Rifampin in the horse: comparison of intravenous, intramuscular, and oral administrations

The plasma concentrations and pharmacokinetics of rifampin disposition were determined after a single IV, IM, or oral dose of 10 mg/kg of body weight and an oral dose of 25 mg/kg. The overall elimination rate constants per minute were similar for the 10 mg/kg dose (0.0021 +/- 0.0004, IV; 0.0017 +/- 0.0002, IM; and 0.0023 +/- 0.0006, orally). The apparent bioavailability was moderate to low for IM and oral administrations (59.8% +/- 3.2% and 39.5% +/- 5.0%, respectively). The rate of absorption was most rapid for oral administration with an absorption half-life of 249.7 +/- 71.6 minutes as compared with 403.5 +/- 89.7 minutes for IM administration. However, the IM route produced longer detectable plasma concentrations (50 hours in 2 of the 4 horses). Based on bacterial sensitivity information derived for human and canine isolates, the daily oral administration of 10 mg of rifampin/kg administered in the feed represents a reasonable dose for susceptible gram-positive bacterial pathogens. Higher doses (greater than or equal to 25 mg/kg) or IV administration would be required for most gram-negative bacteria. Adverse effects of sufficient severity to limit use of the drug, especially by the oral route of administration, were not encountered under the single-dose experimental conditions used.     

Pharmacokinetics of low‐dose methotrexate in healthy beagle dogs

Methotrexate may be an alternative to ciclosporin in the treatment of canine atopic dermatitis (cAD) as suggested by recent data. The aim of the study was to investigate both the tolerance and the pharmacokinetic behavior of methotrexate (MTX) in plasma, following intravenous (i.v.), subcutaneous (s.c.) or oral (OR) administration over several weeks. Six healthy dogs were given oral MTX once a week, respectively, per dog at 2.5 mg/1 week, 5 mg/4 weeks, 7.5 mg/3 weeks, 10 mg/6 weeks and 12.5 mg/5 weeks. No clinically relevant abnormalities of laboratory parameters were noticed. A high inter‐individual variation of MTX plasma concentration was observed with a suspicion of saturation phenomenon in absorption. To compare with other routes of administration, six healthy beagle dogs followed a crossover design study at 7.5 mg per dog MTX. The absolute bioavailability was 93% for SC injection and 30% for the oral route. The inter‐individual variability was quite low following SC administration compared to oral route. Just as in human, given the substantial variability of oral absorption, clinicians cannot assume consistent oral bioavailability of MTX. Therefore, they may consider switching dogs to the SC route in case of absence of clinical response with a weekly oral dose.     

Bioavailability of transdermal methimazole in a pluronic lecithin organogel (PLO) in healthy cats

The antithyroid drug methimazole is widely used for the medical management of feline hyperthyroidism. Recently, custom veterinary pharmacies have offered methimazole in a transdermal gel containing pluronic and lecithin (PLO), with anecdotal evidence of efficacy. The purpose of this study was to determine the bioavailability, relative to i.v. and oral routes of administration, of transdermal methimazole in a PLO gel in cats. Six healthy adult cats were assigned to receive 5 mg of methimazole by the i.v., oral, or transdermal routes, in a randomized triple crossover protocol with 1 week washout between doses. Blood samples were taken for high performance liquid chromatography (HPLC) determination of serum methimazole, at 0, 5, 15, 30, 60 min, and 2, 4, 6, 12 and 24 h after dosing. Methimazole absorption following transdermal administration was poor and variable, with only two of six cats achieving detectable serum methimazole concentrations at any time point following transdermal administration. Area under the concentration-time curve (AUC), maximum concentration (Cmax), and absolute bioavailability were all significantly lower for the transdermal route (0.39 +/- 0.63 microg h/mL, 0.05 +/- 0.09 microg/mL, and 11.4 +/- 18.7%, respectively) than for either i.v. (7.96 +/- 4.38 microg h/mL, 3.34 +/- 2.00 microg/mL, 100%) or oral routes (2.94 +/- 1.24 microg h/mL, 0.51 +/- 0.15 microg/mL, 40.4 +/- 8.1%). The results of this study indicate generally low to undetectable bioavailability of methimazole in a lecithin/pluronic gel given as a single transdermal dose to healthy cats, although one individual cat did achieve nearly 100% transdermal bioavailability relative to the oral route.     

Comparative Disposition Kinetics of Albendazole in Sheep Following Oral and Intraruminal Administration

The pharmacokinetics of albendazole was studied in sheep following single oral and intraruminal administration at nematocidal dose rates. The disposition curves of its metabolites indicated increased uptake of the drug in sheep following intraruminal as compared to oral dosing (p<0.05). The increased bioavailability of benzimidazole anthelmintics given by the intraruminal route could be exploited for optimizing the use of anthelmintic for sustained parasite control in small ruminants.     

Pharmacokinetics of metronidazole given to horses by intravenous and oral routes

Serum and peritoneal fluid concentrations of metronidazole were determined in 6 healthy adult horses given the drug (25 mg/kg) by IV or oral routes. The disposition of metronidazole in horses given the drug by the IV route conformed to a 2-compartment model with a distribution half-life of 0.16 hours, an elimination half-life of 2.9 hours, and a body clearance of 0.40 +/- 0.05 L/kg/hr. The oral absorption half-life was 0.40 hours, and the bioavailability, 85.0 +/- 18.6%. Peritoneal fluid concentrations were approximately equal to serum concentrations at all times, regardless of the route of administration. On the basis of reported minimal inhibitory concentrations for anaerobic bacteria, a dosage of 15 to 25 mg/kg given orally 4 times daily was recommended.     

Comparative bioavailability of fluoxetine after transdermal and oral administration to healthy cats

OBJECTIVE: To determine bioavailability, pharmacokinetics, and safety for transdermal (TD) and oral administration of fluoxetine hydrochloride to healthy cats. ANIMALS: 12 healthy mixed-breed sexually intact 1- to 4-year-old purpose-bred cats. PROCEDURE: A single-dose pharmacokinetic study involving 3 groups of 4 cats each was conducted in parallel. Fluoxetine in a formulation of pluronic lecithin organogel (PLO gel) was applied to the hairless portion of the pinnae of cats at 2 dosages (5 or 10 mg/kg), or it was administered orally in capsules at a dosage of 1 mg/kg. Plasma samples were obtained and submitted for liquid chromatography-mass spectrometry-mass spectrometry analysis of fluoxetine and its active metabolite, norfluoxetine. RESULTS: Peak fluoxetine concentration (Cmax) was lower and time to Cmax longer for TD administration versus oral administration. Relative bioavailability of each dose administered via the TD route was 10% of the value for oral administration of the drug. Mean plasma elimination half-life after oral administration was 47 and 55 hours for fluoxetine and norfluoxetine, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: This study provides evidence that fluoxetine in a 15% (wt:vol) PLO gel formulation can be absorbed through the skin of cats into the systemic circulation. However, the relative bioavailability for TD administration is approximately only 10% of that for the oral route of administration.     

Effect of drug formulation and feeding on the pharmacokinetics of orally administered quinidine in the horse

Quinidine is the drug of choice for the treatment of cardiac arrhythmias in horses. The plasma concentrations vs. time profiles following oral administration of two formulations of quinidine sulphate, an oral solution and an oral suspension paste, were evaluated in nine horses. They received multiple administrations of the oral solution under fed and non-fed conditions and of the paste under non-fed conditions. A loading dose of 20 mg.kg_-1 and a maintenance dose of 10 mg.kg^-1 quinidine with dosing interval of 6 h were used. The relative bioavailability of the oral solution under fed conditions in comparison to the solution under non-fed conditions was 75.0 ± 10.2% for the loading dose and 97.18 ± 31.66% after the fourth dose. For the paste formulation the relative bioavailability values are not reported, as steady-state levels were not reached. There was a large variation in plasma quinidine levels when the paste formulation was administered. Feeding conditions had a significant influence on the C_max, values after administration of the loading dose. The T ^max values were not affected by food intake. It was concluded that an oral solution has to be preferred because of the variable drug bioavailability from the paste formulation and the poor acceptability of the paste by the horse.     

Bioavailability and bioequivalence of veterinary drug dosage forms, with particular reference to horses: an overview.

The route of administration and formulation of the dosage form affect the bioavailability (rate and extent of absorption) of a drug and may thereby influence the intensity and duration of the pharmacological effect. Location of injection site may affect the plasma concentration profile of drugs administered as aqueous suspensions or sustained release parenteral preparations (procaine penicillin G). When absorption influences the rate of elimination ('flip-flop' phenomenon), the apparent half-life of the drug will be increased (cefazolin sodium, i.m.; meclofenamic acid, p.o.). Absorption generally approximates a first-order process and either the absorption half-life or the mean absorption time (statistical moment term) will provide an estimate of the rate of absorption. The method of corresponding areas is the usual technique employed in estimating the extent of absorption (systemic availability). Inherent in this technique is the assumption that clearance of the drug remains unchanged. In horses, the time of feeding relative to oral dosing has been shown to affect systemic availability (rifampin, trimethoprim) and pattern of absorption (phenylbutazone). Oral paste formulations (trimethoprim-sulphadiazine, ivermectin) are convenient to administer, allow precision in dosage compared with powders or granules added to feed, and could provide sustained release. Assessment of bioequivalence is based on relative bioavailability, using a reference dosage form, together with a measure of the uncertainty (variance) of the estimate. Bioequivalence relies on the concept that preparations of a drug which provide essentially equivalent plasma concentration profiles should produce the same therapeutic effect.     

Oral bioavailability of etoposide after administration of a single dose to tumor-bearing dogs

OBJECTIVE: To characterize oral bioavailability and pharmacokinetic disposition of etoposide when the IV formulation was administered orally to dogs. ANIMALS: 8 tumor-bearing dogs. PROCEDURES: An open-label, single-dose, 2-way crossover study was conducted. Dogs were randomly assigned to initially receive a single dose of etoposide (50 mg/m2) IV or PO. A second dose was administered via the alternate route 3 to 7 days later. Medications were administered before IV administration of etoposide to prevent hypersensitivity reactions. Oral administration of etoposide was prepared by reconstituting the parenteral formulation with 0.9% NaCl solution and further diluting the reconstituted mixture 1:1 with a sweetening agent. Plasma samples were obtained after both treatments. Etoposide concentrations were measured with a high-performance liquid chromatography assay, and plasma etoposide concentration-time profiles were analyzed by use of noncompartmental methods. RESULTS: 4 dogs had hypersensitivity reactions during IV administration of etoposide. No adverse effects were detected after oral administration. Plasma etoposide concentrations were undetectable in 2 dogs after oral administration. Oral administration of etoposide resulted in significantly lower values for the maximum plasma concentration and the area under the plasma etoposide concentration-versus-time curve, compared with results for IV administration. Oral bioavailability of etoposide was low (median, 13.4%) and highly variable among dogs (range, 5.7% to 57.3%). CONCLUSIONS AND CLINICAL RELEVANCE-Vehicle-related toxicosis can limit the IV administration of etoposide in dogs. The parenteral formulation of etoposide can be safely administered orally to dogs, but routine use was not supported because of low and variable oral bioavailability in this study.     

Synthesis and detection of toltrazuril sulfone and its pharmacokinetics in horses following administration in dimethylsulfoxide

Triazine-based antiprotozoal agents are known for their lipophylic characteristics and may therefore be expected to be well absorbed following oral administration. However, although an increase in lipid solubility generally increases the absorption of chemicals, extremely lipid-soluble chemicals may dissolve poorly in gastrointestinal (GI) fluids, and their corresponding absorption and bioavailability would be low. Also, if the compound is administered in solid form and is relatively insoluble in GI fluids, it is likely to have limited contact with the GI mucosa, and therefore, its rate of absorption will be low. Based on the above considerations, we sought a solvent with low or no toxicity that would maintain triazine agents in solution. As the oral route is most preferred for daily drug therapy, such a solvent would allow an increased rate of absorption following oral administration. In present study, it was demonstrated that dimethylsulfoxide (DMSO) increased the oral bioavailability of toltrazuril sulfone (Ponazuril) threefold, relative to oral administrations of toltrazuril sulfone suspended in water. The cross-over study of toltrazuril sulfone formulated in DMSO indicated that the absolute oral bioavailability of toltrazuril sulfone in DMSO is 71%. The high bioavailability of the DMSO-preparation suggests that its daily oral administration will routinely yield effective plasma and cerebral spinal fluid (CSF) concentrations in all horses treated. Also, this improved formulation would allow clinicians to administer loading doses of toltrazuril sulfone in acute cases of Equine Protozoal Myeloencephalitis. Another option would involve administration of toltrazuril sulfone in DMSO mixed with feed (1.23 kg daily dose) meeting the US Food and Drug Administration (FDA) recommendations for the levels of DMSO permissible in pharmaceutical preparations.     

Should licking behavior be considered in the bioavailability evaluation of transdermal products?

Antiparasitic drugs, and especially macrocyclic lactones (MLs), are often formulated as pour-on products because of their ease of administration, convenience, and reduction of stress in treated animals. However, because of self- and allo-grooming, much of a drug administered transdermally may be systemically absorbed via the oral route, creating highly variable pharmacokinetic and pharmacodynamic response in treated (and untreated) animals. Testing bioequivalence (BE) of pour-on drugs in cattle under laboratory conditions (with restricted licking) ignores a major factor of drug disposition of these drugs and thus fails to predict therapeutic equivalence in the target population under clinical conditions of use. Therefore, the interanimal and intra-animal variability associated with licking behavior should be considered as a biological fact, rather than a noise that needs to be reduced or eliminated. As a result, it is recommended that the BE testing for pour-on products in cattle be conducted by evaluating both the mean and distribution of bioavailability parameters between the reference and test products when animals are not prevented from allo- and self-licking.     

Drug choice and therapeutic drug monitoring in the management of canine primary epilepsy

Therapeutic drug monitoring is an underutilised resource in the management of canine primary epilepsy. Many of the anti-epileptic drugs, including phenobarbitone, have variable pharmacokinetic profiles in different dogs, with each individual animal showing variable rates of absorption, distribution, metabolism and excretion. This results in variable serum drug concentrations with the same oral dose. Many clinicians interpret this situation as therapeutic failure and classify these patients as refractory to treatment. By measuring blood concentrations of drugs at appropriate times, it is possible to explain the efficacy or failure of treatment, and also to prevent serum concentrations from reaching toxic levels. By analysing paired samples, key pharmacokinetic parameters may be calculated for each patient and a profile for the disposition of the drug obtained. Individual optimal drug dosage can be calculated for each patient at little cost to the pet owner.     

Clinical pharmacokinetics of a dexmedetomidine–methadone combination in dogs undergoing routine anaesthesia after buccal or intramuscular administration

This study aimed to define the pharmacokinetic profiles of dexmedetomidine and methadone administered simultaneously in dogs by either an oral transmucosal route or intramuscular route and to determine the bioavailability of the oral transmucosal administration relative to the intramuscular one of both drugs, so as the applicability of this administration route in dogs. Twelve client‐owned dogs, scheduled for diagnostic procedures, were treated with a combination of dexmedetomidine hydrochloride (10 μg/kg) and methadone hydrochloride (0.4 mg/kg) through an oral transmucosal route or intramuscularly. Oral transmucosal administration caused ptyalism in most subjects, and intramuscular administration caused transient peripheral vasoconstriction. The results showed reduced and delayed absorption of both dexmedetomidine and methadone when administered through an oral transmucosal route, with median (range) C_max values of 0.82 (0.42–1.49) ng/ml and 13.22 (2.80–52.30) ng/ml, respectively. The relative bioavailability was low: 16.34% (dexmedetomidine) and 15.5% (methadone). Intramuscular administration resulted in a more efficient absorption profile, with AUC and C_max values for both drugs approximately 10 times higher. Dexmedetomidine and methadone administered simultaneously by an oral transmucosal route using injectable formulations were not well absorbed through the oral mucosa. Nevertheless, additional studies on these drugs combination using alternative administration routes are recommended.     

Disposition, bioavailability and clinical efficacy of orally administered acepromazine in the horse

The pharmacokinetics and pharmacological efficacy of orally (p.o.) administered acepromazine were studied and compared with the intravenous (i.v.) route of administration in a cross-over study using six horses. The oral kinetics of acepromazine can be described by a two-compartment open model with first-order absorption. The drug was rapidly absorbed after p.o. administration with a half-life of 0.84 h, t _max of 0.4 h and C _max of 59 ng/ml. The elimination was slower after p.o. administration (half-life 6.04 h) than after i.v. injection (half-life 2.6 h). The bioavailability of the orally administered drug formulation was 55.1%. After p.o. administration of 0.5 mg/kg acepromazine, the parameters of the sedative effect were similar to those obtained after i.v. injection of 0.1 mg/kg. The effect of the drug on blood cell count and haemoglobin content was similar after both p.o. administration and injection, while the effects on the parameters of penile prolapse and on the mean arterial blood pressure were less pronounced after p.o. administration than after injection. After p.o. administration, no significant effects on haematoerit-level as well as on the heart and respiratory rates were observed, while these parameters were significantly affected after injection. It is concluded that the high initial plasma level of the drug after i.v. injection may play a role in producing adverse effects of acepromazine.     

Bioavailability of veterinary drugs in vivo and in silico

The physical and chemical properties of a drug determine the behaviour of its molecule in a living organism. In this paper, the relationship between selected physical and chemical parameters and drug bioavailability in vivo was investigated. Data sets from 75 compounds, which can be administered per os to 11 various animal species were analyzed. The selected parameters for the prediction of the in vivo bioavailability were the lipophilicity (LogP) and the polar surface area (PSA) or apolar surface area (aPSA) of a molecule. It was shown that the calculation of the hybrid parameters aPSA/PSA and LogP + (aPSA/PSA) allows to estimate the oral bioavailability of a drug and its allocation to clusters with either an oral bioavailability of <70% or >70%. The performed analysis also showed that an extreme low value of the PSA of a molecule (<40 square ångströms) combined with the extreme high value of LogP (>4) is associated with a lower oral bioavailability (<50%). The results obtained indicate the existence of a relationship between the mean LogP value and aPSA/PSA in silico , and the bioavailability of veterinary drugs as determined in vivo.     

Clinical pharmacokinetics of five oral cephalosporins in calves

The minimal inhibitory concentrations (MIC) of cephalexin, cephradine, cefaclor, cefatrizine and cefadroxil for Salmonella species, Escherichia coli and Pasteurella multocida isolated previously from young calves were determined. The MIC90 values for cephalexin, cephradine and cefadroxil ranged between 3.12 micrograms ml-1 and 12.5 micrograms ml-1, whereas those of cefatrizine and cefaclor were 3.12 micrograms ml-1 and 0.78 microgram ml-1, respectively. Each drug was administered intravenously and orally to groups of pre-ruminating calves and orally to early ruminating calves. Although the pharmacokinetic characteristics of the drugs after intravenous injection were similar to other beta-lactam antibiotics, significant differences between the cephalosporins examined were found in respect of certain kinetic parameters. The drugs showed rapid absorption into the systemic circulation after oral administration to pre-ruminating calves but the elimination half-life values (t1/2 beta) varied between three hours (cefaclor and cefadroxil) and nine hours (cefatrizine). The bioavailability of the drugs was about 35 per cent of the administered dose. Co-administration of probenecid with each antibiotic caused a twofold or greater increase in peak serum drug concentrations (Cmax) but the effect on t1/2 beta was variable. Cephalexin, cephradine and cefaclor given to the ruminating calves resulted in very low serum or plasma concentrations and their use should be restricted to younger calves. Cefadroxil was found to give the highest serum concentrations in this age group but had significantly lower bioavailability when compared with the unweaned calves. Provisional oral dosage regimens were computed for each cephalosporin on the basis of the MIC data and the kinetic parameters derived from intravenous and oral drug administration.     

Intra-articular drug delivery: the challenge to extend drug residence time within the joint

The rationale behind developing sustained release microsphere formulations of non-steroidal anti-inflammatory drugs (NSAIDs) administered via the intra-articular (IA) route is to minimise the systemic bioavailability and attendant side-effects associated with oral drug administration. Overall dose is reduced whilst therapeutic benefit within the joint is maintained. The potential benefits of IA therapy for osteoarthritis (OA) are not achieved using currently available medications and delivery vehicles due to the rapid clearance of therapeutic substances from the synovial space. There is a need for sustained release delivery systems if the potential of IA drug administration is to be realised. Rationally designed microspheres taken up by synovial macrophages offer a strategy to sustain drug delivery within the joint, and to deliver NSAIDs directly to pivotal inflammatory cells. The efficacy of microsphere candidates may be evaluated in large animal models of OA. The principles of IA microsphere drug delivery may also be applicable to other classes of drugs.     

Pharmacokinetics of the insulin-sensitizing agent troglitazone in cats

OBJECTIVE: To determine pharmacokinetics of troglitazone in healthy cats after i.v. and oral administration of a single dose of the drug. ANIMALS: 5 healthy ovariohysterectomized adult cats. PROCEDURE: Using a randomized crossover design, cats were given 5 mg of troglitazone/kg of body weight i.v. and 40 mg of troglitazone/kg orally. Blood and urine samples were collected after drug administration, and concentrations of troglitazone in plasma and urine were determined by use of high-performance liquid chromatography. RESULTS: Area-moment analysis was used to calculate pharmacokinetic variables. Terminal phase half-life was 1.1 +/- 0.1 hours. Steady-state volume of distribution was 0.23 +/- 0.15 L/kg. After i.v. administration, clearance was 0.33 +/- 0.04 L/h/kg. Drug was not detected in urine samples. Mean bioavailability of orally administered troglitazone was 6.9%. CONCLUSIONS AND CLINICAL RELEVANCE: The overall disposition of troglitazone in cats was similar to that reported in other species, including humans. Troglitazone has low and variable oral bioavailability. Clearance of the compound is moderate. Little if any unchanged troglitazone is excreted in urine; thus, metabolism and biliary excretion play predominant roles in elimination of the drug. On the basis of troglitazone pharmacokinetics in healthy cats, as well as on the basis of pharmacodynamics of the drug in humans and other animals, a regimen that uses a dosage of 20 to 40 mg/kg administered orally once or twice per day to cats will produce plasma concentrations of the insulin-sensitizing agent that have been documented to be effective in humans.     

Bioavailability of levamisole after intramuscular and oral administration in sheep

AIMS: To determine the bioavailability of levamisole in sheep. METHODS: Levamisole was administered to three groups of six Merino sheep orally and intramuscularly at three dose levels of 5, 7.5 and 10 mg/kg. There was a washout period of 1 week between treatments. Blood samples were collected by jugular venepuncture and plasma was separated immediately by centrifugation and stored at 20 degrees C until analysed. The levamisole concentration in plasma was determined by high performance liquid chromatography with a U.V. detection method. Individual plasma levamisole concentration-time data were analysed using the compartmental method. RESULTS: The values obtained for k(a), C(max), t(max) and F show a moderate rate and extent of absorption after oral administration of levamisole while, after intramuscular administration, these values demonstrate a high rate and extent of absorption of levamisole. The intramuscular bioavailability was higher than the oral bioavailability (rate of absorption three-fold faster, extent of absorption 25-33% higher and C(max) two-fold higher). The Friedman test involving dose and route of administration showed that the route of administration affects k(a), C(max), t(max) and F; significant differences were found in these parameters. CLINICAL RELEVANCE: On the basis of these data, the recommended routes for the administration of levamisole in sheep are oral for gastro-intestinal nematodiasis and intramuscular for extragastric nematodiasis.