Effects of food intake on pharmacokinetics of mosapride in beagle dogs

This study was performed to determine the pharmacokinetic profile of mosapride in fasting and fed states. A single 5‐mg oral dose of mosapride was administered to fasted (n = 15) and fed (n = 12) beagle dogs, and the plasma concentrations of mosapride were measured by liquid chromatography–tandem mass spectrometry. The resultant data were analyzed by noncompartmental analysis (NCA). Mosapride was absorbed in fasted and fed dogs with similar T_max. Both C_max and AUC were significantly higher in the fasting group than in fed dogs, being four times (10.51 μg/mL vs. 2.76 μg/mL) and 3.5 times higher (38.53 h·μg/mL vs. 10.22 h·μg/mL), respectively. These findings suggest that food intake affects the pharmacokinetics of mosapride and that the dosage regimen for this drug need to be reconsidered.     

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.     

Determination of influence of food intake after a single oral dose of mosapride in beagle dogs using nonlinear mixed effect modeling

The objective of this study was to describe the population pharmacokinetics (PK) of mosapride under fasting and fed conditions. A single 5‐mg oral dose of mosapride was administered to fasted (n = 15) and fed (n = 12) beagle dogs. Plasma concentrations of mosapride were subsequently measured by liquid chromatography–tandem mass spectrometry. Data were analyzed using modeling approaches with the NONMEM 7.2 software. A one‐compartment open PK model utilizing model event time (MTIME) with first‐order absorption and first‐order elimination was found to be more appropriate than all other PK models tested. The absorption rate constants of mosapride were significantly decreased under fed conditions, compared to fasting conditions. The observed bootstrap medians of PK parameters were generally consistent with the corresponding population mean estimates. Furthermore, with the exception of some mosapride concentrations, most of observed data fell into the range of the 5th and 95th percentiles of the simulated values. Overall, the final model was able to describe the observed mosapride concentrations reasonably well. These findings suggest that food intake affects both the rate and extent of absorption of mosapride and that the pharmacological effect of mosapride can differ significantly depending on food intake.     

Nonlinear mixed‐effects pharmacokinetic modeling of the novel COX‐2 selective inhibitor vitacoxib in dogs

The objective of this study was to develop a nonlinear mixed‐effects model of vitacoxib disposition kinetics in dogs after intravenous (I.V.), oral (P.O.), and subcutaneous (S.C.) dosing. Data were pooled from four consecutive pharmacokinetic studies in which vitacoxib was administered in various dosing regimens to 14 healthy beagle dogs. Plasma concentration versus time data were fitted simultaneously using the stochastic approximation expectation maximization (SAEM) algorithm for nonlinear mixed‐effects as implemented in Monolix version 2018R2. Correlations between random effects and significance of covariates on population parameter estimates were evaluated using multiple samples from the posterior distribution of the random effects. A two‐compartment mamillary model with first‐order elimination and first‐order absorption after P.O. and S.C. administration, best described the available pharmacokinetic data. Final parameter estimates indicate that vitacoxib has a low‐to‐moderate systemic clearance (0.35 L hr^?1 kg^?1) associated with a low global extraction ratio, but a large volume of distribution (6.43 L/kg). The absolute bioavailability after P.O. and S.C. administration was estimated at 10.5% (fasted) and 54.6%, respectively. Food intake was found to increase vitacoxib oral bioavailability by a fivefold, while bodyweight (BW) had a significant impact on systemic clearance, thereby confirming the need for BW adjustment with vitacoxib dosing in dogs.     

The pharmacokinetics of oclacitinib maleate,a Janus kinase inhibitor,in the dog

The pharmacokinetics of oclacitinib maleate was evaluated in four separate studies. The absolute bioavailability study used a crossover design with 10 dogs. The effect of food on bioavailability was investigated in a crossover study with 18 dogs. The breed effect on pharmacokinetics was assessed in a crossover study in beagles and mongrels dogs. Dose proportionality and multiple dose pharmacokinetics were evaluated in a parallel design study with eight dogs per group. In all four studies, serial blood samples for plasma were collected. Oclacitinib maleate was rapidly and well absorbed following oral administration, with a time to peak plasma concentration of <1 h and an absolute bioavailability of 89%. The prandial state of dogs did not significantly affect the rate or extent of absorption of oclacitinib maleate when dosed orally, as demonstrated by the lack of significant differences in pharmacokinetic parameters between the oral fasted and oral fed treatment groups. The pharmacokinetics of oclacitinib in laboratory populations of beagles and mixed breed dogs also appeared similar. Following oral administration, the exposure of oclacitinib maleate increased dose proportionally from 0.6 to 3.0 mg/kg. Additionally, across the pharmacokinetic studies, there were no apparent differences in oclacitinib pharmacokinetics attributable to sex.     

Pharmacokinetics of oral amantadine in greyhound dogs

This study reports the pharmacokinetics of amantadine in greyhound dogs after oral administration. Five healthy greyhound dogs were used. A single oral dose of 100 mg amantadine hydrochloride (mean dose 2.8 mg/kg as amantadine hydrochloride) was administered to nonfasted subjects. Blood samples were collected at predetermined time points from 0 to 24 h after administration, and plasma concentrations of amantadine were measured by liquid chromatography with triple quadrupole mass spectrometry. Noncompartmental pharmacokinetic analyses were performed. Amantadine was well tolerated in all dogs with no adverse effects observed. The mean (range) amantadine C_MAX was 275 ng/mL (225–351 ng/mL) at 2.6 h (1–4 h) with a terminal half‐life of 4.96 h (4.11–6.59 h). The results of this study can be used to design dosages to assess multidose pharmacokinetics and dosages designed to achieve targeted concentrations in order to assess the clinical effects of amantadine in a variety of conditions including chronic pain. Further studies should also assess the pharmacokinetics of amantadine in other dog breeds or using population pharmacokinetics studies including multiple dog breeds to assess potential breed‐specific differences in the pharmacokinetics of amantadine in dogs.     

Pharmacokinetics of acetaminophen after intravenous and oral administration in fasted and fed Labrador Retriever dogs

Acetaminophen (paracetamol) is used in dogs to manage fever and mild pain. The aim of this study was to assess the pharmacokinetics of acetaminophen in both fed and fasted Labrador Retrievers after a single intravenous and oral administration (20 mg/kg). Six healthy dogs underwent three treatments in a randomized block study (a, n = 2; b, n = 2; c, n = 2). In phase one, group a received acetaminophen intravenously, group b and c orally after being fasted and fed, respectively. In phase two and three, groups were swapped, and the experiment was repeated. At the end of the trial, each dog received the same treatment. Acetaminophen plasma concentrations were detected using a validated HPLC‐UV method. The pharmacokinetic analysis was performed using a noncompartmental model. Clearance, volume at steady state and half‐life of acetaminophen in Labrador Retrievers were 0.42 L/kg hr, 0.87 L/kg and 1.35 hr, respectively. No significant statistical differences were found between fasted and fed dogs regarding maximum plasma concentration, time at maximum concentration and bioavailability as measured by the AUC. Feeding does not significantly affect the acetaminophen oral pharmacokinetics.     

Evaluation of the pharmacokinetics of oral amitriptyline and its active metabolite nortriptyline in fed and fasted Greyhound dogs

This study reports the pharmacokinetics of oral amitriptyline and its active metabolite nortriptyline in Greyhound dogs. Five healthy Greyhound dogs were enrolled in a randomized crossover design. A single oral dose of amitriptyline hydrochloride (actual mean dose 8.1 per kg) was administered to fasted or fed dogs. Blood samples were collected at predetermined times from 0 to 24 h after administration, and plasma drug concentrations were measured by liquid chromatography with mass spectrometry. Noncompartmental pharmacokinetic analyses were performed. Two dogs in the fasted group vomited following amitriptyline administration and were excluded from analysis. The range of amitriptyline C_MAX for the remaining fasted dogs (n = 3) was 22.8–64.5 ng/mL compared to 30.6–127 ng/mL for the fed dogs (n = 5). The range of the amitriptyline AUC_INF for the three fasted dogs was 167–720 h·ng/mL compared to 287–1146 h·ng/mL for fed dogs. The relative bioavailability of amitriptyline in fasted dogs compared to fed dogs was 69–91% (n = 3). The exposure of the active metabolite nortriptyline was correlated to amitriptyline exposure (R² = 0.84). Due to pharmacokinetic variability and the small number of dogs completing this study, further studies are needed assessing the impact of feeding on oral amitriptyline pharmacokinetics. Amitriptyline may be more likely to cause vomiting in fasted dogs.     

Pharmacokinetics of levofloxacin after single intravenous,oral and subcutaneous administration to dogs

The pharmacokinetic properties of the fluoroquinolone levofloxacin (LFX) were investigated in six dogs after single intravenous, oral and subcutaneous administration at a dose of 2.5, 5 and 5 mg/kg, respectively. After intravenous administration, distribution was rapid (T_½dist 0.127 ± 0.055 hr) and wide as reflected by the volume of distribution of 1.20 ± 0.13 L/kg. Drug elimination was relatively slow with a total body clearance of 0.11 ± 0.03 L kg^?1 hr^?1 and a T_½ for this process of 7.85 ± 2.30 hr. After oral and subcutaneous administration, absorption half‐life and T_max were 0.35 and 0.80 hr and 1.82 and 2.82 hr, respectively. The bioavailability was significantly higher (p ? 0.05) after subcutaneous than oral administration (79.90 vs. 60.94%). No statistically significant differences were observed between other pharmacokinetic parameters. Considering the AUC_24 hr/MIC and C_max/MIC ratios obtained, it can be concluded that LFX administered intravenously (2.5 mg/kg), subcutaneously (5 mg/kg) or orally (5 mg/kg) is efficacious against Gram‐negative bacteria with MIC values of 0.1 μg/ml. For Gram‐positive bacteria with MIC values of 0.5 μg/kg, only SC and PO administration at a dosage of 5 mg/kg showed to be efficacious. MIC‐based PK/PD analysis by Monte Carlo simulation indicates that the proposed dose regimens of LFX, 5 and 7.5 mg/kg/24 hr by SC route and 10 mg/kg/24 hr by oral route, in dogs may be adequate to recommend as an empirical therapy against S. aureus strains with MIC ≤ 0.5 μg/ml and E. coli strains with MIC values ≤0.125 μg/ml.     

Clinical pharmacokinetics and outcomes of oral fluconazole therapy in dogs and cats with naturally occurring fungal disease

This multi-institutional study was designed to determine the clinical pharmacokinetics of fluconazole and outcomes in client-owned dogs (n = 37) and cats (n = 35) with fungal disease. Fluconazole serum concentrations were measured. Pharmacokinetic analysis was limited to animals at steady state (≥72 hr of treatment). The mean (range) body weight in 31 dogs was 25.6 (2.8–58.2) kg and in 31 cats was 3.9 (2.4–6.1) kg included in pharmacokinetic analyses. The dose, average steady-state serum concentrations (C_SS), and oral clearance in dogs were 14.2 (4.5–21.3) mg/kg/d, 26.8 (3.8–61.5) µg/mL, and 0.63 ml min⁻¹ kg⁻¹, respectively, and in cats were 18.6 (8.2–40.0) mg/kg/d, 32.1 (1.9–103.5) µg/mL, and 0.61 ml min⁻¹ kg⁻¹, respectively. Random inter-animal pharmacokinetic variability was high in both species. Two dogs had near twofold increases in serum fluconazole when generic formulations were changed, suggesting lack of bioequivalence. Median C_SS for dogs and cats achieving clinical remission was 19.4 and 35.8 µg/ml, respectively. Starting oral doses of 10 mg/kg q12h in dogs and 50–100 mg total daily dose in cats are recommended to achieve median C_SS associated with clinical remission. Due to the large pharmacokinetic variability, individualized dose adjustments based on C_SS (therapeutic drug monitoring) and treatment failure should be considered.     

Pharmacokinetics of intravenous and oral amitriptyline and its active metabolite nortriptyline in Greyhound dogs

ObjectiveTo evaluate the pharmacokinetics of amitriptyline and its active metabolite nortriptyline after intravenous (IV) and oral amitriptyline administration in healthy dogs.Study designProspective randomized experiment.AnimalsFive healthy Greyhound dogs (three males and two females) aged 2–4 years and weighing 32.5–39.7 kg.MethodsAfter jugular vein catheterization, dogs were administered a single oral or IV dose of amitriptyline (4 mg kg⁻¹). Blood samples were collected at predetermined time points from baseline (0 hours) to 32 hours after administration and plasma concentrations of amitriptyline and nortriptyline were measured by liquid chromatography triple quadrupole mass spectrometry. Non-compartmental pharmacokinetic analyses were performed.ResultsOrally administered amitriptyline was well tolerated, but adverse effects were noted after IV administration. The mean maximum plasma concentration (C_MAX) of amitriptyline was 27.4 ng mL⁻¹ at 1 hour and its mean terminal half-life was 4.33 hours following oral amitriptyline. Bioavailability of oral amitriptyline was 6%. The mean C_MAX of nortriptyline was 14.4 ng mL⁻¹ at 2.05 hours and its mean terminal half-life was 6.20 hours following oral amitriptyline.Conclusions and clinical relevanceAmitriptyline at 4 mg kg⁻¹ administered orally produced low amitriptyline and nortriptyline plasma concentrations. This brings into question whether the currently recommended oral dose of amitriptyline (1–4 mg kg⁻¹) is appropriate in dogs.     

The influence of age and body weight gain on enrofloxacin pharmacokinetics in turkeys—Allometric approach to dose optimization

Enrofloxacin is a concentration-dependent antimicrobial used in bacterial infections in poultry. During a few months of a turkey's life, pharmacokinetics of drugs undergoes substantial changes which may compromise their efficacy due to variability in internal exposure (measured by area under the concentration–time curve, AUC). The aim of this study was to describe the effects of age on the pharmacokinetics of a single intravenous (i.v.) and oral administration of enrofloxacin at a dose of 10 mg/kg to turkeys. It was found that during a 2.5-month-long period of growth from 1.4 to 14.6 kg, the AUC after i.v. administration increased almost threefold due to a significant decrease in the body clearance (from a mean of 0.76–0.28 L hr⁻¹ kg⁻¹). Over the same period, the mean elimination half-life was prolonged from 2.65 to 7.03 hr. Oral administration resulted in a similar trend in pharmacokinetic parameters. For both routes, formation of the major metabolite, ciprofloxacin, was marginal. Protein binding was not age-dependent and never exceeded 50%. Body clearance, volume of distribution and elimination half-life were subjected to an allometric analysis and a novel, nonlinear dosage protocol has been proposed to improve the internal exposure to the drug in different age groups of turkeys.     

The pharmacokinetics of maropitant citrate dosed orally to dogs at 2 mg/kg and 8 mg/kg once daily for 14 days consecutive days

The pharmacokinetics of maropitant were evaluated in beagle dogs dosed orally with Cerenia^® tablets (Pfizer Animal Health) once daily for 14 consecutive days at either 2 mg/kg or 8 mg/kg bodyweight. Noncompartmental pharmacokinetic analysis was performed on the plasma concentration data to measure the AUC_0–24 (after first and last doses), C_t (trough concentration—measured 24 h after each dose), C_max (after first and last doses), t_max (after first and last doses), λ_z (terminal disposition rate constant; after last dose), t_1/2 (after last dose), and CL/F (oral clearance; after last dose). Maropitant accumulation in plasma was substantially greater after fourteen daily 8 mg/kg doses than after fourteen daily 2 mg/kg doses as reflected in the AUC_0–24 accumulation ratio of 4.81 at 8 mg/kg and 2.46 at 2 mg/kg. This is most likely due to previously identified nonlinear pharmacokinetics of maropitant in which high doses (8 mg/kg) saturate the metabolic clearance mechanisms and delay drug elimination. To determine the time to reach steady‐state maropitant plasma levels, a nonlinear model was fit to the least squares (LS) means maropitant C_t values for each treatment group. Based on this model, 90% of steady‐state was determined to occur at approximately four doses for daily 2 mg/kg oral dosing and eight doses for daily 8 mg/kg oral dosing.     

The pharmacokinetics of vedaprofen and its enantiomers in dogs after single and multiple dosing

Vedaprofen is a chiral nonsteroidal anti-inflammatory drug that has been developed as a gel formulation for oral administration to dogs and horses. The pharmacokinetics of vedaprofen and its enantiomers were studied in beagle dogs after single (intravenous solution and oral gel) and multiple (oral gel) dosing at a dosage of 0.5 mg/kg body weight. Plasma concentrations of vedaprofen and its enantiomers were analysed by HPLC. The plasma protein binding of vedaprofen was studied by ultrafiltration. The absorption of vedaprofen was rapid (tmax 0.63 +/- 0.14 h) and almost complete after oral administration (bioavailability 86 +/- 7%). The terminal half-lives after intravenous and oral administration, 16.8 +/- 2.2 and 12.7 +/- 1.7 h respectively, were of the same order of magnitude. Enantioselective analysis showed that the R(-) enantiomer predominated in plasma. The change in the plasma time course of the plasma R(-)/S(+) enantiomer concentration ratio over time was similar after single intravenous and oral dosing, with R(-)/S(+) ratios in the AUC of 1.7 +/- 0.5 and 1.9 +/- 0.2 respectively. Plasma protein binding of vedaprofen and its enantiomers was high (> 99.5%). Vedaprofen is absorbed rapidly from the gastrointestinal tract, has a high bioavailability and does not accumulate in plasma in dogs following repeated oral administration.     

Pharmacokinetics of low-dose methotrexate in horses

This study aimed to investigate both the pharmacokinetic behavior and tolerance of methotrexate (MTX) in horses to design a specific dosing regimen as a new immunomodulatory drug for long-term treatment. To determine the primary plasma pharmacokinetic variables after single intravenous, subcutaneous or oral administration, six horses were administered 0.3 mg/kg MTX in a crossover design study. After a 10-week washout, MTX was administered subcutaneously to three of the six previously treated horses at a dose of 0.3 mg/kg once per week for 3 months. In both studies, MTX and metabolite concentrations were measured using LC-MS/MS. The absolute bioavailability of MTX was 73% following subcutaneous administration but less than 1% following oral administration. The plasma clearance was 1.54 ml min⁻¹ kg⁻¹ (extraction ratio = 2%). After 24 hr, plasma concentrations were below the LOQ. No adverse effects were noted except for a moderate reversible elevation in liver enzymes (GLDH). With regards to the main metabolites of MTX, very low concentrations of 7-hydroxy-MTX were found, whereas polyglutamated forms (mainly short chains) were found in red blood cells. A subcutaneous dose of 0.2 mg kg⁻¹ week⁻¹ may be safe and relevant in horses, although this has yet to be clinically confirmed.     

Pharmacokinetics and bioavailability of dapsone in the beagle dog

The plasma concentration of dapsone (4,4′-diaminodiphenyl-sulphone) was measured after intravenous and oral administration (±5 mg/kg) to female beagle dogs. Analysis of the plasma concentrations showed a bioavailability of the tablet of 99 per cent. The biological half-life in plasma was estimated to be 13±4 hours after intravenous and 11±5 hours after oral application. In order to test the pharmacokinetic models for their validity a chronic experiment was performed with one dog. The plasma curve, predicted from the oral single-dose data, closely matched the measured experimental data points, which indicates that the applied models are likely to be correct.     

Multiple oral dosing of ketoconazole influences pharmacokinetics of quinidine after intravenous and oral administration in beagle dogs

In this study, we investigated the effect of multiple oral dosing of ketoconazole (KTZ) on pharmacokinetics of quinidine (QN), a CYP3A substrate with low hepatic clearance, after i.v. and oral administration in beagle dogs. Four dogs were given p.o. KTZ for 20 days (200 mg, b.i.d.). QN was administered either i.v. (1 mg/kg) or p.o. (100 mg) 10 and 20 days before the KTZ treatment and 10 and 20 days after start of KTZ treatment. Multiple oral dosing of KTZ decreased significantly alpha and beta, whereas increased t(1/2beta), V(1), and k(a). The KTZ treatment also decreased significantly both total body clearance (Cl(tot)) and oral clearance (Cl(oral)). No significant change in bioavailability was observed in the presence of KTZ. Co-administration of KTZ increased C(max) of QN to about 1.5-fold. Mean resident time after i.v. administration (MRT(i.v.)), and after oral administration (MRT(p.o.)) of QN were prolonged to about twofold, whereas mean absorption time (MAT) was decreased to 50%. Volume of distribution at steady state (V(d(ss))) of QN was unchanged in the presence of KTZ. These alterations may be because of a decrease in metabolism of QN by inhibition of KTZ on hepatic CYP3A activity. In conclusion, multiple oral dosing of KTZ affected largely pharmacokinetics of QN after i.v. and oral administration in beagle dogs. Therefore, KTZ at a clinical dosing regimen may markedly change the pharmacokinetics of drugs primarily metabolized by CYP3A with low hepatic clearance in dogs. In clinical use, much attention should be paid to concomitant administration of KTZ with the drug when given either p.o. or i.v.     

Pharmacokinetics of an intravenous and oral dose of enrofloxacin in white rhinoceros (Ceratotherium simum)

South Africa currently loses over 1000 white rhinoceros (Ceratotherium simum) each year to poaching incidents, and numbers of severely injured victims found alive have increased dramatically. However, little is known about the antimicrobial treatment of wounds in rhinoceros. This study explores the applicability of enrofloxacin for rhinoceros through the use of pharmacokinetic‐pharmacodynamic modelling. The pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin were evaluated in five white rhinoceros after intravenous (i.v.) and after successive i.v. and oral administration of 12.5 mg/kg enrofloxacin. After i.v. administration, the half‐life, area under the curve (AUC_tot), clearance and the volume of distribution were 12.41 ± 2.62 hr, 64.5 ± 14.44 μg ml^?1 hr^?1, 0.19 ± 0.04 L h^?1 kg^?1, and 2.09 ± 0.48 L/kg, respectively. Ciprofloxacin reached 26.42 ± 0.05% of the enrofloxacin plasma concentration. After combined i.v. and oral enrofloxacin administration oral bioavailability was 33.30 ± 38.33%. After i.v. enrofloxacin administration, the efficacy marker AUC₂₄: MIC exceeded the recommended ratio of 125 against bacteria with an MIC of 0.5 μg/mL. Subsequent intravenous and oral enrofloxacin administration resulted in a low Cmax: MIC ratio of 3.1. The results suggest that intravenous administration of injectable enrofloxacin could be a useful drug with bactericidal properties in rhinoceros. However, the maintenance of the drug plasma concentration at a bactericidal level through additional per os administration of 10% oral solution of enrofloxacin indicated for the use in chickens, turkeys and rabbits does not seem feasible.     

Metoclopramide modifies oral cephalexin pharmacokinetics in dogs

The purpose of this study was to investigate whether previous administration of metoclopramide affects cephalexin pharmacokinetics after its oral administration in dogs as well as whether these changes impair its predicted clinical efficacy. Six healthy beagle dogs were included in this study. Oral 25 mg/kg cephalexin monohydrate and intravenous 0.5 mg/kg metoclopramide HCl single doses were administered. Each dog received cephalexin or cephalexin following metoclopramide, with a 2-week washout period. Plasma concentrations of cephalexin were determined by microbiological assay. Cephalexin peak plasma concentration and area under the curve from 0 to infinity significantly increased from 18.77+/-2.8 microg/mL and 82.65+/-10.4 microg.h/mL to 21.88+/-0.8 microg/mL and 113.10+/-20.9 microg.h/mL, respectively, after pretreatment with metoclopramide. No differences between treatments were found for other pharmacokinetic parameters. Pharmacokinetic/pharmacodynamic indices calculated for highly susceptible staphylococci were similar for both experiences. Metoclopramide pretreatment may have increased cephalexin absorption by affecting its delivery to the intestine, and/or enhancing intestinal transporter PEPT1 function. Neither difference in the efficacy of cephalexin nor an increase in toxicity is expected as a result of this modification. Consequently, no dose adjustment is required in cephalexin-treated patients pretreated with metoclopramide.     

Pharmacokinetics of deflazacort in rabbits after intravenous and oral administration and its interaction with erythromycin

The pharmacokinetic of deflazacort after intravenous and oral administration and the effect of erythromycin on the disposition of deflazacort in rabbits were investigated. A parallel study was carried out in twelve rabbits. The plasma concentration–time profiles of deflazacort were determined after intravenous and oral administration of single dosages of 5 mg/kg in the presence and absence (baseline) of multiple dose erythromycin regimens. Plasma concentrations of 21‐desacetyldeflazacort were determined by HPLC. Plasma concentration–time curves were analysed by compartmental pharmacokinetic and noncompartmental methods. The t_½λz values following intravenous and oral administration were 3.67 and 4.96 hr, respectively. The apparent volume of distribution at steady‐state (V_ss) was 4.08 ± 0.31 L/kg, this value indicates that deflazacort is widely distributed into the extravascular tissues. Moreover, bioavailability after oral administration of deflazacort (F = 87.48%) was high. Pharmacokinetic analysis after both routes of administration revealed a significant reduction in total body clearance, a significant increase in mean residence time, half‐life and plasma concentrations of the steroid in the presence of multiple dose erythromycin. The results indicated the influence of the erythromycin on deflazacort disposition, which is consistent with a pharmacokinetic‐type interaction in the elimination of the drug from the body. Moreover, this interaction should be considered to avoid adverse effects when using both drugs concomitantly.