.

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Promethazine

This antihistaminic was injected i.v. at a dose of 0.5 mg/kg, and its concentrations inserum and urine were measured for up to 48 h thereafter (Was¢ et al., 1999a). Theelimination half-life was found to be 5.6 h, and the total body clearance was 24.5 ml/(min kg). This half-life value in camels was a little longer than that in rabbits given 10mg/kg (4.8 h), but shorter than that in humans (15 h). The contribution of renalclearance to the total body clearance was about 20%, which suggests that the mainroute of elimination of promethazine in camels is via metabolism. In the study byWas¢and colleagues (1999a), no attempt was made to measure the urinary metabolites,although it is known that monodesmethylpromethazine and sulphoxide and glucuronicacid conjugates appear in the urine of promethazine-treated rabbits and humans.

Lidocaine (Lignocaine)

This drug is often used as a model (probe) drug for studying the activity of cytochromeP450 (isoenzyme 3A2 or 3A4), and it has been shown to be metabolized in rat andhumans to monoethylglycinexylidine by a process of de-ethylation (Imaoka et al.,1990). It is also assumed to be a measure of blood £ow to the liver. Ben-Zvi andcolleagues (1995a) studied the kinetics and metabolism of lidocaine in hydrated anddehydrated camels in Israel. The kinetic parameters of the drug in hydrated camelswere found to be signi¢cantly di¡erent from those reported for sheep, pigs, horses,dogs and humans. For example, the absorption and elimination t1

2in camels were 20.7

and 160.6 min, respectively. They were, however, respectively 4.3 and 67.2 min in pigs,and 1.9 and 41.5 min in sheep. The clearance in camels (4.2 ml/(min kg)) wassigni¢cantly slower than that in pigs (24.4), sheep (38.0), dogs (30.5), horses (52.0)and humans (9.2). Dehydration did not signi¢cantly a¡ect the kinetics or metabolismof lidocaine in camels, probably suggesting that it does not a¡ect the cytochrome P450isoenzymes involved in the degradation of lidocaine, nor hepatic blood £ow. It shouldbe mentioned, however, that dehydration in camels does a¡ect the disposition ofantipyrine (Ben-Zvi et al., 1995b), a drug that is biotransformed by certain isoenzymesof cytochrome P450 (Vesell, 1979). Thus, the e¡ects of dehydration on the hepaticcytochrome P450 superfamily of isoenzymes in camels appear to be selective.

DRUG-METABOLIZING ENZYMES (DME)

The basal activities of some phase I and phase II DME were measured in the liver,duodenal mucosa and kidney of young and adult camels of both sexes, and werecompared to the activities in Desert sheep, Nubian goats and Wistar rats (Ali andElsheikh, 1992a,b). The DME activities in the camel were, more or less, similar to thosein rats but were lower than those in sheep and goats. Although the in£uence of sex onDME was variable for the di¡erent enzymes, adults had DME activities higher thanthose in young camels. More recently, Elsheikh (1997) extended these studies and

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measured the activities of some DME in the lung tissues of camels, desert sheep andNubian goats. The general pattern of results obtained earlier in other tissues (Ali andElsheikh, 1992a,b) was also found in the lung. However, the activity of anilinehydroxylase was found to be higher in both male and female camels than in goats andsheep (Elsheikh, 1997). In agreement with previous reports in laboratory animals, theactivity of this enzyme in the lung tissue from female camels was more than that foundin liver. For the rest of the enzymes studied, the activity in the lungs represented about4^62% of the hepatic activity. These results indicated that lung tissues are a rich sourceof DME in the camel. Raza and colleagues (1998) con¢rmed and extended their earlierwork on the multiple forms of DME (cytochrome P450) in camels. Using immuno-chemical and enzymatic methods employing various substrates, these authors wereable to demonstrate multiple forms of P450 in di¡erent camel tissues (liver, kidney,intestine and brain). The activity in these tissues was comparable to that in rats andhumans. The similarity between the camel and the rat in the activities of DME hadalready been reported (Ali and Elsheikh, 1992a,b). However, Raza and colleagues(1998) showed that the expression of cytochrome P450 in camel tissues wassigni¢cantly higher than in rat tissues. They also demonstrated P450 isoenzyme-speci¢c metabolism of various substrates catalysed mainly by the CYP 1A, 2B, 2Eand 4A family of enzymes (Gonzales, 1992) in camel tissues. As in other species, camelliver showed a higher activity than extrahepatic tissues towards various substrates.However, camel kidney was found to exhibit higher activity than the liver towardslauric acid, a physiological substrate preferentially catalysed by CYP 4A family. Thesigni¢cance of this ¢nding is unknown.

The e¡ect of dehydration on drug disposition in camels

Most of the pharmacokinetic data reported in camels were obtained from hydratedanimals. In its natural arid and semi-arid habitat, the camel is often confronted withscarcity of water, and may only be allowed to drink water every 4 or more days.Dehydration may lead to signi¢cant changes in the basic physiological functions of thecamel (Yagil, 1985). Dehydration for 7^14 days causes 15^25% loss in body weight andcan severely a¡ect both hepatic and renal functions. The liver and kidneys are the mainorgans of metabolism and excretion of most drugs. Therefore, it is expected thatdehydration may in£uence these processes in camels.

Most of the reported studies on the e¡ect of dehydration on drug kinetics in thecamel have been discussed elsewhere (Ali et al., 1996b). In general, the alterations in thekinetic behaviour of drugs in the dehydrated camel may be related to decreaseddistribution of the drug into the tissues, reduced bioavailability, and/or a slowerelimination rate. It is reasonable, therefore, to conclude that, when examining druge¤cacy, and when treating sick animals, the delay in absorption and excretion of drugsinduced by dehydration should be taken into account.

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Future research

Despite the progress made in our understanding and knowledge of the metabolism anddisposition of several xenobiotics in camels, much remains to be studied. It is evidentthat doses recommended for other ruminants should not automatically be extrapolatedto the camel on a mg/kg basis. More studies on the kinetics of NSAIDs, antibiotics andother drugs should be conducted in young, mature and aged camels in order toestablish dosage regimens for these animals, and so help avoid illegal residues in foodand racing animals. Considering the harsh environmental conditions under whichcamels survive, attention should be given to the e¡ects of environmental factors such asheat, dehydration, exercise and other forms of stress on drug actions and disposition.

Despite their importance, the dynamic actions of drugs on camel tissues havereceived less attention than kinetic studies. In view of its unique anatomy, physiology,and biochemistry, more studies into the e¡ect of drugs on the various systems of thecamel could yield results that may be quantitatively or even qualitatively di¡erent fromthose for other related species.

As far as we are aware, no pharmacokinetic studies have been reported in the two-humped camels (Camelus bactrianus). It would be of interest to compare thepharmacokinetic data obtained from the dromedary camel with that in the two-humped camel, as the two species live under environmentally very di¡erent habitats.

No studies have yet been conducted on the important topic of drug residues in themeat and milk of camels, particularly in regions where this species is now recognized asa farm animal (e.g. the Arabian Gulf countries), and in countries where raw camel liveris commonly consumed (e.g. Sudan).

Employment of modern methods of cellular and molecular pharmacology toelucidate receptor^drug interactions and genetic mapping in camels may be of boththeoretical and applied interest. Recent developments in the ¢eld of reproduction/endocrinology of the camel (see, e.g. Skidmore et al., 1998, 1999) may stimulate thesearch for newer agents, and for novel applications of old drugs that may be used toenhance breeding and selection of camels, especially those intended for racing.

CONCLUSIONS

The pharmacokinetics of several drugs are di¡erent in camels from those in otherdomestic animals. The basis of this di¡erence is not certain, but may be related to oneor more of the following:

(1) Drug disposition may be a function of the metabolic rate of the animal. Thepharmacokinetic processes that in£uence the concentration of drugs in bloodand tissues are related to the functions of the liver and kidneys, and these arerelated to the basic metabolism (Fink-Gremmels and Van Miert, 1994; VanMiert, 1989). The smaller an animal species, the higher its metabolic rate.Therefore, smaller species generally have a relatively higher drug biotransforma-tion capacity than do larger species.

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(2) Camels have peculiar physiological and biochemical characteristics that may bere£ected in their responses to xenobiotics and in the disposition of drugs given tothem.

(3) The activities of certain drug-metabolizing enzymes or isoenzymes are de¢cientor lacking in camels (Ali and Elsheikh, 1992a,b). In addition, the metabolicpathways and the protein binding capacities of some drugs in camels may bedi¡erent from those in other species (Ali et al., 1996a; M. Oukessou, personalcommunication, 1996).

The reported di¡erences between camels, sheep and goats (Ali and Elsheikh, 1992a)cannot be ascribed to environmental factors such as diet, housing conditions orconcomitant treatment with other drugs, as, in comparative trials, the animals of allthree species were housed under standard and similar conditions and were providedwith the same feed and water ad libitum.

The above results stress the need to study the pharmacokinetics of any particulardrug in the target species itself, and to avoid or minimize extrapolation of dosageregimens from one species to another. Modi¢ed dosage schedules of drugs should beprovided for dehydrated camels.

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(Accepted: 19 November 1999)

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