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.     

Pharmacokinetic estimation for therapeutic dosage regimens (PETDR) – a software program designed to determine intravenous drug dosage regimens for veterinary applications

Pharmacokinetic estimation for therapeutic dosage regimens (PETDR) is a soft-ware program used to design individualized intravenous dosage regimens, determine concentration-time profiles, predict serum concentrations at a specific time after intravenous dosing and predict the time after the last dose to achieve a specified concentration of drug. The reference pharmacokinetic parameters may be based on an individual animal's pharmacokinetic disposition of drug or on FARAD (Food Animal Residue Avoidance Databank) mean population kinetic parameters. An individual animal's kinetic parameters may be input for predetermined analysis or the program can calculate these values by input of raw serum concentration-time data. The program allows the user to specify certain parameters of the dosage regimen, then calculates the other parameters (given desired maximum and minimum serum concentrations, dose and interval are calculated; given desired maximum serum concentration and interval, dose is calculated, etc.). Given the kinetic parameters, the dose and dosing interval, the program calculates and plots the serum concentration-time profile of the drug for that animal. The time and the number of doses to reach steady state can be calculated as well as the determination of loading dose. The percentage of the time of a dosing interval at steady state that the serum concentration is above a specific minimum inhibitory concentration (MIC) allows evaluation of efficacy of an antimicrobial regimen. Similarly, the time to reach a specific concentration (e.g. residue tolerance) or the MIC of a drug can be calculated. Legal tissue tolerances can be accessed from FARAD to aid in predicting for what period of time illegal residues will remain in the animal.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of in vitro chemosensitivity of vaccine-associated feline sarcoma cell lines to vincristine and paclitaxel

OBJECTIVE: To determine the in vitro sensitivity of 4 vaccine-associated feline sarcoma (VAFS) cell lines to the chemotherapeutic agents vincristine and paclitaxel. SAMPLE POPULATION: Cell lines derived from 4 VAFS specimens. PROCEDURES: Cell lines were cultured in vitro and individually exposed to various concentrations of vincristine and paclitaxel. Survival was estimated after 24 and 72 hours of exposure to each drug, and the drug concentrations that resulted in 50 and 90% reduction in number of viable cells (IC50 and IC90, respectively) were calculated. RESULTS: Both vincristine and paclitaxel had significant dose-dependent effects on the viability of the VAFS cell lines. After 72 hours of drug exposure, the IC50 and IC90 of vincristine for the 4 cell lines were between 0.005 to 0.039 microg/ml and 0.045 to 1.027 microg/ml, respectively. The IC50 and IC90 values for paclitaxel were between 0.037 to 0.092 microg/ml and 2.450 to 15.413 microg/ml, respectively. CONCLUSIONS: Results of pharmacokinetic studies on vincristine and paclitaxel in other species suggest that concentrations greater than the IC50 values may be possible for both drugs in feline patients as well. The drug concentrations at which viable cell numbers were reduced by 90% may also be attained in vivo for some cases, but detailed information is needed regarding the distribution, concentration, duration of availability, and toxicity of various drugs in cats. Carefully chosen combinations of antineoplastic agents need to be screened to identify treatment protocols that may be further evaluated clinically for the treatment of VAFS.     

Pharmacokinetics of trimethoprim/sulfadiazine in neonatal calves: influence of synovitis

The effect of synovitis on the distribution of antibacterial drugs into the joint space was studied in 1-week-old calves. Sodium urate crystals were used to induce inflammation in the tibio-tarsal joint of calves and the antibacterial drug combination, trimethoprim/sulfadiazine (Tribrissen), 30 mg/kg, was administered intravenously 3 h after synovitis was induced. The degree of synovitis was monitored by serial WBC counts in synovial fluid. Trimethoprim (TMP) and sulfadiazine (SDZ) concentrations in serum and synovial fluid were measured and pharmacokinetic parameters were calculated. The results indicated that inflammation had no effect upon the concentrations of TMP/SDZ that reach the joint and that synovial fluid and blood are both representative of the central compartment as shown by the non-significant differences in selected pharmacokinetic parameters for TMP and SDZ in these two body fluids. The distribution and elimination of TMP and SDZ in serum were described by a two-compartment model.     

Prolonged-release hard gelatin capsules of furosemide for the treatment of dogs

The object of this study was to examine whether prolonged-release hard gelatin capsule formulations could be developed for dogs. Different viscosity grades of hydroxypropyl methylcellulose (HPMC) and sodium carboxymethylcellulose (NaCMC) were used to control drug release. Furosemide was chosen because of its wide use in the management of heart failure in dogs. In vitro , selecting different viscosity grades allowed good control of drug release, whereas in vivo the difference between formulations was clearly smaller. Although all formulations gave prolonged release, both inter- and intra-individual variation in the plasma concentration-time curves was high. It is difficult to develop prolonged-release formulations for drugs such as furosemide with highly variable pharmacokinetic properties. However, hard gelatin capsules containing hydrophilic polymers could still be a suitable choice for some drugs.     

Modelling the concentration-time relationship in milk from cattle administered an intramammary drug

Whittem, T., Whittem, J. H., Constable, P. D. Modelling the concentration–time relationship in milk from cattle administered an intramammary drug. J. vet. Pharmacol. Therap.  35 , 460–471. Antimicrobial drugs are often infused directly through the streak canal into the bovine udder for the treatment or prevention of mastitis. These infusions have two major problems: drug residues in milk and variable antimicrobial efficacy. Both problems are influenced by the pharmacokinetics of intramammary delivery and elimination of drugs. This pharmacokinetics does not conform to the assumptions of traditional first‐order mamillary pharmacokinetic models. To help understand drug delivery into and elimination from the udder, a new approach to pharmacokinetic modelling of the udder is proposed. This new model was used to predict the movement of drug within the udder and the concentrations of drug achieved within physiological compartments of the udder. These predictions were examined using computer modelling. The model was evaluated using data from in vivo intramammary infusion of cefuroxime. The model predicts that changes in milking efficiency (residual volume), milk productivity and milking frequency can impact both the drug residue persistence and the time that milk drug concentrations exceed the minimum inhibitory concentrations for pathogens. The model provides a new tool for future evaluation of intramammary dosing studies.     

The lack of effect of inoculation with equine influenza vaccine on theophylline pharmacokinetics in the horse

Several studies conducted during the past few years have shown that the pharmacokinetics of a variety of drugs may be altered following viral infection or vaccination. The elimination of drugs which are extensively metabolized, such as theophylline, may be prolonged, especially following exposure to RNA viruses such as Type A influenza or similar orthomyxoviruses. The purpose of this study was to determine whether vaccination of horses with equine influenza virus affected pharmacokinetic parameters describing the distribution and elimination of intravenously administered theophylline. Three thoroughbred horses and three ponies were vaccinated with a trivalent vaccine containing inactivated strains of A/Equi 1 (Prague), A/Equi 2 (Miami) and A/Equi 2 (Kentucky 81). Antibody titre, serum interferon concentrations, and the pharmacokinetic parameters t1/2 beta, Vc, Vd(ss), Vd(area) and ClB were measured at various intervals after vaccination. Antibody titre increased substantially in only two animals, while plasma interferon was detectable in low concentrations in four subjects. There was no significant change in any parameter describing the pharmacokinetics of theophylline when measured 2, 6, or 12 days after vaccination. It is suggested that the failure of vaccination to substantially increase plasma interferon concentrations, and thereby alter theophylline elimination, was related to the use of an inactivated viral vaccine, the only type available for vaccination of horses against infection with equine influenza. Regular use of such vaccines, as is required by most Racing Authorities, is therefore unlikely to affect drug withdrawal times.     

Factors Influencing the Bioavailability of Peroral Formulations of Drugs for Dogs

The oral route is presently the preferred route of drug delivery. Poor oral bioavailability results in variable concentrations of drugs in the plasma and variable pharmacological responses, in addition to higher product costs. The unique canine physiology, anatomy and biochemistry makes designing canine dosage forms a challenging exercise. This article reviews the physicochemical, physiological, pharmacokinetic, pharmacological and formulation factors that can influence the drug availability of the oral formulations in dogs in an effort to provide a source of data to aid development of canine drug products with superior bioavailability.     

Pharmacokinetic disposition and arthropathic potential of oral ofloxacin in dogs

We examined the relation between the pharmacokinetic disposition and arthropathic potential of ofloxacin, a new quinolone antibacterial agent, using both male immature (3-month-old) and mature (18-month-old) beagles. Ofloxacin was orally administered to these dogs at 20 mg/kg once daily for 8 consecutive days, and the animals were killed 2 h after the last treatment. Serum ofloxacin concentrations were repeatedly measured on days 1 and 7 by use of high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were calculated. In addition, on day 8, the drug concentrations in the joint synovial fluid and humeral and femoral condyles were measured. Clinico-pathological tests of blood and serum or histopathological examination of bone specimens were also performed. Arthropathy was macroscopically observed in the cartilage surface of all immature dogs, but not in mature dogs. There were, however, no noticeable differences in pharmacokinetic parameters between the two age groups of dogs or between single and 7-day treatments. In contrast to the occurrence of arthropathic lesions, the synovial fluid and condylar drug concentrations in immature dogs was equal to or lower than those in mature dogs, suggesting that the pharmacokinetic disposition of ofloxacin may not be essential for cartilage lesions.     

Some pharmacokinetic parameters of the trypanocidal drug homidium bromide in Friesian and Boran steers using an enzyme-linked immunosorbent assay (ELISA)

Pharmacokinetic studies on the trypanocidal drug homidium bromide using a competitive enzyme immunoassay (detection limit 0.1 ng/mL) are reported for non-infected Friesian and Boran steers following treatment with homidium bromide at a dose of 1.0 mg/kg b.w. Following intravenous (i.v.) treatment of Friesian steers (n = 5), the mean serum drug concentrations were 31.9 +/- 2.1 and 3.9 +/- 0.4 ng/mL at 1 and 24 h, respectively. The decline in serum drug concentration was tri-exponential with half-lives of 0.064 +/- 0.037 h for t1/2 alpha, 7.17 +/- 1.87 h for t1/2 beta and 106.3 +/- 6.6 h for t1/2 gamma for distribution and elimination phases 1 and 2, respectively. Drug was detectable in serum for 17 days following treatment. The mean residence time (MRT) was 63.4 +/- 7.5 h. Following intramuscular (i.m.) treatment of Friesian steers (n = 5), the drug concentration at 1 h after treatment was 72.5 +/- 2.2 ng/mL. This declined to 9.8 +/- 1.8 ng/mL at 24 h. Low concentrations of between 0.1 and 0.3 ng/mL remained in circulation for up to 90 days post-treatment. Following intramuscular treatment of Boran steers (n = 5), the mean serum drug concentration at 1 h after treatment was 112.1 +/- 40.3 ng/mL. By 24 h after treatment, the concentration had fallen to 13.0 +/- 3.3 ng/mL. Thereafter, the serum drug concentration-versus-time profile and the pharmacokinetic parameters obtained following non-compartmental analysis were similar to those obtained following intramuscular treatment of Friesian steers.     

A physiologically based pharmacokinetic model for oxytetracycline residues in sheep

A physiologically based pharmacokinetic model (PBPK) for oxytetracycline (OTC) residues in sheep was developed using previously published data from a combined serum pharmacokinetic and tissue residue study [Craigmill et al. (2000) J. Vet. Pharmacol. Ther.23, 345]. Physiological parameters for organ weights and tissue blood flows were obtained from the literature. The tissue/serum partition coefficients for OTC were estimated from the serum and tissue residue data obtained at slaughter. The model was developed to include all of the tissues for which residue data were available (serum, kidney, liver, fat, muscle and injection site), and all of the remaining tissues were combined into a slowly perfused compartment with low permeability. Total body clearance of OTC calculated in the previous study was used as the starting value for clearance in the PBPK model, with the kidney being the only eliminating organ. The model was built using ACSL (Advanced Continuous Simulation Language) Graphic Modeler, and the model was fit to the serum and tissue data using the ACSL Math/Optimizer software (AEgis Technologies Group, Inc., Huntsville, AL, USA). A sensitivity analysis was also performed to determine which parameters had the greatest effect on the goodness of fit. Numerous strategies were tested to model the injection site, and a model providing a biexponential absorption of the drug from the injection bolus gave the best fit to the experimental data. The model was validated using the clearance parameters calculated from the traditional pharmacokinetic model for each individual animal in the PBPK model. This simple PBPK model well predicted OTC residues in sheep tissues after intramuscular dosing with a long-acting preparation and may find use for other species and other veterinary drugs.     

Pharmacokinetics of sulfadimethoxine and ormetoprim in a 5:1 ratio following intraperitoneal and oral administration, in the hybrid striped bass (Morone chrysops x Morone saxitalis)

Selected pharmacokinetic parameters for sulfadimethoxine and ormetoprim, administered in a 5:1 ratio, via the oral and intraperitoneal (i.p.) routes were determined in the hybrid striped bass (Morone chrysops x Morone saxitalis). Plasma concentrations of both drugs were determined by high-performance liquid chromatography. A first-order one-compartment model adequately described plasma drug disposition. The elimination half-lives for sulfadimethoxine following i.p. and oral administration were 26 and 10.5 h, respectively. The half-lives for ormetoprim administered via i.p. and oral routes were 7.5 and 3.9 h, respectively. Cmax for sulfadimethoxine via the i.p. and oral routes were calculated to be 27.7 (+/-9.0) microg/mL at 3.6 h and 3.2 (+/-1.2) microg/mL at 1.2 h, respectively. Cmax for ormetoprim via the i.p. route was calculated to be 1.2 (+/-0.5) microg/mL at 9.1 h and 1.58 (+/-0.7) microg/mL at 5.7 h for the oral route. The oral availability of sulfadimethoxine relative to the i.p. route was 4.6%, while the oral availability of ormetoprim relative to the i.p. route was 78.5%. Due to the nonconstant ratio of these drugs in the plasma of the animal, the actual drug ratio to use for determining minimum inhibitory concentration (MIC) is unclear. Using the ratio of the total amount of each drug that is absorbed as a surrogate for the mean actual ratio may be the best alternative to current methods. Using this ratio as determined in these studies, (2.14:1 sulfadimethoxine:ormetoprim) to determine the MICs the single 50 mg/kg oral dose of the 5:1 combination of sulfadimethoxine and ormetoprim appears to provide plasma concentrations high enough to inhibit the growth of Yersinia ruckeri, Edwardsiella tarda, and Escherichia coli.     

Detection, quantification, and pharmacokinetics of furosemide and its effects on urinary specific gravity following IV administration to horses

Furosemide is a potent loop diuretic used for the prevention of exercise-induced pulmonary hemorrhage in horses. This drug may interfere with the detection of other substances by reducing urinary concentrations, so its use is strictly regulated. The regulation of furosemide in many racing jurisdictions is based on paired limits of urinary SG (<1.010) and serum furosemide concentrations (>100 ng/ml). To validate this regulatory mechanism, a liquid chromatography/mass spectrometry/mass spectrometry method employing a solid-phase extraction procedure and furosemide-d5 as an internal standard was developed. The method was used to determine the pharmacokinetic parameters of furosemide in equine serum samples and its effects on urinary SG after IV administration (250 mg) to 10 horses. Pharmacokinetic analysis showed that serum concentrations of furosemide were well described by a two-compartmental open model. Based on results in this study, it is very unlikely for horses to have serum furosemide concentrations greater than 100 ng/ml or urine SG less than 1.010 at 4 hours after administration (250 mg IV). However, it should be remembered that urine SG is a highly variable measurement in horses, and even without furosemide administration, some horses might naturally have urine SG values less than 1.010.     

Interspecies allometric analysis of the comparative pharmacokinetics of 44 drugs across veterinary and laboratory animal species

The purpose of this study was to apply the method of allometric analysis to a study of the comparative disposition of veterinary drugs using the Food Animal Residue Avoidance Databank (FARAD) as a source of the comparative pharmacokinetic data. An initial filtration of the FARAD data was performed in order to exclude drugs for which no pharmacokinetic data were available, in at least four species the route of administration was other than intravenous, and the matrix was different from blood, plasma or serum. This process restricted the study to a total of 44 candidate drugs. The primary pharmacokinetic parameter selected for study was half-life (t_1/2). As this parameter is a composite of clearance (Cl) and volume of distribution (Vd), it was considered to be the most robust for interspecies scaling. Volume of distribution at steady state (Vd_ss) and clearance showed weak allometric correlations with weight across species. The relationships between body weight and elimination half-life (t_1/2β) were determined for this selected group of drugs by using the empirically determined function Y=a W^b. The function Y represents the parameter of concern (half-life), a is a coefficient typical of every drug (intercept), W is the species average body weight, and b is the scaling exponent. A total of 11 drugs (tetracycline, oxytetracycline, chlortetracycline, erythromycin, diazepam, prednisolone, cephapirin, ampicillin, gentamicin, apramycin and carbenicillin) showed statistically significant correlations and consequently are excellent candidates for interspecies extrapolation of pharmacokinetic parameters (half-life) in species of relevance to veterinary medicine. The remaining 33 drugs were divided into two groups which showed various degrees of lack of correlation. Many of the drugs that showed no allometric correlation were low hepatic extraction drugs. However, some other drugs demonstrated equivocal results which could either be due to a true lack of allometric correlation, or be inconclusive due to the lack of quality data or excessive variability due to the multi-laboratory origin of the FARAD data. The results of this study show that interspecies scaling is applicable to certain veterinary drugs. The experimental determination of the coefficients of the allometric equation for relevant pharmacokinetic parameters (clearance and volume of distribution) could be an important tool in estimating dose in species where the drug has never been studied. This could have important consequences in terms of avoiding the use of dose-titration studies in Phase I of drug development, for drugs that are experimentally ‘well behaved’.     

A new dosing schedule for gentamicin in blood pythons (Python curtus): a pharmacokinetic study

Gentamicin is frequently used in the treatment of aerobic Gram-negative infections in reptiles. Pharmacokinetic data to ensure proper dosing are scant, especially for large snakes. A pharmacokinetic study of gentamicin was therefore conducted in four blood pythons. Snakes were given intramuscular injections of either 2.5 mg kg-1 or 3.0 mg kg-1 loading dose followed by 1.5 mg kg-1 at 72 and 96 hours. A linear pharmacokinetic relationship between gentamicin serum concentrations and time was demonstrated in each of the four snakes studied. Peak serum concentrations occurred six to 10 hours after injection and ranged from 4.6 to 8.9 micrograms ml-1. Half-life was variable and ranged from 32 to 110 hours. Total body clearance and apparent volume of distribution varied little between the individual snakes studied. There was no evidence of renal toxicity. For blood pythons a loading dose of 2.5 mg kg-1 followed by 1.5 mg kg-1 at 96 hour intervals is recommended. If higher concentrations are desired, a loading dose of 3.0 mg kg-1 followed by 1.5 mg kg-1 at 96 hours can be given. These dosing schedules will provide serum concentrations in excess of the minimum inhibitory concentrations for most aerobic Gram-negative bacilli that are pathogenic in snakes; gentamicin accumulation with subsequent renal dysfunction should not occur.     

Kinetic modelling and residue depletion of drugs in eggs

1. A physiologically-based pharmacokinetic model was developed for the purpose of describing the relationship between plasma concentration of drugs and their deposition into eggs. 2. By incorporating the physiology of egg formation into the model, the transfer of drugs into the egg albumen and yolk could be described using rate constants. 3. The model was used to describe concentrations in albumen and yolk of sulphanilamide, sulphaquinoxaline and pyrimethamine as a function of time using datasets from the literature. 4. The model could be used as a tool to obtain an insight into those properties of a drug which are responsible for the amount of residue in eggs, and could help in the design of critical studies for determining withdrawal periods for eggs.     

Disposition of the anti‐ulcer medications ranitidine,cimetidine, and omeprazole following administration of multiple doses to exercised Thoroughbred horses

The use of anti‐ulcer medications, such as cimetidine, ranitidine, and omeprazole, is common in performance horses. The use of these drugs is regulated in performance horses, and as such a withdrawal time is necessary prior to competition to avoid a medication violation. To the authors' knowledge, there are no reports in the literature describing repeated oral administrations of these drugs in the horse to determine a regulatory threshold and related withdrawal time recommendations. Therefore, the objective of the current study was to describe the disposition and elimination pharmacokinetics of these anti‐ulcer medications following oral administration to provide data upon which appropriate regulatory recommendations can be established. Nine exercised Thoroughbred horses were administered 20 mg/kg BID of cimetidine or 8 mg/kg BID of ranitidine, both for seven doses or 2.28 g of omeprazole SID for four doses. Blood samples were collected, serum drug concentrations were determined, and elimination pharmacokinetic parameters were calculated. The serum elimination half‐life was 7.05 ± 1.02, 7.43 ± 0.851 and 3.94 ± 1.04 h for cimetidine, ranitidine, and omeprazole, respectively. Serum cimetidine and ranitidine concentrations were above the LOQ and omeprazole and omeprazole sulfide below the LOQ in all horses studied upon termination of sample collection.     

Pharmacokinetic adjustment of gentamicin dosing in horses with sepsis

Serum gentamicin concentrations were measured and pharmacokinetic values were calculated for 12 equine patients receiving parenteral gentamicin therapy. Horses were selected for monitoring of gentamicin pharmacokinetics if they met several criteria of high risk for gentamicin-induced toxicosis. Two blood samples were obtained, one immediately before gentamicin dosing and one at 1 hour after dosing. Gentamicin serum concentrations were analyzed and dosage adjustments were made on the basis of calculated one-compartment pharmacokinetic values. Nine of the 12 horses required dosage adjustment to optimize therapeutic concentrations. Even for horses for which there was no evidence of decreased renal function, variation in the disposition of gentamicin was substantial. Because of the larger volume of distribution in foals, an initial dosage of 3 mg/kg every 12 hours was found to best approximate target concentrations. Therefore, published standard dosages were a poor means of achieving desired peak and trough concentrations in many animals. Seemingly, for optimal treatment of horses with sepsis, gentamicin dosage adjustments based on the patient's pharmacokinetic values is required.     

Elimination of cetirizine following administration of multiple doses to exercised thoroughbred horses

Cetirizine is an antihistamine used in performance horses for the treatment of hypersensitivity reactions and as such a withdrawal time is necessary prior to competition. The objective of the current study was to describe the disposition and elimination of cetirizine following oral administration in order to provide additional serum concentration data upon which appropriate regulatory recommendations can be established. Nine exercised thoroughbred horses were administered 0.4 mg/kg of cetirizine orally BID for a total of five doses. Blood samples were collected immediately prior to drug administration and at various times postadministration. Serum cetirizine concentrations were determined and selected pharmacokinetic parameters determined. The serum elimination half‐life was 5.83 ± 0.841 h. Average serum cetirizine concentrations were still above the LOQ of the assay (0.05 ng/mL) at 48 h (final sample collected) postadministration of the final dose.     

The pharmacokinetics and tissue levels of polymyxin B, colistin and gentamicin in calves

Following a single intravenous injection of polymyxin B, colistin (5 mg/kg, each) and gentamicin (3 mg/kg) to calves, the decline in serum antibiotic concentration generally suggested a three-compartment (open system) pharmacokinetic model. Tissue binding is a dominant factor in the distribution and elimination kinetics of the drugs. Less than 65% of the dose of polymyxin B and colistin was recovered in the urine during 48 h after treatment. Concentrations of nonbound polymyxin B and colistin in the kidney, liver, lung, heart, and skeletal muscles were similar to total (free and bound) serum drug levels, but considerably higher concentrations were found, in bound form, in chloroform-ethanol extracts of these organs.
At 24 h after treatment, more than 50% of the doses of polymyxin B and colistin were present bound to the tissues; the largest amount was in the skeletal muscles. Gentamicin was concentrated in the kidney, predominantly in the free form. At 48 h after treatment the amount of gentamicin in the kidney was 6.3% of the administered dose, being more than five times greater than the corresponding amounts of polymyxin B and colistin.
The extent of tissue uptake of polymyxin B and colistin limits the usefulness of kinetic values, which are derived from the analysis of serum drug levels, for the purpose of designing dosage schedules. The strong affinity of the polymyxins to the muscle tissue, and gentamicin to the kidney, can result in drug residues persisting in the body for several weeks.