Pharmacokinetic modeling and Monte Carlo simulation of ondansetron following oral administration in dogs.

Ondansetron is a potent antiemetic drug that has been commonly used to treat acute and chemotherapy-induced nausea and vomiting (CINV) in dogs. The aim of this study was to perform a pharmacokinetic analysis of ondansetron in dogs following oral administration of a single dose. A single 8-mg oral dose of ondansetron (Zofran(®) ) was administered to beagles (n = 18), and the plasma concentrations of ondansetron were measured by liquid chromatography-tandem mass spectrometry. The data were analyzed by modeling approaches using ADAPT5, and model discrimination was determined by the likelihood-ratio test. The peak plasma concentration (Cmax ) was 11.5 ± 10.0 ng/mL at 1.1 ± 0.8 h. The area under the plasma concentration vs. time curve from time zero to the last measurable concentration was 15.9 ± 14.7 ng·h/mL, and the half-life calculated from the terminal phase was 1.3 ± 0.7 h. The interindividual variability of the pharmacokinetic parameters was high (coefficient of variation > 44.1%), and the one-compartment model described the pharmacokinetics of ondansetron well. The estimated plasma concentration range of the usual empirical dose from the Monte Carlo simulation was 0.1-13.2 ng/mL. These findings will facilitate determination of the optimal dose regimen for dogs with CINV.

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 Tmax . Both Cmax 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.

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.

Modelling the atypical absorption of menatetrenone and the metabolism to its epoxide: effect of VKORC1 polymorphism.

WHAT IS KNOWN AND OBJECTIVE: This study aimed to model the atypical absorption of menatetrenone and its epoxide metabolite and to examine the influence of the single nucleotide polymorphism (SNP) of vitamin K2 epoxide reductase complex subunit 1 (VKORC1) on the pharmacokinetics. METHODS: After the administration of 30 mg of menatetrenone to 26 healthy subjects, the plasma concentrations of menatetrenone and its epoxide were measured using LC-MS/MS. For the haplotype analysis, the SNP of the VKORC1 gene was investigated in the 26 volunteers. The model parameters were estimated using the ADAPT II program. RESULTS AND DISCUSSION: A two-compartment model with Weibull-type absorption and saturable elimination described the pharmacokinetics of menatetrenone and its epoxide. The plasma concentrations of both tended to be lower in the H1/H7 genotype group than in the wild-type H1/H1 group. WHAT IS NEW AND CONCLUSION: We present the first detailed pharmacokinetic modelling of menatetrenone in relation to VKORC1 genotype. This study suggests that VKORC1 genotype is unlikely to be helpful in dose-selection because of the very high inter-individual variation in systemic exposure within each genotype group, and the small inter-group difference observed.

Favorable outcomes among recipients of living-donor nephrectomy using video-assisted minilaparotomy.

BACKGROUND: Minimally invasive, living-donor nephrectomy (LDN) is an attractive procedure for the donor in kidney transplantation (KTx). Its advantages include better cosmesis, shorter hospital stay, and rapid recovery. The most commonly performed, minimally invasive nephrectomy is done laparoscopically. However, the technical challenges, a steep learning curve for the surgeon, the risk of impaired early graft function, and the high cost of the procedure, have prevented minimally invasive LDN from gaining wide acceptance. To overcome these problems, we have developed a new surgical procedure named video-assisted minilaparotomy (VAM) for LDN. VAM-LDN is performed entirely with a small retrieval incision. Moreover, it does not require the induction of pneumoperitoneum, thereby avoiding potential vascular and renal complications. METHODS: We evaluated the outcome of transplant recipients receiving kidneys with the VAM-LDN procedure by retrospectively comparing the surgical outcomes of patients who underwent KTx with the conventional open nephrectomy (group I, n=82) and VAM-LDN (group II, n=70) procedures from March 1, 1997, to June 30, 2002, at our institution. We compared postoperative complications, patient and graft survival, and graft functions between these two groups during a 12-month follow-up period. RESULTS: There were no differences in demographic data, ABO compatibility, degree of human leukocyte antigen matching, or method of immunosuppression between the two groups (P >0.05). No significant difference was observed in complications such as delayed graft function, acute rejection, ureter complication, graft failure, or patient's mortality. There was no difference in graft function between the two groups, as determined by serum creatinine level measured during the 12-month follow-up. CONCLUSION: The short-term recipient outcome was favorable in patients who underwent KTx with the VAM-LDN procedure.

Effect of caffeine on the plasma protein binding and the disposition of ceftriaxone.

The effects of caffeine on the in-vitro protein binding and the pharmacokinetics of ceftriaxone (a highly protein bound cephalosporin) were investigated. Caffeine failed to decrease in-vitro protein binding of ceftriaxone. Rabbit plasma concentrations of ceftriaxone (30 mg kg-1 i.v.) were elevated significantly (P less than 0.05 at 0.3, 0.6 and 1 h after injection) when caffeine 5 or 10 mg kg-1 i.v. was co-administered compared with ceftriaxone given alone. Caffeine increased the volume of distribution of the central compartment (V1) for ceftriaxone significantly from 49 +/- 38 ml kg-1 (mean +/- s.d., n = 6) to 97 +/- 33 ml kg-1 (caffeine 5 mg kg-1, P less than 0.05), and 94 +/- 8 ml kg-1 (caffeine 10 mg kg-1, P less than 0.05) and decreased the volume of distribution of the peripheral compartment (V2) from 145 +/- 106 ml kg-1 (mean +/- s.d., n = 6) to 31 +/- 18 ml kg-1 (caffeine 5 mg kg-1, P less than 0.5) and 36 +/- 31 ml kg-1 (caffeine 10 mg kg-1, P less than 0.1). The rate of transfer of ceftriaxone to the peripheral compartment (k12) was also decreased significantly (P less than 0.05) after caffeine. The elevated plasma concentration of ceftriaxone, increased V1 value and the decreased V2 and k12 values are probably the result of caffeine altering the distribution of ceftriaxone to the central and the peripheral compartments.

Gastrointestinal absorption of phenytoin from an oil-in-water microemulsion.

The absorption profile of phenytoin Na emulsion were examined compared to that of phenytoin suspension after oral administration in the rat. The corn oil-in-water emulsion, particle size of 184+/-57.8 nm, was prepared using a microfludizer, and phenytoin Na added by shaft homogenizer. The phenytoin emulsion or suspension, 100 mg/kg, were intubated intragastrically using oral dosing needle and blood samples were withdrawn via an indwelling cannula from the conscious rat. Plasma concentrations of phenytoin were measured with HPLC using phenacetin as an internal standard. The plasma concentration versus time data were fitted to a one compartment open model and the pharmacokinetic parameters were calculated using the computer program, Boomer. The phenytoin plasma concentrations from the emulsion at each observed time were about 1.5-2 times higher than those from the suspension, significantly at time of 5, 6 and 7 hr after administration. The absorption (k(a)) and elimination rate constant (k(e)) were not altered significantly, however the AUC increased from 65.6 to 106.7 mug.hr/ml after phenytoin suspension or emulsion oral administration, respectively. From an equilibrium dialysis study, the diffusion rate constant (k(IE)) was considerably higher from the phenytoin Na emulsion (0.0439 hr(-1)) than phenytoin suspension (0.0014 hr(-1)).

Determination of omeprazole in rat plasma by HPLC with column switching.

A new high-performance liquid chromatographic method with column switching has been developed for the determination of omeprazole in plasma. The plasma samples were injected onto a Bondapak phenyl/corasil (37-50 microns) precolumn and polar plasma components were washed with 0.06 M borate buffer. After valve switching, the concentrated drug were eluted in the back-flush mode and separated on a mu-Bondapak C18 column with acetonitrile-phosphate buffer as the mobile phase. The method showed excellent precision, accuracy and speed with detection limit of 0.01 microgram/ml-1. Total analysis time per sample was less than 20 min and the coefficients of variation for intra and inter-assay were less than 5.63%. This method has been successfully applied to plasma samples from rats after oral administration of omeprazole.

Advanced method for determination of omeprazole in plasma by HPLC.

An advanced and sensitive high-performance liquid chromatographic (HPLC) method for determination of omeprazole in human plasma has been developed. After omeprazole was extracted from plasma with diethylether, the organic phase was transferred to another tube and trapped back with 0.1 N NaOH solution. The alkaline aqueous layer was injected into a reversed-phase C8 column. Lansoprazole was used as an internal standard. The mobile phase consisted of 30% of acetonitrile and 70% of 0.2 M KH2P04, pH 7.0. Recoveries of the analytes and internal standard were >75.48%. The coefficients of variation of intra- and inter-day assay were <5.78 and 4.59% for plasma samples. The detection limit in plasma was 2 ng/ml. The clinical applicability of this assay method was evaluated by determining plasma concentration-time courses of the respective analytes in 24 healthy volunteers after oral administration 40 mg of omeprazole. The present assay is considered to be simple, accurate, economical and suitable for the study of the kinetic disposition of omeprazole in the body.

Effect of food on the pharmacokinetics of rosuvastatin after administration of a single oral dose in dogs.

Rosuvastatin is a highly effective inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and is used for the treatment of patients with hyperlipidemia. We examined the effect of food on the pharmacokinetics of rosuvastatin by administering it while fasting and after intake of low-fat and high-fat meals. We administered a single 10-mg oral dose of rosuvastatin while fasting and after intake of a low-fat and high-fat meal in a parallel design. The plasma concentrations of rosuvastatin were measured using liquid chromatography tandem mass spectrometry (LC-MS/MS), and the pharmacokinetics of rosuvastatin was analyzed using both noncompartmental and compartmental models. The values of area under the curve at 24 h (AUC 24 h ) and peak plasma concentration (C max) in fed conditions were significantly lower than the corresponding values in the fasting conditions. In addition, consumption of a high-fat meal significantly delayed the time required to achieve the maximum concentration (T max) of rosuvastatin. Both the models sufficiently explained the effect of food on the pharmacokinetics of rosuvastatin and showed that the volume of distribution (V c) was increased and absorption rate constant (K a) was decreased in fed dogs. These findings suggest that food intake affects both the rate and extent of absorption of rosuvastatin, and that rosuvastatin should be administered on an empty stomach to avoid food effect.

Pharmacokinetic analysis of two different doses of duloxetine following oral administration in dogs.

BACKGROUND: Duloxetine is a potent and balanced dual inhibitor of serotonin and norepinephrine reuptake that is being investigated for the treatment of depression and urinary incontinence. The purpose of this study was to investigate the pharmacokinetic properties of duloxetine in 20 beagle dogs following a single oral administration of a 30- or 60-mg enteric-coated pellet in a capsule (Cymbalta). METHOD: Following the administration of 30 or 60 mg of Cymbalta to 20 beagle dogs, the plasma concentration of duloxetine was measured using LC-MS/MS. Pharmacokinetic parameters were analyzed using both noncompartmental and compartmental approaches. RESULTS: The values of C max and AUC increased in proportion to the dose of duloxetine. The one compartment model with first-order absorption and a lag time was used successfully for pharmacokinetic analysis of duloxetine following a single oral administration of Cymbalta 30 mg or 60 mg. CONCLUSIONS: The studies described here are the first to report the pharmacokinetics of oral duloxetine in dogs, and these findings provide important information for pharmaceutical formulation research of duloxetine using dogs.

Pharmacokinetics of angiotensin II receptor blockers in the dog following a single oral administration.

Angiotensin II receptor blockers (ARBs) are effective and well-tolerated orally active anti-hypertensive agents. The purpose of this study was to investigate the pharmacokinetic properties of typical ARBs in the dog. 60 beagles were administered a single oral dose of Micardis® 80 mg (telmisartan), Cozaar® 50 mg (losartan), or Diovan® 80- and 160-mg (valsartan). The plasma concentrations of these ARBs were measured using liquid chromatography/tandem mass spectrometry and their pharmacokinetic properties were analyzed using both non-compartmental and compartmental approaches. The half-life and volume of distribution in dogs were in the order losartan>valsartan>telmisartan after oral administration. Systemic exposure was estimated by calculating the area under the plasma concentration-vs.-time curve from time zero to infinity (AUC inf ), and resulted in the order telmisartan>valsartan>losartan. The values of C max and AUC increased in proportion to the dose of valsartan. In compartmental analysis, the pharmacokinetics of telmisartan and losartan pharmacokinetics fit a 2-compartment model, while valsartan fit a 1-compartment model. These results provide detailed pharmacokinetic information of ARBs in the dog, and may aid in future development of improved formulations or fixed-dose combinations.

Pharmacokinetic and pharmacodynamic modelling of the effects of glimepiride on insulin secretion and glucose lowering in healthy humans.

Glimepiride is an oral sulfonylurea antihyperglycaemic agent. We used pharmacokinetic-pharmacodynamic (PK-PD) modelling to analyse the relationship between plasma glimepiride concentration, insulin secretion and glucose lowering to determine the effects of the drug in healthy volunteers. A single 2-mg oral dose of glimepiride was administered to six healthy volunteers. The control group received a placebo. All subjects consumed 12 g of sugar immediately after drug administration in order to standardize the initial plasma glucose levels. Serial blood sampling was performed for 9 h after oral dosing. Plasma glimepiride, insulin and glucose levels were determined by validated methods (LC/MS/MS assay, hexokinase method and radioimmunoassay respectively). Time courses of plasma glimepiride concentration, insulin secretion, and glucose lowering effects were analysed by means of PK-PD modelling with the ADAPT II program. The time course of the plasma concentrations followed a two-compartmental model with a lag time. The glimepiride concentration peaked at 191.5 ng/mL at approximately 4 h after administration. The maximal increase in insulin secretion was 9.98 mIU/L and the maximal decrease in plasma glucose was 19.33 mg/dL. Both peak effects occurred at approximately 2.5 h after drug intake. The glucose disappearance model was used to analyse glimepiride's insulin secretion and glucose lowering effects. The PK-PD model described well the relationship between plasma glimepiride and its insulin secretion and hypoglycaemic effects in healthy volunteers.

Assessing the bioequivalence of 4- and 8-mg benidipine tablets in healthy volunteers after a single oral dose.

OBJECTIVE: To assess the bioequivalence of a new tablet formulation of benidipine hydrochloride with reference to a marketed product. METHODS: Two groups, consisting of 24 healthy volunteers each, received a 4- or 8-mg (one or two tablets) reference benidipine hydrochloride tablet and one or two test tablets in a 2 x 2 cross-over study. There was a 6-day washout period between doses. The plasma benidipine concentration was monitored using LC/MS/MS for 8 h after the dose. The area under the plasma concentration-time curve from time 0 to the last sampling time (AUCt) was calculated using the linear-log trapezoidal rule. The maximum plasma drug concentration (Cmax) and the time to reach Cmax (Tmax) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUCt and Cmax, and untransformed Tmax. RESULTS: The geometric mean AUCt was 2.23 ng/mL/h (test medication) and 2.47 ng/mL/h (reference medication) for the 4-mg tablet, and 9.57 and 9.97 ng/mL/h for the 8-mg tablet, respectively. A Cmax of 1.94 and 2.01 ng/mL was achieved for the test and reference medication for the 4-mg tablet, and 5.94 and 6.53 ng/mL for the 8-mg tablet, respectively. The 90% confidence intervals for AUCt and Cmax were 0.8441-1.0481 and 0.8739-1.2037 for the 4-mg tablet, and 0.8559-1.1273 and 0.9926-1.2176 for the 8-mg tablet, respectively, satisfying the bioequivalence criteria of the US Food and Drug Administration Guidelines, and the Korea Food and Drug Administration Guidelines. These results indicate that the 4- and 8-mg tablets of benidipine are bioequivalent to the reference formulations.

Pharmacokinetics and pharmacodynamics of benidipine using a slow receptor-binding model.

PURPOSE: This study examined the relationship between the plasma concentration of benidipine, a long-lasting antihypertensive agent with Ca(2+)-channel-blocking properties, and its cardiovascular effects (reduction in blood pressure and increase in heart rate) in order to assess the usefulness of pharmacokinetic-pharmacodynamic (PK-PD) modelling in describing this relationship. METHODS: Two groups of 24 healthy volunteers received either a 4- or 8-mg benidipine hydrochloride tablet; 11 additional subjects received a placebo. Serial blood sampling and PD measurements were performed over 8 h thereafter. Plasma concentrations of benidipine were measured with a validated LC/MS/MS system, and the effects on blood pressure and heart rate were assessed during the same period. A two-compartment open model with lag time was used to explain the PK properties, and the PD model was characterized by slow receptor binding, reflecting the binding of benidipine to the ion-channel receptor. RESULTS: Benidipine reached mean peak plasma concentrations of 1.04 and 3.85 ng/mL at 0.5 and 0.75 h after 4 and 8 mg doses, respectively. Peak cardiovascular effects were detected approximately 2 h after the administration of either dose. Maximal decreases in diastolic blood pressure with 4 and 8 mg of benidipine were 7.79 and 14.75 mmHg, respectively, and maximal increases in heart rate were 7.32 and 17.56 bpm, respectively. No significant changes in systolic blood pressure were observed. The cardiovascular effects were analysed according to a slow receptor-binding model. CONCLUSIONS: The tested PK-PD model successfully described the relationship between the plasma concentration of benidipine and its cardiovascular effects.

Effect of caffeine on ceftriaxone disposition and plasma protein binding in the rat.

Previous studies have shown that caffeine can affect drug kinetics by altering drug binding to plasma protein, drug absorption, or drug distribution. In this study, the effect of caffeine on the in vivo protein binding and the disposition of ceftriaxone (a highly protein-bound cephalosporin) were investigated in the rat. Ceftriaxone 100 mg/kg and caffeine 20 mg/kg were i.v. injected via the tail vein and ceftriaxone in plasma, plasma filtrate, urine, feces, and tissues (brain, heart, kidney, liver, gut, lung, and muscle) was assayed by HPLC with UV detection. The fraction of free ceftriaxone in plasma ranged from 5.6 to 32.8% of total ceftriaxone (3-347 micrograms/ml) without caffeine and showed no alteration by caffeine. The total amount of ceftriaxone excreted in urine and feces was increased significantly (p less than 0.05) from 13.1 +/- 1.8 mg (mean +/- SD, 54.6% of total) to 15.3 +/- 1.1 mg (63.8% of total) by caffeine coadministration. The terminal half-life of ceftriaxone in plasma was shortened from 59 to 47 min, and the area under the plasma drug concentration-time curve (AUC) was reduced from 612 to 516 micrograms hr/ml. Although the peak drug concentrations and the times of peak concentration of ceftriaxone in tissues were not altered by caffeine administration, the elimination of ceftriaxone was increased, as indicated by generally shorter half-lives (decreases ranged from 17.5% in liver to 34.2% in brain) and lower AUC values (from 9.0% in heart to 54.5% in brain). These results suggest that caffeine does not alter the protein binding of ceftriaxone, but enhances the elimination of ceftriaxone in the rat.

Simultaneous determination of cefamandole and cefamandole nafate in human plasma and urine by high-performance liquid chromatography with column switching.

A high-performance liquid chromatographic method with column switching has been developed for the simultaneous determination of cefamandole and cefamandole nafate in plasma and urine. The plasma and urine samples were injected onto a precolumn packed with Corasil RP C18 (37-50 microns) after simple dilution with an internal standard solution in 0.05 M phosphoric acid. Polar plasma and urine components were washed out using 0.05 M phosphoric acid. After valve switching, the concentrated drugs were desorbed in back-flush mode and separated by a reversed-phase C8 column with methanol-5 mM tetrabutylammonium bromide (45:55, v/v) as the mobile phase. The method showed excellent precision with good sensitivity and speed, and a detection limit of 0.5 microgram/ml. The total analysis time per sample was less than 30 min, and the mean coefficients of variation for intra- and inter-assay were both less than 4.9%. The method has been successfully applied to plasma and urine samples for human volunteers after intravenous injection of cefamandole nafate.