study indicate that liposomeralginate particles show little promise as a drug carrier for OTC in oral formulations to fish since it did not increase the bioavailability of the drug. q 2000 Elsevier
Science B.V. All rights reserved.
Keywords: Oxytetracycline; Pharmacokinetics; Bioavailability; SalÕelinus alpinus; Liposomes; Aortic cannula- tion; Therapy of fish diseases
1. Introduction
Ž .
Oxytetracycline OTC is a broad-spectrum antibiotic drug which has been widely used in the treatment of systemic bacterial infections in farmed fish. It is administered
orally, incorporated into pelleted feed. The common practice in Norwegian fish farming is to administer a dose of 100 mg OTCrkg fishrday for 6–10 days.
Ž The pharmacokinetics of OTC has previously been studied in Atlantic salmon Salmo
. Ž .
Ž salar
Pye-MacSwain et al., 1992; Elema et al., 1996 , amago salmon Oncorhynchus . Ž
. Ž
. Ž .
rhodurus Uno et al., 1992 , chinook salmon O. tshawytscha
Abedini et al., 1998 , Ž
. Ž rainbow trout O. mykiss
Grondel et al., 1989; Bjorklund and Bylund, 1990,1991;
¨
. Black et al., 1991; Rogstad et al., 1991; Nouws et al., 1992; Abedini et al., 1998 , carp
Ž . Ž
. Cyprinus carpio
Haenen et al., 1985; Grondel et al., 1987; Nouws et al., 1992 , Ž
. Ž .
Ž .
European eel Anguilla anguilla
Nouws et al., 1993 , ayu Plocoglossus altiÕelis
Ž .
Ž . Ž
. Uno, 1996 , African catfish Clarias gariepinus
Grondel et al., 1989 , striped bass Ž
. Ž .
Ž . Ž
. Morone saxatilis
Xu and Rodgers, 1993 , tench Tinca tinca Reja et al., 1996 , and
Ž . Ž
. yellowtail Seriola quinqueradiata
Uno et al., 1992 . In addition, the pharmacokinetics Ž
. Ž of tetracycline has been studied in channel catfish Ictalurus punctatus
Plakas et al., .
Ž . Ž
. 1988 and dogfish shark Squalus acanthias
Guarino, 1986 . However, to our knowl- Ž
. edge, there are no studies on the pharmacokinetics in Arctic charr SalÕelinus alpinus , a
fish species now being farmed in northern Norway. In addition, there are few publica- tions concerning the pharmacokinetics of antibacterial agents in fish at low temperatures.
The water temperature shows great seasonal variation, and temperatures down to 08C are occasionally encountered during winter in the northern part of Norway.
Previous pharmacokinetic studies of OTC have revealed that the bioavailability of this drug is relatively low in fish. Some of the studies, however, have shown that the
oral bioavailability of antibacterial agents can be improved by using different ap- Ž
. Ž
proaches in dosage Rogstad et al., 1993 and drug formulation Endo et al., 1987; .
Martinsen et al., 1993 . Liposomes are microscopic phospholipid vesicles composed of one or more concentric phospholipid bilayers. The use of liposomes as an oral dosage
form may protect the encapsulated drug from digestive degradation or interaction with other molecules, and thereby increase absorption of poorly absorbed drugs from the
gastrointestinal tract. Encapsulation of bacterial antigens in liposomeralginate particles
Ž has been shown to improve the effect of vaccines administered orally to fish Eggset et
. al., 1995 . Encapsulation in liposomeralginate particles may therefore also improve the
absorption and thereby the bioavailability of antibacterial agents in fish. Pharmacokinetic and bioavailability studies of antibacterial agents in farmed fish are
important in order to determine optimal dosage regimens and formulations, to establish
safe withdrawal periods, and to minimize the environmental effects of the drugs used in aquaculture. The pharmacokinetics of drugs may be affected by parameters such as fish
species, age, water temperature and salinity, route of administration and other experi- mental conditions. Therefore, the extrapolation of pharmacokinetic data obtained in one
species to another species, living under different conditions, should be done with caution.
The aim of the present study was twofold; firstly, to describe the pharmacokinetics of Ž
. Ž
. OTC in Arctic charr, living at low temperatures, after intravascular i.v. and oral p.o.
administration, and secondly, to determine the relative bioavailability of OTC after p.o. administration of a liposomeralginate formulation compared to the drug dissolved in
water with agar as a viscosity-increasing agent.
2. Materials and methods
