• View in gallery
    Figure 1—

    Semilogarithmic time-concentration curves of mean ± SD total plasma (circles), ISF (triangles), and protein-unbound (squares) concentrations of cefpodoxime after oral administration of a single dose (mean, 9.6 mg of cefpodoxime proxetil/kg; time 0) in 6 adult dogs. ATlag was calculated for the collection of ISF because of the length of the nonpermeable portion of the tubing of the in vivo ultrafiltration probe. The Tlag value was then used to adjust the reported concentrations of cefpodoxime in ISF. The MIC90 (0.5 μg/mL; dashed line) for Staphylococcus pseudintermedius and Escherichia coli reported in another study5 is provided for comparison with the observed cefpodoxime concentrations.

  • View in gallery
    Figure 2—

    Semilogarithmic time-concentration curves of mean ± SD total plasma (circles), ISF (triangles), and protein-unbound (squares) concentrations of cephalexin after oral administration of a single dose (mean, 25 mg/kg; time 0) in 6 adult dogs. A Tlag was calculated for the collection of ISF because of the length of the nonpermeable portion of the tubing of the in vivo ultrafiltration probe. The Tlag value then was used to adjust the reported concentrations of cephalexin in ISF. The MIC90 for S pseudintermedius (2 μg/mL; long dashes) and E coli (16 μg/mL; short dashes) reported in another study31 is provided for comparison with the observed cephalexin concentrations.

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Pharmacokinetics, protein binding, and tissue distribution of orally administered cefpodoxime proxetil and cephalexin in dogs

Mark G. PapichDepartments of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606

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Jennifer L. DavisClinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606

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Amanda M. FloerchingerDepartments of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606

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Abstract

Objective—To determine the effect of protein binding on the pharmacokinetics and distribution from plasma to interstitial fluid (ISF) of cephalexin and cefpodoxime proxetil in dogs.

Animals—6 healthy dogs.

Procedures—In a crossover study design, 25 mg of cephalexin/kg or 9.6 mg of cefpodoxime/kg was administered orally. Blood samples were collected before (time 0) and 0.33, 0.66, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours after treatment. An ultrafiltration device was used in vivo to collect ISF at 0, 2, 4, 6, 8, 10, 12, 16, and 24 hours. Plasma and ISF concentrations were analyzed with high-pressure liquid chromatography. Plasma protein binding was measured by use of a microcentrifugation technique.

Results—Mean plasma protein binding for cefpodoxime and cephalexin was 82.6% and 20.8%, respectively. Mean ± SD values for cephalexin in plasma were determined for peak plasma concentration (Cmax, 31.5 ± 11.5 μg/mL), area under the time-concentration curve (AUC, 155.6 ± 29.5 μg•h/mL), and terminal half-life (T½, 4.7 ± 1.2 hours); corresponding values in ISF were 16.3 ± 5.8 μg/mL, 878 ± 21.0 μg•h/mL, and 3.2 ± 0.6 hours, respectively. Mean ± SD values for cefpodoxime in plasma were 33.0 ± 6.9 μg/mL (Cmax), 282.8 ± 44.0 μg•h/mL (AUC), and 5.7 ± 0.9 hours (T1/2); corresponding values in ISF were 4.3 ± 2.0 μg/mL, 575 ± 174 μg•h/mL, and 10.4 ± 3.3 hours, respectively.

Conclusions and Clinical Relevance—Tissue concentration of protein-unbound cefpodoxime was similar to that of the protein-unbound plasma concentration. Cefpodoxime remained in tissues longer than did cephalexin.

Abstract

Objective—To determine the effect of protein binding on the pharmacokinetics and distribution from plasma to interstitial fluid (ISF) of cephalexin and cefpodoxime proxetil in dogs.

Animals—6 healthy dogs.

Procedures—In a crossover study design, 25 mg of cephalexin/kg or 9.6 mg of cefpodoxime/kg was administered orally. Blood samples were collected before (time 0) and 0.33, 0.66, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours after treatment. An ultrafiltration device was used in vivo to collect ISF at 0, 2, 4, 6, 8, 10, 12, 16, and 24 hours. Plasma and ISF concentrations were analyzed with high-pressure liquid chromatography. Plasma protein binding was measured by use of a microcentrifugation technique.

Results—Mean plasma protein binding for cefpodoxime and cephalexin was 82.6% and 20.8%, respectively. Mean ± SD values for cephalexin in plasma were determined for peak plasma concentration (Cmax, 31.5 ± 11.5 μg/mL), area under the time-concentration curve (AUC, 155.6 ± 29.5 μg•h/mL), and terminal half-life (T½, 4.7 ± 1.2 hours); corresponding values in ISF were 16.3 ± 5.8 μg/mL, 878 ± 21.0 μg•h/mL, and 3.2 ± 0.6 hours, respectively. Mean ± SD values for cefpodoxime in plasma were 33.0 ± 6.9 μg/mL (Cmax), 282.8 ± 44.0 μg•h/mL (AUC), and 5.7 ± 0.9 hours (T1/2); corresponding values in ISF were 4.3 ± 2.0 μg/mL, 575 ± 174 μg•h/mL, and 10.4 ± 3.3 hours, respectively.

Conclusions and Clinical Relevance—Tissue concentration of protein-unbound cefpodoxime was similar to that of the protein-unbound plasma concentration. Cefpodoxime remained in tissues longer than did cephalexin.

Cefpodoxime proxetil and cephalexin are the most frequently administered oral formulations of cephalosporins in dogs. Cefpodoxime is a third-generation oral formulation approved for use in dogs. Cephalexin is a first-generation oral formulation that is used in an extralabel manner in dogs. The human generic formulation of cephalexin is the product most often prescribed for use in dogs. Both antimicrobials are effective for the treatment of bacterial infection in dogs. Studies have revealed the efficacy of cephalexin when administered orally for the treatment of skin infections (eg, pyoderma) in dogs at dosages between 22 and 35 mg/kg administered every 12 hours,1 15 mg/kg administered every 12 hours,2,a–c and 30 mg/kg administered every 24 hours.2,a–c Cephalexin (26 to 39 mg/kg, PO, q 12 h) is effective (90% of dogs had good or excellent response to treatment) when used for the treatment of skin, soft tissue, urinary tract, and respiratory tract infections associated with bacterial infection in dogs.3 Cephalexin and cefadroxil were equally effective for the treatment of pyoderma associated with bacterial infections in dogs at dosages ranging from 22 to 35 mg/kg when administered orally every 12 hours.1 In another study,4 157 dogs with pyoderma associated with bacterial infection were treated with cefpodoxime (5 mg/kg, PO, q 24 h) or cephalexin (26 mg/kg, PO, q 12 h) and treatment success was 96.8% and 93.9% for cefpodoxime-treated and cephalexin-treated dogs, respectively.

Pharmacokinetic studies in dogs have been reported for the oral administration of cefpodoxime5,d and cephalexin,6–11,e,f but these studies were limited to the measurement of total (protein-bound and protein-unbound fractions) plasma concentrations. In addition, investigators in these studies reported only the pharmacokinetics of plasma concentrations and did not indicate the concentration of drug at the biophase (site of infection) or determine the effect of protein binding on drug concentrations.

Antimicrobial experts have concluded that measurement of active drug concentrations in extracellular fluid is the preferred method to correlate pharmacokinetic-pharmacodynamic indices with clinical efficacy12,13 In another study,14 investigators provided evidence that indicated antimicrobial concentrations at the target site (ie, ISF) are responsible for the antimicrobial effect and are more relevant than are plasma concentrations for predicting therapeutic efficacy. This conclusion was reiterated by other veterinary pharmacologists,15 who stated that plasma protein binding should be taken into account when examining pharmacokinetic factors because antimicrobial activity is dependent on the unbound drug concentration, rather than the total drug concentration, and that the protein-unbound drug concentration at the site of action (ie, ISF) is the most important predictor of therapeutic efficacy. Failure to recognize the differences between total plasma antimicrobial concentrations and active ISF antimicrobial concentrations may result in misinterpretation of pharmacokinetic-pharmacodynamic properties of a drug and its therapeutic efficacy.

Studies16–18 in dogs have revealed that drug concentrations in the ISF of tissues are determined more by plasma protein binding than by other chemical features of the drug. Investigators in those studies16–18 used an in vivo ultrafiltration device, which was a reliable and convenient method for collecting ISF samples from tissues in dogs. The use of an ultrafiltration device is the preferred method, rather than collection of tissue biopsy specimens or use of tissue cages, in animals because of ease of insertion and the ability to collect serial samples with the same device, without residual wounds or lesions after removal of the ultrafiltration probes. In addition, an ultrafiltration device provides a convenient method for continuous collection of samples and monitoring of drug distribution in unrestrained animals.

Other methods for measuring tissue drug concentrations in animals have traditionally included the processing of homogenized tissues or samples collected from implanted tissue cages. Pharmacology experts agree that the method of obtaining whole tissues, homogenizing them, and measuring the whole tissue concentration is of little value for understanding the relationship between tissue concentration and drug effect, particularly when evaluating this relationship in antimicrobials.19–25 The flaw in relying on this type of tissue concentration data was indicated in a review report.25 Evaluation of tissue biopsy specimens can overestimate lipophilic and underestimate hydrophilic drug concentrations because of the artificial mixing of intracellular fluid, blood, and tissue components during homogenization.21–23 In addition, because tissue biopsy specimens require that animals be euthanatized or that animals be anesthetized for biopsy procedures, it is difficult to achieve serial collection of samples for measurement of plasma-tissue fluid dynamics.

Tissue cages, which have been used by some investigators to estimate tissue drug concentrations, do not represent natural compartments.21–23 Furthermore, sedation, anesthesia, or both is required for cage implantation, and a 4- to 6-week waiting period is necessary before samples can be collected. Influx of fibrin into cages prevents repeated collection of samples and long-term use of the cages. The artificial compartments that arise from the use of tissue cages have a high volume because of the sample space within the device, and the actual volume of extracellular fluid of the tissues cannot be estimated from these compartments. Tissue cages are used to determine drug concentrations in fluids collected from tissues, but they typically misrepresent the true ISF concentrations because of delayed peaks and overestimated rates of drug elimination from tissues.26–29 In addition, drug concentrations in fluids collected in tissue cages may overrepresent the microbiologically active drug fraction in tissues because fluids include protein-bound and protein-unbound drug fractions, and only the protein-unbound fraction is microbiologically active. The purpose of the study reported here was to determine the effect of protein binding on the pharmacokinetics and distribution of cephalexin and cefpodoxime from tissues to ISF in dogs and to compare observed drug concentrations with the MIC90 of Staphylococcus pseudintermedius30,31 (formerly Staphylococcus intermedius) and Escherichia coli.31

Materials and Methods

Animals—Six adult mixed-breed dogs weighing between 19.8 and 32.3 kg (mean, 25.2 kg) were used in this study. Results of physical examination were used to determine that the dogs were healthy. Dogs were housed at the North Carolina State University Laboratory Animal Resources facility and fed a maintenance diet. The study was reviewed and approved by the Institutional Animal Care and Use Committee at North Carolina State University.

Study design—A 2-period, 2-treatment crossover design with a 7-day washout period between each treatment was used in this study. Dogs were assigned to the order in which they would receive treatments by random number selection. Cephalexin or cefpodoxime proxetilb was administered orally. A mean dose of the base antimicrobial was calculated, which resulted in a dosage of 25 mg of cephalexin/kg or 9.6 mg of cefpodoxime proxetil/kg, respectively, administered orally as a single dose. Food was withheld for 18 hours before drug administration. Each dose was administered orally to each dog and immediately followed by administration of 12 mL of water to ensure the entire dose was swallowed.

Blood collection—Eighteen hours prior to drug administration, dogs were lightly sedated by the administration of medetomidine hydrochlorideg (0.02 mg/kg, IV) and a catheter was inserted into a jugular vein of each dog. Catheters were flushed with sterile saline (0.9% NaCl) solution to maintain catheter patency. Blood samples were collected before (time 0) and 0.33, 0.66, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours after the administration of cephalexin and transferred into glass tubes containing lithium heparin (anticoagulant); additional blood samples were collected at 32 and 48 hours after administration of cefpodoxime because of an anticipated longer T1/2. Blood samples were immediately placed in ice and were later centrifuged at 1,000 × g for 10 minutes. Plasma from centrifuged samples was separated and stored at −70°C.

ISF collection—Eighteen hours prior to the start of the study, an ultrafiltration probe was inserted into each dog. Interstitial fluid subsequently was collected by use of an in vivo ultrafiltration sampling kit.h The ultrafiltration probe contained 3 loops with a 12-cm semipermeable membrane. The semipermeable membrane in the loop consisted of pores that allowed water, electrolytes, and low-molecular-weight molecules (< 30 KDa) to diffuse across the membrane but excluded the passage of proteins and other high-molecular-weight compounds. The length of the nonpermeable tubing from the end of the 12-cm semipermeable membrane to the end of the external collection tube of the probe was 46 cm, and this 46-cm portion of the tube had a fluid capacity of 160 μL.

The ultrafiltration probe was inserted 18 hours prior to the start of the study to allow equilibration between the fluid in the ISF and the fluid collected into the ultrafiltration probe. Each probe (1 probe/dog) was inserted into the interstitial space overlying the lateral thorax. Although the dogs were still sedated after the administration of medetomidine, skin surrounding the insertion site of the probe was aseptically prepared and the insertion site was infused with a solution of 2% lidocaine hydrochloride. A guide needle was used to insert the ultrafiltration probe into the interstitial space under the skin so that the 3 loops of the probe remained under the skin in the interstitial space while the nonpermeable portion of the probe extended external to the dog's skin. Once the ultrafiltration probe was in place, the guide needle was removed. An evacuated glass tube was connected to the nonpermeable portion of the probe to apply negative pressure on the probe system for ISF collection through the semipermeable membrane. After insertion of the ultrafiltration probe, sedation was reversed by the administration of atipamezole hydrochloridei (0.3 mg/kg, IV). Dogs were fully recovered from sedation by the time of drug administration the following day. A new ultrafiltration probe was inserted (as described) in another location prior to each treatment period. Interstitial fluids were collected in conjunction with blood samples at the times described and immediately stored at −70°C. The mean ± SD volume of fluid collected into the evacuated glass tubes and the mean ± SD collection rate were calculated for each treatment period.

HPLC drug analysis—Plasma and ISF samples were analyzed via HPLC to determine the concentrations of cefpodoxime and cephalexin. The HPLC system consisted of a quaternary solvent delivery systemj (flow rate, 1 mL/min), an autosampler,k and UV detector.l Wavelengths of 235 and 265 nm were set for the UV detector for cefpodoxime and cephalexin, respectively. Chromatograms were integrated with a computer program.m The analytic columnn was a reverse-phase, 4.6 × 15-cm C18 column that was maintained at a constant temperature (40°C). The mobile phase consisted of 85% distilled water and 15% acetonitrile. A 0.1% solution of trifluoroacetic acid was added to the mobile phase to lower the pH and improve the shape of the eluting peaks.

Cephalexin was measured as its base in plasma and ISF. Although cefpodoxime was administered as an ester, the parent drug is released after enzyme hydrolysis and cefpodoxime was measured in plasma and ISF. Reference standards of cephalexin hydrateo and cefpodoximep were purchased or supplied, respectively, by the drug manufacturer.d A stock solution of cefpodoxime (1 mg/mL) was prepared by dissolving the pure cefpodoxime reference standard in a 3:1 solution of 0.1% sodium bicarbonate to distilled water. A stock solution of cephalexin (1 mg/mL) was prepared by dissolving cephalexin hydrateo in distilled water. Stock solutions were sealed and stored in the dark in a refrigerator.

Stock solutions were further diluted to create spiking solutions that would be used to fortify blank canine plasma and ISF for development of the HPLC method, calibration curves, and quality-control standards. Calibration curves for each drug consisted of 9 standard solutions that ranged between 0.05 and 30 μg/mL and included a blank (0 μg/mL) sample. The blank sample was used to detect interfering peaks that elute into the window of the chromatographic peak of interest and to measure background interference. The calibration curve was accepted if the linear coefficient of determination (r2) was ≥ 0.99 and if the calibration curve concentrations could be back-calculated to ≤ 15% of the true concentration of the standard.

All plasma, calibration, quality-control, and blank plasma samples were prepared in an identical manner. Solid-phase extraction cartridgesq were conditioned with 1 mL of methanol, which was followed by 1 mL of distilled water for cefpodoxime analysis or 1 mL of a 0.01M sodium acetate buffer for cephalexin analysis. Five hundred microliters of each plasma sample was added to a conditioned cartridge, which was followed by washing with 1 mL of a water-to-methanol (95:5) solution. The eluate from the cartridge was discarded. Then, drug was collected into a clean glass tube by elution with 1 mL of 100% methanol. The eluted samples were evaporated to yield a dry residue by heating the tubes at 40°C under a flow of air for 20 minutes. The residue of each tube was reconstituted by the addition of 200 μL of the mobile phase; solutions were vortexed briefly and transferred to an HPLC injection vial. Twenty-five microliters of each sample was used for injection into the HPLC system.

Retention time for cefpodoxime and cephalexin was 6.2 to 6.5 minutes and 7.2 to 7.4 minutes, respectively Fresh calibration and blank samples were prepared for analysis each day. Limit of quantification for each drug in canine plasma was 0.05 μg/mL, which was determined from the lowest point on a linear calibration curve that yielded an acceptable accuracy. All plasma samples had concentrations above the limit of quantification. Laboratory procedures were conducted in accordance with published guidelines on validation procedures.32

Because ISF samples were free of protein and other matrix components found in plasma, these could be injected directly into the HPLC system without prior preparation or extraction. For calibration of the standard curve, blank ISF was spiked with standard solutions of each drug to construct a calibration curve of 6 standard solutions that ranged between 0.10 and 20 μg/mL and included a blank (0 μg/mL) sample. All other conditions and criteria were identical to those described for the HPLC method for plasma sample analysis.

Plasma protein binding—Plasma protein binding was determined by use of an in vitro microcentrifugation system.r Stock solutions of cephalexin and cefpodoxime were prepared by dissolving the drugs as described previously. Aliquots (3 mL) of pooled canine plasma were spiked with the stock solutions to generate cefpodoxime concentrations of 1, 5, 10, 15, 20, and 30 μg/mL. In addition, aliquots (3 mL) of pooled canine plasma were spiked with cephalexin to generate concentrations of 1 and 10 μg/mL. The samples were incubated and divided into 3 replicates, and 1 mL of each aliquot was added to a microcentrifugation systemr to obtain a protein-free ultrafiltrate in the reservoir for analysis by HPLC. Protein binding was determined by use of the following equation:
article image
where total concentration is the sum of the protein-bound and protein-unbound drug concentration in plasma, and protein-unbound concentration is the protein-unbound drug concentration in plasma.

MIC90 comparison—The MIC90 values for 5 pseud-intermedius and E coli were recorded for isolates collected from dogs in the United States and Europe for cephalexin31 and studies conducted in dogs and reported on the product label for cefpodoxime.6–11,d–f These MIC90 values were used for comparison with observed plasma, ISF, and protein-unbound concentrations of cephalexin and cefpodoxime.

Pharmacokinetic analysis—Plasma and ISF drug concentrations were plotted on linear and semilogarithmic graphs for analysis and visual assessment of the best model for pharmacokinetic analysis. Analysis of curves and pharmacokinetic modeling were then performed by use of a commercial pharmacokinetic program.s For noncompartmental analysis, AUC from time 0 to the last measured concentration was calculated by use of the log-linear trapezoidal method. The AUC from time 0 to infinity was calculated by adding the terminal portion of the curve, estimated from the relationship between CnZ, to the AUC from time 0 to the last measured concentration, where λZ is the terminal slope of the curve and Cn is the last measured concentration. Values for Cmax and Tmax after drug administration were determined directly from the data. The T1/2 was calculated from the terminal rate constant by use of the following equation:
article image
where ln is the natural logarithm. Secondary parameters were calculated in accordance with methods described elsewhere.33 Because of the length of the tubing, a Tlag was calculated for the amount of time required for ISF to collect in the evacuated glass tube, which was based on the length of the nonpermeable portion of the ultrafiltration probe and rate of collection. In addition, Tlag values were used to adjust the time for the reported antimicrobial concentration and Tmax in the ISF for both antimicrobials by subtracting the Tlag from the time of sample collection. Plasma values that were dose dependent were calculated as the parameter per F. A tissue penetration factor was calculated by use of the following equation:
article image
Relative bioavailability of cefpodoxime and cephalexin was calculated by use of the following equation:
article image

Statistical analysis—We conducted a review of the literature and identified pharmacokinetic studies of cefpodoxime proxetil5 and cephalexin6–11,e,f in dogs. Data were pooled from pharmacokinetic studies6–11,e,f of cephalexin. Least squares means were calculated to account for differences in the number of observations for each study of cephalexin and reported as weighted mean values. This calculation generated overall mean values among pharmacokinetic studies while considering both the intrastudy and interstudy variation. These weighted mean values then were used for comparison with pharmacokinetic results of the present study. Values for Cl/F and the apparent volume of distribution per absolute fraction of the dose absorbed after oral administration (ie, Vd/F) were not included in the study8 of cefpodoxime but were estimated from the pharmacokinetic data and by use of equations described elsewhere.33

Results

Mean Ttag for ISF collection after cefpodoxime and cephalexin administration was 3.3 and 2.15 hours, respectively. Adjustments were made to the ISF drug concentration time points by use of the respective calculated Tlag, and semilogarithmic concentration-time curves were constructed for plasma, ISF, and protein-unbound concentrations of both antimicrobials (Figures 1 and 2). Compartmental analysis was attempted. However, after it became obvious that there was no consistent compartmental model that would be suitable for all the animals in the study, noncompartmental analysis was used because this type of analysis does not assume any compartmental structure. Pharmacokinetic parameters determined by use of noncompartmental analysis for each antimicrobial were summarized (Tables 1 and 2). In addition, protein binding results for each antimicrobial were summarized (Table 3).

Figure 1—
Figure 1—

Semilogarithmic time-concentration curves of mean ± SD total plasma (circles), ISF (triangles), and protein-unbound (squares) concentrations of cefpodoxime after oral administration of a single dose (mean, 9.6 mg of cefpodoxime proxetil/kg; time 0) in 6 adult dogs. ATlag was calculated for the collection of ISF because of the length of the nonpermeable portion of the tubing of the in vivo ultrafiltration probe. The Tlag value was then used to adjust the reported concentrations of cefpodoxime in ISF. The MIC90 (0.5 μg/mL; dashed line) for Staphylococcus pseudintermedius and Escherichia coli reported in another study5 is provided for comparison with the observed cefpodoxime concentrations.

Citation: American Journal of Veterinary Research 71, 12; 10.2460/ajvr.71.12.1484

Figure 2—
Figure 2—

Semilogarithmic time-concentration curves of mean ± SD total plasma (circles), ISF (triangles), and protein-unbound (squares) concentrations of cephalexin after oral administration of a single dose (mean, 25 mg/kg; time 0) in 6 adult dogs. A Tlag was calculated for the collection of ISF because of the length of the nonpermeable portion of the tubing of the in vivo ultrafiltration probe. The Tlag value then was used to adjust the reported concentrations of cephalexin in ISF. The MIC90 for S pseudintermedius (2 μg/mL; long dashes) and E coli (16 μg/mL; short dashes) reported in another study31 is provided for comparison with the observed cephalexin concentrations.

Citation: American Journal of Veterinary Research 71, 12; 10.2460/ajvr.71.12.1484

Table 1—

Mean ± SD values for pharmacokinetic parameters of cefpodoxime after oral administration of a mean dose of 9.6 mg of cefpodoxime proxetil/kg in 6 adult dogs.

ParameterISF*Total plasma
Terminal rate constant (/h)0.07 ± 0.020.12 ±0.02
T½ (h)10.38 ± 3.325.75 ± 0.91
Tmax (h)3.27 ± 2.063± 1.10
Cmax (μg/mL)4.33 ±1.9632.96 ± 6.92
AUC(h•μg/mL)57.47 ± 17.45282.84 ± 44.05
MRT (h)17.31 ± 3.42
Tissue penetration factor (%)20 ± 6
VD/F(mL/kg)288.59 ± 65.58
CL/F (mL/kg/h)34.63 ± 4.92
MRT (h)8.77 ± 1.48

A Tlag was calculated for the collection of ISF because of the length of the nonpermeable portion of the tubing of the in vivo ultrafiltration probe. The Tlag value then was used to adjust the reported concentrations and Tmax in ISF.

Values represent the sum of the protein-bound and protein-unbound drug concentration in plasma.

MRT = Mean residence time. VD/F= Apparent volume of distribution per absolute fraction of the dose absorbed after oral administration.

— = Not determined.

Table 2—

Mean ± SD values for pharmacokinetic parameters of cephalexin after oral administration of a mean dose of 25 mg/kg in 6 adult dogs.

ParameterISF*Total plasma
Terminal rate constant (/h)0.23 ± 0.050.15 ± 0.03
T½ (h)3.19 ± 0.634.74 ± 1.15
Tmax (h)2.67 ± 1.562.83 ± 1.72
Cmax (μg/mL)16.34 ± 5.8231.52 ± 11.49
AUC(h•μg/mL)87.79 ± 21.02155.63 ± 29.53
MRT (h)7.51 ± 1.06
Tissue penetration factor (%)58 ± 17
VD/F (mL/kg)1,162.12 ± 431.88
CL/F (mL/kg/h)168.17 ± 29.95
MRT (h)5.50 ± 2.07

See Table 1 for key.

Table 3—

Protein-bound and protein-unbound fractions of cefpodoxime and cephalexin determined in blank canine plasma samples spiked with known concentrations of cefpodoxime or cephalexin.

CefpodoximeCephalexin
Concentration (μg/mL)Protein bound (%)*Protein unbound (%)Protein bound (%)*Protein unbound (%)
183.06 ± 3.5416.9425.94 ± 5.1474.06
591.25 ±0.388.75
1089.33 ± 2.4410.6715.74 ± 6.484.26
1582.41 ± 0.9717.59
2083.60 ± 0.7716.4
3066.17 ± 0.3033.83
Overall mean82.6417.3620.8479.16

Values are reported as the mean ± SD from the results of 3 replicates. Protein-unbound fraction was determined by subtracting the mean protein-bound fraction from 100%.

— = Not determined.

Alter celpodoxime administration, the mean ± SD volume collection rate of ISF was 48.23 ± 22.33 μL/h. After cephalexin administration, mean ± SD volume collection rate of ISF was 74.34 ± 29.28 μL/h. Drug concentration was not affected by the rate of ISF collection.

Plasma protein binding of cefpodoxime ranged between 82% and 91%, except at the highest concentration (30 μg/mL) when binding was 66% (Table 3). Furthermore, this represents a protein-unbound fraction of cefpodoxime ranging between 9% and 34%. Mean overall protein-unbound fraction across the entire range of cefpodoxime plasma concentrations was 17%. Mean ± SD tissue penetration factor for cefpodoxime was 20.5 ± 5.6%. A close agreement between protein-unbound drug concentrations in plasma and protein-unbound cefpodoxime concentrations in ISF was observed; the largest discrepancy was at the highest concentrations, where there appeared to be concentration-dependent protein binding (Figure 1; Table 3).

Plasma protein binding of cephalexin ranged between 25.9% and 15.7% at 1 and 10 μg/mL, respectively (Table 3). Furthermore, this represented a protein-unbound fraction of cephalexin ranging between 74.1% and 84.3% or an overall protein-unbound fraction of 79%. Mean ± SD tissue penetration factor of cephalexin was 58.2 ± 17.0%, which was slightly less than the value predicted by protein binding. Relative bioavailability of cefpodoxime, compared with cephalexin, was 4.73 times as high as that of cephalexin.

The relationship between observed plasma, ISF, and protein-unbound concentrations and the MIC90 of S pseudintermedius and E coli was compared (Figures 1 and 2). Mean protein-unbound concentration of cef podoxime in ISF exceeded the MIC90 (0.5 μg/mL for both bacteria) for approximately 24 hours after drug administration. Mean protein-unbound concentration of cephalexin in ISF exceeded the MIC90 for S pseudintermedius (2 μg/mL) for approximately 12 hours after drug administration, but it did not achieve the MIC90 for E coli (16 μg/mL).

Pharmacokinetic results of the present study were compared with results of other studies8–16 (Table 4). For cephalexin, mean T1/2 and Cmax in the present study were longer and higher, respectively, than those in other studies, even though similar doses were administered. For cefpodoxime, a similar mean T1/2 was reported. However, a higher Cmax, by almost a 2-fold factor, was observed in the present study.

Table 4—

Comparison between values for the pharmacokinetic parameters reported in the present study and those reported in other studies for cefpodoxime proxetil and cephalexin when administered orally at similar doses in dogs.

CephalexinCefpodoxime
ParameterPresent study*Other studies9–16Present study*Other study8
CL/F (mL/kg/min)2.8 ± 0.53.14 ± 0.870.58 ± 0.081.07§
Observations652612
VD/F (L/kg)1.16 ± 0.430.92 ± 0.480.29 ± 0.070.52§
Observations633612
T1/2 (h)4.74 ± 1.152.74 ± 1.605.75 ± 0.915.61 ± 1.15
Observations662612
Cmax (μg/mL)31.52 ± 11.4919.52 ± 6.9032.96 ± 6.9217.85 ± 11.4
Observations656612

Values reported for pharmacokinetic parameters are mean ± SD.

Values for cephalexin were calculated by use of a least squares means procedure to account for differences in the number of observations in each study and reported as the weighted mean ± SD.

Values reported for pharmacokinetic parameters are mean ± SD.

Values for pharmacokinetic parameters were not provided but were estimated from other pharmacokinetic data provided.

See Table 1 for remainder of key.

Discussion

Although other pharmacokinetic studies have been reported on these antimicrobials in dogs, to our knowledge, the study reported here is the first in which ISF concentrations of protein-unbound cephalexin or cefpodoxime were measured in dogs. Because it is the concentration of the protein-unbound antimicrobial in the tissue biophase (site of bacterial infection) that is important for drug action, these data are relevant for predicting antimicrobial activity In addition, the present study revealed that when plasma protein binding is taken into consideration, the measure of protein-unbound cefpodoxime in plasma is predictive of the protein-unbound drug concentration in the extracellular fluid (ISF) in tissues. Similar to another study34 with cephalosporins, we calculated a tissue penetration factor to represent the relationship between unbound drug concentrations in ISF and the total plasma drug concentration. This factor was calculated from the ratio of protein-unbound drug concentration in ISF to the total drug concentration in plasma. The protein-unbound drug concentration in plasma should be in equilibrium with the protein-unbound drug concentration in tissue, which was apparent for cefpodoxime in which these values were approximately 17% and 20%, respectively This is also apparent from a visual examination of the concentrations, in which there is close similarity between ISF drug concentration and the protein-unbound drug concentration in plasma after a single dose of cefpodoxime (Figure 1).

Mean tissue penetration factor of cephalexin was 58%, but the mean protein-unbound drug concentration in plasma was 79%. A plausible explanation for the lower penetration factor, compared with the protein-unbound drug concentration in plasma, is that cephalexin is eliminated faster than is cefpodoxime after administration of a single dose. Because tissue and plasma concentrations were not measured at steady-state concentrations, equilibrium may not have been achieved. A drug that is eliminated more rapidly (shorter T½) will not have as much time to achieve equilibrium between plasma and tissue, compared with a drug with slower elimination or compared with a drug that has achieved a steady-state concentration. This principle was described in a review35 of cephalosporins, in which a clear association was detected between the percentage of tissue penetration and the drug's T1/2.

As reported by investigators in other studies,16,18,23,34 tissue distribution is influenced more by protein binding than by other chemical features of the drug. These results agreed with the results of another study34 of the distribution of cefpodoxime in humans. In that study,34 microdialysis was used to collect protein-free drug in ISF, whereas this study in dogs used ultrafiltration. Both methods are based on the principle of collecting protein-unbound ISF by use of an implanted dialysis probe in the tissue. In the study34 in humans, tissue penetration factors for cefpodoxime and cefixime were related to plasma protein binding, similar to our observations in the study reported here. In addition, that study34 revealed that mean ± SD plasma protein binding and plasma T1/2 for cefpodoxime were 21 ± 4% and 2.6 ± 0.4 hours, respectively. In the study reported here, mean ± SD plasma T1/2 was 5.75 ± 0.91 hours and mean plasma protein binding was 82.64%. This agrees with observations made by investigators of another study35 in that the more highly protein-bound cephalosporins are eliminated more slowly than are the cephalosporins that are less protein bound.

Cephalosporins are time-dependent drugs for which antimicrobial efficacy is based on the duration of time that the drug concentrations of cefpodoxime and cephalexin exceed the MIC.36 A difference was observed in the duration that antimicrobial drug concentrations exceed the MIC90 of S pseudintermedius and E coli. The mean protein-unbound drug concentrations of cefpodoxime in the ISF exceeded the MIC90 of S pseudintermedius and E coli for approximately 24 hours (Figure 1). Conversely, mean cephalexin concentration in ISF exceeded the MIC90 for S pseudintermedius for approximately 12 hours, but it did not achieve concentrations greater than the MIC90 of E coli (Figure 2). Cefpodoxime is approved for use in dogs with a dosing interval of 24 hours, whereas most clinicians in the United States administer cephalexin to dogs every 12 hours. There was equal efficacy for treatment of bacterial pyoderma in 157 dogs when cefpodoxime was administered orally once daily and cephalexin was administered orally twice daily.4

The study reported here revealed the advantages of ISF collection by use of an in vivo ultrafiltration technique. This technique allowed for serial collection of samples of ISF that could be evaluated for drug concentrations and compared with plasma drug concentration. This technique also avoided the problem associated with interpretation of results generated from the measurement of ISF concentrations via processing of homogenized tissues or samples collected from implanted tissue cages. In addition, use of this procedure avoided the need to anesthetize the dogs and collect surgical biopsies to determine drug tissue concentration.

Review of the literature identified pharmacokinetic studies of cefpodoxime5 and cephalexin6–11,e,f in dogs that were used for comparison with the pharmacokinetics of the present study (Table 4). For cephalexin, mean T1/2 and Cmax were longer and higher, respectively, for the study reported here. The F of cephalexin was not reported in those studies6–11,e,f; therefore, the reasons for the discrepancies in T1/2 and Cmax are not known, despite the fact that similar doses were administered. For cefpodoxime, a similar T1/2 and a greater Cmax were observed in the present study, despite administration of a similar dose in the study5 used for comparison. Investigators of that study5 reported an approximate F of 35% after oral administration of cefpodoxime. The AUC of cefpodoxime in the present study was approximately 1.8 times as high. It is possible that F in the present study was much greater.

Three properties that favor the use of cefpodoxime when treating bacterial infections are high protein binding, high antimicrobial activity (low MIC because it is a third-generation cephalosporin), and time-dependent antimicrobial activity. High protein binding contributes to a longer T1/2, which when coupled with lower MIC values, yielded protein-unbound drug concentrations in tissues that were maintained longer than for cephalexin (Figures 1 and 2). Because cephalosporins are time-dependent drugs, the long duration of active drug concentrations allows for once-daily administration. The duration of protein-unbound drug concentrations in tissues of the study reported here appears to agree with that of a clinical study4 in which investigators evaluated the efficacy of both of these antimicrobials.

Abbreviations

AUC

Area under the time-concentration curve

CL/F

Drug clearance per fraction of the dose absorbed

Cmax

Maximum concentration

F

Fraction of the dose absorbed

HPLC

High-pressure liquid chromatography

ISF

Interstitial fluid

MIC90

Concentration required to inhibit the growth of 90% of bacterial isolates

T1/2

Terminal half-life

Tlag

Lag time

Tmax

Time of maximum concentration

a.

Guaguère E, Maynard L, Salomon C, et al. Cephalexin in the treatment of canine pyoderma: comparison of two dose rates (abstr), in Proceedings. Eur Soc Vet Dermatol Cong 1996;82.

b.

Guaguère E, Salomon C, Cadot P. Comparison of two protocols of administration of cephalexin in the treatment of deep pyoderma in dogs (abstr). Vet Dermatol 2000;11(suppl 1):20.

c.

Maynard L, Bousquet E, Medaille C. Clinical efficacy of cefalexin administered by oral route at two dosages in the treatment of superficial pyoderma in dogs (abstr), in Proceedings. 18th Eur Soc Vet Dermatol Cong 2002;198.

d.

Simplicef tablets for dogs, Pfizer Animal Health, New York, NY.

e.

Lavy E, Shem-Tov M, Or-Bach A, et al. Oral availability and bioequivalence studies in dogs of two cephalexin tablets and a cephalexin capsule (abstr). J Vet Pharmacol Ther 1997;20(suppl 1):63–64.

f.

Wackoweiz G, Richard JJ, Fabreguettes G. Pharmacokientics of cefalexin in plasma and urine after single intravenous and oral (tablets) administration in dogs (abstr). J Vet Pharmacol Ther 1997;20(suppl 1):63.

g.

Domitor, Pfizer Animal Health, New York, NY.

h.

In vivo ultrafiltration sampling kit, canine ultrafiltration probe, Bioanalytical Systems Inc, West Lafayette, Ind.

i.

Antisedan, Pfizer Animal Health, New York, NY.

j.

Agilent 1100 Series solvent delivery system, Agilent Technologies, Wilmington, Del.

k.

Agilent 1100 Series autosampler, Agilent Technologies, Wilmington, Del.

l.

Agilent 1100 Series Variable Wavelength Detector, Agilent Technologies, Wilmington, Del.

m.

Agilent 1100 Series Chemstation 2D software, Agilent Technologies, Wilmington, Del.

n.

Zorbax Rx C18 column, Agilent Technologies, Wilmington, Del.

o.

Cephalexin reference standard, Sigma Chemical Co, St Louis, Mo.

p.

Cefpodoxime reference standard (PNU-0076253), Pfizer Corp, Kalamazoo, Mich.

q.

Solid-phase extraction cartridges, Sep-Pak C18, 3 mL, 500-mg cartridges, Waters Corp, Milford, Mass.

r.

CentrifreeMicropartition system, Amicon Millipore, Billerica, Mass.

s.

WinNonlin, version 5.2, Pharsight Corp, Mountain View, Calif.

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Contributor Notes

Dr. Floerchinger was a veterinary student and a Merck-Merial summer scholar at the time of the study.

Supported in part by Pfizer Animal Health, New York, NY.

Dr. Papich has received honoraria for speaking at conferences, payment for consulting, gifts, and research support from Pfizer Animal Health.

Presented in abstract form at the American College of Veterinary Internal Medicine Annual Forum, Seattle, 2007.

The authors thank Delta R. Dise for assistance with the drug analysis and Dr. Marilyn N. Martinez for assistance with the statistical calculation of cephalexin pharmacokinetic data.

Address correspondence to Dr. Papich (mark_papich@ncsu.edu).