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.     

Pharmacokinetic analysis of mosapride following intravenous and oral administration in beagle dogs

The aim of this study was to investigate the pharmacokinetic properties of mosapride after intravenous and oral administration to beagle dogs. To obtain the advanced pharmacokinetic parameters of mosapride, both noncompartmental analysis and pharmacokinetic modeling were performed. Twenty beagle dogs were randomly sorted into intravenous (1 mg single administration of mosapride) and oral (5 mg once a day administration of mosapride) groups. Blood samples were collected according to the reported schedule for pharmacokinetics. The plasma concentration of mosapride was analyzed using liquid chromatography–tandem mass spectrometry. According to the pharmacokinetic analysis, the absorption rate of mosapride was 3.14 ± 1.14 hr⁻¹ and oral bioavailability of mosapride was approximately 1%. The one-compartment model well described the pharmacokinetics of mosapride after both intravenous and oral administration to dogs. These findings will help facilitate the determination of the optimal dose regimen of mosapride for dogs with gastrointestinal disorder.     

Effects of food intake and food withholding on plasma ghrelin concentrations in healthy dogs

OBJECTIVE: To investigate the physiologic endocrine effects of food intake and food withholding via measurement of the circulating concentrations of acylated ghrelin, growth hormone (GH), insulin-like growth factor-I (IGF-I), glucose, and insulin when food was administered at the usual time, after 1 day's withholding, after 3 days' withholding and after refeeding the next day in healthy Beagles. ANIMALS: 9 healthy Beagles. PROCEDURES: Blood samples were collected from 8:30 AM to 5 PM from Beagles when food was administered as usual at 10 AM, after 1 day's withholding, after 3 days' withholding, and after refeeding at 10 AM the next day. RESULTS: Overall mean plasma ghrelin concentrations were significantly lower when food was administered than after food withholding. Overall mean plasma GH and IGF-I concentrations did not differ significantly among the 4 periods. Circulating overall mean glucose and insulin concentrations were significantly higher after refeeding, compared with the 3 other periods. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs, food withholding and food intake were associated with higher and lower circulating ghrelin concentrations, respectively, suggesting that, in dogs, ghrelin participates in the control of feeding behavior and energy homeostasis. Changes in plasma ghrelin concentrations were not associated with similar changes in plasma GH concentrations, whereas insulin and glucose concentrations appeared to change reciprocally with the ghrelin concentrations.     

Effects of orchidectomy on bone metabolism in beagle dogs

The effects of orchidectomy on bone metabolism in male beagle dogs were examined using twelve 2-year-old dogs that were orchidectomized. The dogs' bilateral iliac bones, double-labeled with tetracycline and calcein for the histomorphometry, were obtained from three dogs prior to orchidectomy and at 3, 6, 9, and 12 months afterwards. The serum biochemical constituents related to bone metabolism were examined before and every month after orchidectomy. Between 1 and 6 months after orchidectomy, the value of serum testosterone decreased (1 month), while the levels of parathyroid hormone, calcitonin, total calcium, osteocalcin, and alkaline phosphatase activity increased significantly, indicating a high bone turnover. The mean trabecular thickness and the fraction of labeled osteoid surface decreased significantly 3 months after orchidectomy, but other histomorphometric parameters were unchanged. In the period 7-12 months after orchidectomy, the parathyroid hormone level increased ever and above that of the first 6-month period, while the levels of calcitonin, osteocalcin, alkaline phosphatase activity, and phosphorus decreased. The bone volume, mean trabecular thickness, and the fraction of labeled trabecular surface decreased significantly compared with the pre-orchidectomy values. These findings indicate an imbalance in bone metabolism (i.e. bone resorption > bone formation). These results indicate that a loss of bone volume accompanied the fall in sex hormone levels following orchidectomy and suggest that the orchidectomized dog is available as an animal model for studying osteoporosis caused by hypogonadism and the decline of sex functions in men.     

Influence of food intake on the absorption of lysine-acetylsalicylate in dogs

The influence of food intake on the absorption of a water-soluble aspirin, lysine-acetylsalicylate, was examined in six healthy adult mongrel dogs. Single-dose kinetics were determined following ingestion of 90 mg/kg of lysine-acetylsalicylate in dogs either fasted for 12 h or following a standard meal of either dry food or the same meal containing 20% of olive oil. Concurrent intake of food both reduced the serum salicylate concentration for 3 h after administration, and reduced the total amount of drug absorbed as reflected by the area under the plasma concentration/time curve(AUC). The effects were more pronounced following the fatty meal. Data from this investigation suggest that lysine-acetylsalicylate is therapeutically effective, without side effects when taken at the rate of 80 mg/kg at 12 h intervals, during or after feeding rather than before feeding.     

Effect of food on the pharmacokinetics of oral cefuroxime axetil in dogs

Cefuroxime axetil pharmacokinetic profile was investigated in 12 Beagle dogs after single intravenous and oral administration of tablets or suspension at a dose of 20 mg/kg, under both fasting and fed conditions. A three-period, three-treatment crossover study (IV, PO under fasting and fed condition) was applied. Blood samples were withdrawn at predetermined times over a 12-hr period. Cefuroxime plasma concentrations were determined by HPLC. Data were analyzed by compartmental analysis. No statistically significant differences were observed between formulations and feeding conditions on PK parameters. Independently of the feeding condition, absorption of cefuroxime axetil after tablet administration was low and erratic. The drug has been quantified in plasma in 3 out of 6 and 5 out of 6 dogs in the fasted and fed groups. For this formulation, the bioavailability (F), peak plasma concentration (C_max), and area under the concentration–time curve (AUC) of cefuroxime axetil were significantly enhanced (p < .05) by the concomitant ingestion of food (32.97 ± 13.47–14.08 ± 7.79%, 6.30 ± 2.62–2.74 ± 0.66 µg/ml, and 15.75 ± 3.98–7.82 ± 2.76 µg.hr/ml for F, C_max, and AUC in fed and fasted dogs, respectively), while for cefuroxime axetil suspension, feeding conditions affected only the rate of absorption, as reflected by the significantly shorter absorption half-life (T_½(a)) and time to peak concentration (T_max) (0.55 ± 0.27–1.15 ± 0.19 hr and 1.21 ± 0.22–1.70 ± 0.30 for T_½(a) and T_max in fed and fasted dogs, respectively). For cefuroxime axetil tablets, T > MIC (≤1 µg/ml) was <2 hr in fasted and ≈4 hr in fed animals, and for cefuroxime axetil suspension, T > MIC (≤1 µg/ml) was ≈5 hr and for T >MIC (≤4 µg/ml) was ≈2.5 hr for fasted and fed dogs, respectively. Cefuroxime axetil as a suspension formulation seems to be a better option than tablets. However, its short permanence in plasma could reduce its clinical usefulness in dogs.     

Effects of calcium supplementation and sunlight exposure on growing beagle dogs

Nine 7-week-old Beagle dogs were given 2.3 g of dietary calcium supplementation once a day and were exposed to sunlight to permit endogenous vitamin D formation. After 70 days, the serum calcium and phosphorus concentrations, thyroid morphometry, and bone density and composition were compared with those values in a similar group of 10 dogs not given calcium supplementation and maintained in restricted, artificial light. Lower serum calcium and phosphorus concentrations in the supplement-fed dogs may be attributed to hypercalcitonism, which was assumed to be present because of increased proportions of C cells and decreased proportions of thyroid follicles. They also had significantly more trabecular bone of a lower specific gravity containing more water and less combustible matter. The findings indicate that the high dietary calcium intake and sunlight exposure induced C-cell hyperplasia during a relatively short period of 70 days. It is possible that Beagles maintained through maturity on a diet high in calcium concentration and in outdoor runs may develop chronic C-cell hyperplasia. The possible contribution of high calcium intake and chronic C-cell hyperplasia to reduced thyroid function and skeletal changes is not yet clear.     

The comparative plasma pharmacokinetics of intravenous cefpodoxime sodium and oral cefpodoxime proxetil in beagle dogs

The pharmacokinetic properties of cefpodoxime, and its prodrug, cefpodoxime proxetil, were evaluated in two separate studies, one following intravenous (i.v.) administration of cefpodoxime sodium and the second after oral (p.o.) administration of cefpodoxime proxetil to healthy dogs. After cefpodoxime administration, serial blood samples were collected and plasma concentrations were determined by high performance liquid chromatography (HPLC). A single i.v. administration of cefpodoxime sodium at a dose of 10 mg cefpodoxime/kg body weight resulted in a cefpodoxime average maximum plasma concentration (Cmax) of 91 (+/-17.7) microg/mL, measured at 0.5 h after drug administration, an average half-life (t1/2) of 4.67 (+/-0.680) h, an average AUC(0-infinity) of 454 (+/-83.1) h.microg/mL, an average V(d(ss)) of 151 (+/-27) mL/kg, an average Cl(B) of 22.7 (+/-4.2) mL/h/kg and an average MRT(0-infinity) of 5.97 (+/-0.573) h. When dose normalized to 10 mg cefpodoxime/kg body weight, cefpodoxime proxetil administered orally resulted in Cmax of 17.8 +/- 11.4 microg/mL for the tablet formulation and 20.1 +/- 6.20 microg/mL for the suspension formulation and an average AUC(0-LOQ) of 156 (+/-76.1) h.microg/mL for the tablet formulation and 162 (+/-48.6) h.microg/mL for the suspension formulation. Relative bioavailability of the two oral formulations was 1.04 (suspension compared with tablet), whereas the absolute bioavailability of both oral formulations was estimated to be approximately 35-36% in the cross-study comparison with the i.v. pharmacokinetics. Combined with previous studies, these results suggest that a single daily oral dose of 5-10 mg cefpodoxime/kg body weight as cefpodoxime proxetil maintains plasma concentrations effective for treatment of specified skin infections in dogs.     

Effects of diet on pharmacokinetics of phenobarbital in healthy dogs

OBJECTIVE: To determine effects of various diets on the pharmacokinetics of phenobarbital and the interactive effects of changes in body composition and metabolic rate. DESIGN: Prospective study. ANIMALS: 27 healthy sexually intact adult female Beagles. PROCEDURE: Pharmacokinetic studies of phenobarbital were performed before and 2 months after dogs were fed 1 of 3 diets (group 1, maintenance diet; group 2, protein-restricted diet; group 3, fat- and protein-restricted diet) and treated with phenobarbital (approx 3 mg/kg [1.4 mg/lb] of body weight, p.o., q 12 h). Pharmacokinetic studies involved administering phenobarbital (15 mg/kg [6.8 mg/lb], i.v.) and collecting blood samples at specific intervals for 240 hours. Effects of diet and time were determined by repeated-measures ANOVA. RESULTS: Volume of distribution, mean residence time, and half-life (t1/2) of phenobarbital significantly decreased, whereas clearance rate and elimination rate significantly increased with time in all groups. Dietary protein or fat restriction induced significantly greater changes: t1/2 (hours) was lower in groups 2 (mean +/- SD; 25.9 +/- 6.10 hours) and 3 (24.0 +/- 4.70) than in group 1 (32.9 +/- 5.20). Phenobarbital clearance rate (ml/kg/min) was significantly higher in group 3 (0.22 +/- 0.05 ml/kg/min) than in groups 1 (0.17 +/- 0.03) or 2 (0.18 +/- 0.03). Induction of serum alkaline phosphatase activity (U/L) was greater in groups 2 (192.4 +/- 47.5 U/L) and 3 (202.0 +/- 98.2) than in group 1 (125.0 +/- 47.5). CONCLUSIONS AND CLINICAL RELEVANCE: Clinically important differences between diet groups were observed regarding pharmacokinetics of phenobarbital, changes in CBC and serum biochemical variables, and body composition. Drug dosage must be reevaluated if a dog's diet, body weight, or body composition changes during treatment. Changes in blood variables that may indicate liver toxicosis caused by phenobarbital may be amplified by diet-drug interactions.     

Pharmacokinetics of tildipirosin in beagle dogs

The objective of this study was to investigate the pharmacokinetic profile of tildipirosin (TD) in 24 beagle dogs following intravenous (i.v.) and intramuscular (i.m.) administration, respectively, at 2, 4, and 6 mg/kg. Plasma samples at certain time points (0–14 days) were collected, and the concentrations of drug were quantified by UPLC‐MS/MS. Plasma concentration–time data and relevant parameters were described by noncompartmental through WinNonlin 6.4 software. After single i.m. injection at 2, 4, and 6 mg/kg body weight, mean maximum concentration (C_max) was 412.73 ± 76.01, 1,051 ± 323, and 1,061 ± 352 ng/ml, respectively. Mean time to reach C_max was 0.36 ± 0.2, 0.08 ± 0.00, and 0.13 ± 0.07 hr after i.m. injection at 2, 4, and 6 mg/kg, respectively. The mean value of T_1/2λz for i.m. administration at doses of 2, 4, and 6 mg/kg was 71.39 ± 28.42, 91 .33 ± 50.02, and 96.43 ± 45.02 hr, respectively. The mean residence times were 63.81 ± 10.96, 35.83 ± 15.13, and 38.18 ± 16.77 hr for doses of 2, 4, and 6 mg/kg, respectively. These pharmacokinetic characteristics after i.m. administration indicated that TD could be rapidly distributed into tissues on account of the high lipid solubility and then released into plasma. In addition, the absolute bioavailability of 2 mg/kg after i.m. injection was 112%. No adverse effects were observed after i.v. and i.m. administration.     

Influence of restricted food intake on estrous cycles and pseudopregnancies in dogs.

OBJECTIVE: To examine effects of restricted food intake on estrous cycle frequency, interestrus interval, and pseudopregnancy prevalence in dogs. ANIMALS: 28 female Labrador Retrievers. PROCEDURE: Dogs were paired by body weight when they were 6 weeks old and fed so that the limit-fed pair-mate received 75% of the amount of food offered to its maintenance-fed counterpart. Estrous cycle, interestrus interval, and pseudopregnancy data were recorded. RESULTS: Mean annual frequency of estrous cycles and duration of interestrus intervals did not differ between feeding groups. Prevalence of clinically evident pseudopregnancy was significantly greater among females that were maintenance fed, although results of endocrinologic testing did not identify a mechanism for this observation. CONCLUSIONS AND CLINICAL RELEVANCE: Pseudopregnancy in dogs can be influenced by physiologic factors related to nutrition. Clinicians should consider a variety of physiologic and environmental factors when evaluating reproductive function in dogs.     

Effects of long-term oral administration of ketoprofen in clinically healthy beagle dogs

To investigate the adverse effects of long-term administration of ketoprofen in dogs, ketoprofen (1 mg/kg) was administered to five clinically healthy beagle dogs (ketoprofen group) and gelatin capsules (control group) were administered to four clinically healthy beagle dogs for 30 days. We monitored the dogs through periodic physical examination, blood analyses, endoscopic examinations, fecal occult blood tests, renal function tests, urinalysis, urinary enzyme indices and cuticle bleeding time analysis. The lesions in the stomach, especially in the pyloric antrum, and fecal occult blood progressively worsened in the ketoprofen group. However, the differences between the ketoprofen group and the control group were not statistically significant. One dog in the ketoprofen group temporarily exhibited a decrease in renal plasma flow and two dogs exhibited enzymuria. However, these changes did not persist and the other examinations showed no significant difference between premedication and postmedication in the ketoprofen group. Therefore, the adverse effects of long-term administration of ketoprofen observed in this study were not clinically important in healthy dogs. Nevertheless, further investigation of adverse renal effects from long-term administration of ketoprofen is necessary in the dogs with subclinical renal disease.     

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.     

Effects of dietary protein conditioning on gentamicin pharmacokinetics in dogs*

Eighteen, six-month-old male Beagles with normal renal function were randomly divided into three groups of 6. Each group was fed a diet that was similar except for protein content (high = 26%, medium = 13% and low = 9%, all on an as fed basis) throughout the experimental period. After a 21 day dietary protein conditioning period (including a terminal 2 day testing period), gentamicin was administered at a dosage of 10 mg/kg q. 8 h for 8 days. The first dose on days 1 and 7 was administered i.v. and all others were given i.m. Pharmacokinetic parameters were determined using blood samples collected over an 8 h period following the i.v. dose on day 1. The elimination rate constant was calculated on days 1 and 7. The data best fit a two-compartment open model for all dogs on day 1. The volume of distribution was higher and the clearance greater in the high protein group compared to the other two groups. No difference was found in the rate of elimination between days 1 and 7 for the high protein group: however, in the medium and low protein groups the rate of elimination decreased over the 7 days of treatment. Therefore, high dietary protein prior to and during gentamicin administration induced faster gentamicin clearance and a larger volume of distribution and preserved the ability to eliminate gentamicin in dogs with normal renal function.     

Effects of selection on food intake in the adult mouse

SUMMARY: Replicated lines of mice were selected High and Low for adjusted food intake and contemporaneous control lines were maintained. The selection criterion was food intake between 8 and 10 weeks, adjusted by phenotypic regression on mean body weight at 8 and 10 weeks of age to reduce correlated changes in body weight. Responses are given for the first 23 generations of selection, after which adjusted food intake had diverged by a factor of 1.7-1.95. A small correlated response in body weight occurred and mice from the High line were slightly heavier: at 10 weeks of age body weight had diverged by a factor of 1.09-1.11. The realized within-family heritability varied between the replicates from 0.16-0.27 from which a mean estimated mass selection heritability (h(2) = 0.35±0.05) was derived. Mice from the Low line were fatter, however not significantly, because of a High between replicate variance (p > 0.05). Differences in growth over the selection period may account for around 5% of the divergence and increased maintenance costs associated with the larger lean mass of the high lines may explain a further 5%. Mice from the High lines spilled significantly (p < 0.05) more food which accounted for 23% of the divergence in apparent food intake. The heat increment of feeding, brown adipose tissue activity and locomotor activity all appear to be unchanged. ZUSAMMENFASSUNG: Auswirkungen der Selektion auf Futteraufnahme in der adulten Maus In einem Experiment mit Wiederholungen wurden M?uselinien auf hohe und niedrige korrigierte Futteraufnahme selektiert und korrespondierende Konttrollen gehalten. Das Selektionskriterium war die Futteraufnahme im Alter von 8 bis 10 Wochen, die mittels ph?notypischer Regression korrigiert wurde, um die K?rpermasse m?glichst konstant zu halten. Der direkte Selektionserfolg über die ersten 23 Generationen ist beschrieben. Die Linien divergierten zu diesem Zeitpunkt bezüglich des Selektionsmerkmals um 70 bis 95%. In der K?rpermasse trat ein geringfügiger korrelierter Selektionserfolg auf. Die Tiere der 'high'-Linie waren im Alter von 8 bis Wochen ca. um 6 bis 11% schwerer. Die realisierte Intra-Familien-Heritabilit?t variierte zwischen den Wiederholungen zwischen 0.16 und 0.27, woraus sich eine mittlerer Heritabilit?tskoeffizient von h(2) = 0.35±0.05 für die Massenselektion ergab. M?use der 'low'-Linie hatten mit 10 Wochen 2.4% (P > 0.05) und mit 17 Wochen ca. 7% (P < 0.05%) mehr Fett. Mit Unterschieden im Wachstum lassen sich weniger als 5% der Linienunterschiede in der Futteraufnahme erkl?ren. Der h?here Erhaltungsbedarf, der aus einer h?heren fett-freien K?rpermasse in der 'high'-Linie resultiert, k?nnte weitere 5% erkl?ren. Tiere der 'high'-Linie verstreuten deutlich (P < 0.05) mehr Futter, worauf sich 23% der Divergenz in der scheinbaren Futteraufnahme zurückführen lie?en. Die Aktiv?t des braunen Fettgewebes, die lokomotorische Aktivit?t und die fütterungsbedingte Wàrmeproduktion sind scheinbar unver?ndert.     

Effects of urine pH modification on pharmacokinetics of phenobarbital in healthy dogs

Although pH modification is one of the effective strategies for dissolving or preventing uroliths, little is known about its effects on the pharmacokinetics of phenobarbital in dogs. Five spayed, female Beagles were fed with a twice‐daily diet that included potassium citrate and ammonium chloride for urine alkalinization and acidification, respectively. After a stabilizing period of 7 days, a single clinical dose of phenobarbital (3 mg/kg) was orally administered, and time‐course changes in its serum and urine concentrations were determined by high‐performance liquid chromatography. Total amounts of unchanged phenobarbital excreted into urine for 216 h were decreased by urine acidification and increased by urine alkalinization. The elimination half‐life of serum phenobarbital in dogs with urine alkalinization was shortened and Cl_R increased when compared with dogs with urine acidification. Other pharmacokinetic parameters, including C_max, T_max, AUC_0–216, Cl/F, and A_e0–216 were not changed by modification of the urine pH. These results suggest that the pH of urine is likely to be a determinant of the pharmacokinetics, especially urine excretion rate, of a clinical dose of oral phenobarbital. It is possible that the serum concentration of phenobarbital might be altered when a pH modifying‐diet is administered for the purpose of dissolving or preventing uroliths.