Pharmacokinetic Modeling of the Impact of P-glycoprotein on Ondansetron Disposition in the Central Nervous System.

PURPOSE: Modulation of 5-HT3 receptor in the central nervous system (CNS) is a promising approach for treatment of neuropathic pain. The goal was to evaluate the role of P-glycoprotein (Pgp) in limiting exposure of different parts of the CNS to ondansetron (5-HT3 receptor antagonist) using wild-type and genetic knockout rat model. METHODS: Plasma pharmacokinetics and CNS (brain, spinal cord, and cerebrospinal fluid) disposition was studied after single 10 mg/kg intravenous dose. RESULTS: Pgp knockout resulted in significantly higher concentrations of ondansetron in all tested regions of the CNS at most of the time points. The mean ratio of the concentrations between KO and WT animals was 2.39-5.48, depending on the region of the CNS. Male and female animals demonstrated some difference in ondansetron plasma pharmacokinetics and CNS disposition. Mechanistic pharmacokinetic model that included two systemic disposition and three CNS compartments (with intercompartmental exchange) was developed. Pgp transport was incorporated as an efflux from the brain and spinal cord to the central compartment. The model provided good simultaneous description of all data sets, and all parameters were estimated with sufficient precision. CONCLUSIONS: The study provides important quantitative information on the role of Pgp in limiting ondansetron exposure in various regions of the CNS using data from wild-type and Pgp knockout rats. CSF drug concentrations, as a surrogate to CNS exposure, are likely to underestimate the effect of Pgp on drug penetration to the brain and the spinal cord.

New and validated RP-HPLC Method for Quantification of Safinamide Mesylate in Presence of Its Basic Degradate, Levodopa and Ondansetron: Application to Human Plasma.

A simple, precise, rapid and accurate reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated for analysis of safinamide mesylate (SAF) in presence of its basic degradate, and co-administered drugs levodopa and ondansetron. The mobile phase consisted of acetonitrile and 20 mM potassium dihyrogen orthophosphate buffer having pH = 5 (40: 60 v/v). Quantification was achieved with ultraviolet detector at 226 nm. The linear range was 0.5-10 µg/mL with mean recovery ± SD of 99.72 ± 1.59. The peak purity of SAF in pharmaceutical preparation spiked with its degradate and co-administered drugs revealed symmetry factor (999.8) within the calculated threshold (>998.1). The suggested method was validated in compliance with the International Conference on Harmonization (ICH) guidelines and statistically compared with the manufacturer HPLC method with no significant difference in terms of accuracy and precision. The assay method was successfully used to estimate SAF in tablets with good percentage recoveries. The high sensitivity (lower than Cmax of the drug 0.65 µg/mL) of the proposed HPLC method enabled the determination of SAF in presence of its basic degradate and co-administered drug, ondansetron in human plasma with acceptable accuracy. The suggested HPLC method could be used in Quality Control (QC) lab for analysis of the studied drug in pharmaceutical preparation.

A Prospective, Randomized, Double-Blinded Study of the Effect of Intravenous Ondansetron on the Effective Dose in 50% of Subjects of Prophylactic Phenylephrine Infusions for Preventing Spinal Anesthesia-Induced Hypotension During Cesarean Delivery.

BACKGROUND: Ondansetron has been shown to reduce the incidence of hypotension and vasopressor requirement during spinal anesthesia for obstetric and nonobstetric surgery. However, the magnitude of this effect has not been fully quantified. In this parallel-group, randomized, double-blinded study, we determined the effective dose in 50% of subjects (ED50) of a prophylactic phenylephrine infusion for preventing hypotension in patients who received a single dose of intravenous ondansetron 4 mg or saline control before combined spinal-epidural anesthesia for elective cesarean delivery. ED50 values obtained were compared to estimate the effect of ondansetron versus placebo on vasopressor requirement. METHODS: Sixty parturients were randomly assigned to receive ondansetron (group O) or saline control (group C) 10 minutes before positioning for induction of spinal anesthesia. A prophylactic phenylephrine infusion was used to prevent hypotension. The first patient in each group received a phenylephrine infusion at the rate of 0.5 µg/kg/min. The infusion rate for each subsequent patient was varied with increments or decrements of 0.05 µg/kg/min based on the response of the previous patient, and the effective dose of the phenylephrine infusion for preventing hypotension in 50% of patients (ED50) was calculated for each group and compared using up-down sequential analysis. Probit regression was applied as a backup and sensitivity analysis was used to compare ED50 values for phenylephrine between groups by comparing calculated relative mean potency. RESULTS: The ED50 (mean [95% confidence interval (CI)]) of the rate of phenylephrine infusion was lower in group O (0.24 µg/kg/min [0.10-0.38 µg/kg/min]) compared with group C (0.32 µg/kg/min [0.14-0.47 µg/kg/min]) (P < .001). The total consumption of phenylephrine (mean ± standard deviation [SD]) until delivery was lower in group O (316.5 ± 25.9 µg) than in group C (387.7 ± 14.7 µg, P = .02). The estimate of relative median potency for phenylephrine for group O versus group C was 0.74 (95% CI, 0.37-0.95). CONCLUSIONS: Under the conditions of this study, intravenous ondansetron 4 mg reduced the ED50 of a prophylactic phenylephrine infusion by approximately 26% in patients undergoing cesarean delivery under combined spinal-epidural anesthesia.

Simultaneous quantification of ondansetron and tariquidar in rat and human plasma using a high performance liquid chromatography-ultraviolet method.

Ondansetron, a widely used antiemetic agent, is a P-glycoprotein (P-gp) substrate and therefore expression of P-gp at the blood-brain barrier limits its distribution to the central nervous system (CNS), which was observed to be reversed by coadministration with P-gp inhibitors. Tariquidar is a potent and selective third-generation P-gp inhibitor, and coadministration with ondansetron has shown improved ondansetron distribution to the CNS. There is currently no reported bioanalytical method for simultaneously quantifying ondansetron with a third-generation P-gp inhibitor. Therefore, we aimed to develop and validate a method for ondansetron and tariquidar in rat and human plasma samples. A full validation was performed for both ondansetron and tariquidar, and sample stability was tested under various storage conditions. To demonstrate its utility, the method was applied to a preclinical pharmacokinetic study following coadministration of ondansetron and tariquidar in rats. The presented method will be valuable in pharmacokinetic studies of ondansetron and tariquidar in which simultaneous determination may be required. In addition, this is the first report of a bioanalytical method validated for quantification of tariquidar in plasma samples.

Highly sensitive HPLC-MS/MS assay for the quantitation of ondansetron in rat plasma and rat brain tissue homogenate following administration of a very low subcutaneous dose.

Ondansetron is a highly selective 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist that is well tolerated in the clinic. Pre-clinical studies in rats have shown interesting effects of small doses of ondansetron on cognition, behavioural sensitisation and epilepsy. However, the pharmacokinetic profile at a very low dose has not been reported, possibly because currently, there are no published analytical methods capable of quantifying trace levels of ondansetron in plasma or brain. The objective of this study was to develop and validate a highly sensitive HPLC-MS/MS assay capable of quantifying ondansetron in rat plasma and rat brain homogenate following a low subcutaneous administration of 1.0 µg/kg. Ondansetron was extracted by protein precipitation with methanol containing labeled ondansetron. The chromatography was performed on a Thermo Scientific Aquasil C18 analytical column (100 x 2.1 mm I.D., 5 µm) operating at 40 °C. The mobile phase consisted of acetonitrile and 10 mM ammonium formate pH 3 at a ratio of 30:70, respectively. The flow rate was fixed at 300 µL/min and ondansetron and the internal standard were both eluted at 2.3 min. A linear (1/x) relationship was used to perform the calibration over an analytical range from 20.0 - 10,000 pg/mL in plasma and from 2.00 to 1000 pg/mL in rat brain homogenate. The inter-batch precision and accuracy ranged from 3.7 to 4.7% and from 0.7 to 10.9% in rat plasma, respectively. The inter-batch precision and accuracy observed in rat brain was 4.5 to 6.4% and -5.1 to 4.9% respectively. The method met all requirements and the assay was suitable for the determination of the pharmacokinetic profile following a subcutaneous dose of 1.0 µg/kg body weight (BW) in rats.

Determination of Ondansetron by Spectrofluorimetry: Application to Forced Degradation Study, Pharmaceuticals and Human Plasma.

The current manuscript describes a validated, responsive and rapid spectrofluorimetric method for quantifying ondansetron (OND) in authentic form, spiked human plasma and dosage forms. This is the first reported fluorescence study of Ondansetron in Triton X 100 system. Various variables affecting fluorescence response were studied precisely and optimised. The described method involved the fluorescence measurement in Triton X 100 system at λem/λex 354/317 nm. The calibration plot attained linearity over concentration range of 0.2 - 2 µg/mL. The developed method has been extensively applied to degradation studies of OND as per International Conference on Harmonisation (ICH) guidelines by exposing to oxidative, thermal, photo, acidic and alkaline conditions and also the degradation pathway has been proposed.

Pharmacokinetics of R-(-)ondansetron compared with that of S-(-)ondansetron in rats using an LC-MS/MS method.

The pharmacokinetics of R-(-)ondansetron (R-ond) compared with that of S-(-)ondansetron (S-ond) was studied in rats. R-ond and S-ond were injected intravenously into rats at a dose of 2.0 mg/kg. The stability of ondansetron enantiomers in rat was determined by chiral HPLC, and the concentrations of R-ond and S-ond in plasma were determined by an LC/MS/MS method. The pharmacokinetic parameters were calculated and analyzed statistically using the t-test. The enantiomer inversions between R-ond and S-ond did not occur in rat. The pharmacokinetic parameters (t1/2 , AUC, MRT, CL) of R-ond and S-ond differed significantly. The concentration in plasma of the R/S-enantiomeric ratio reached a maximum value of 9.5 at 4.0 h post-dose. The pharmacokinetics of R-ond and S-ond are stereoselective in rat, which indicates substantial stereoselectivity in the disposition of ondansetron enantiomers in rat. R-ond has more potential than S-ond to be developed as a single enantiomer drug.

Quantification of ondansetron, granisetron and tropisetron in goat plasma using hydrophilic interaction liquid chromatography-solid phase extraction coupled with hydrophilic interaction liquid chromatography-triple quadrupole tandem mass spectrometry.

An assay method to quantify ondansetron (OND), granisetron (GRA) and tropisetron (TRO) in goat plasma has been successfully developed and validated. This method procedure for the analysis of OND, GRA and TRO was involved of extracting samples with hydrophilic interaction liquid chromatography (HILIC) solid phase extraction (SPE) and determination by liquid chromatography coupled to tandem mass spectroscopy. An SPE method for the simultaneous extraction of OND, GRA and TRO with high efficiency and selectivity was developed. Prior to HPLC-MS/MS analysis, most of the sources of interference present in the supernatant after protein precipitation of plasma proteins was efficiently removed from the samples by the HILIC SPE treatment. For the quantification of OND, GRA and TRO in the samples, tandem mass spectrometry operating in positive electrospray ionization mode with multiple reaction monitoring was used. The calibration curve was performed in the range of 0.2-20 ng/mL for the target OND, GRA and TRO in goat plasma samples. The precision of the intra- and inter-day assay for OND, GRA and TRO were 1.84-6.23% and 3.89-5.31%, 2.63-6.29% and 3.76-5.31%, 1.99-5.67% and 2.64-4.70%, respectively. The accuracy of the intra- and inter-day assay for OND, GRA and TRO were 89.15-97.39% and 89.46-95.17%, 91.08-100.82% and 91.24-99.47%, 92.30-100.74% and 94.21-97.90%, respectively. For the determination of OND, GRA and TRO in plasma samples, no significant matrix effects were observed. The mean absolute recoveries were 103-150%, 115-121%, and 98-141% for OND, GRA and TRO, respectively. Furthermore, the mean process efficiency values of silica SPE were 98-135%, 92-124%, and 72-109% for OND, GRA and TRO, respectively.

Population pharmacokinetics and prophylactic anti-emetic efficacy of ramosetron in surgical patients.

AIMS: This study characterized the pharmacokinetics of ramosetron and compared prophylactic anti-emetic efficacy with that of ondansetron in a large population. METHODS: Fifty-eight patients consented to the pharmacokinetic analysis and were assigned randomly to receive 0.3, 0.45 or 0.6 mg ramosetron after induction of anaesthesia. Blood samples were acquired at preset intervals. Non-compartmental and population pharmacokinetic analyses were performed. In total, 1102 patients consented to the evaluation of prophylactic anti-emetic efficacy and were allocated randomly to receive 0.3 mg ramosetron or 4 mg ondansetron at the end of surgery. An additional 16 mg ondansetron were mixed in the intravenous patient-controlled analgesia pump of the ondansetron group. Post-operative nausea and vomiting (PONV) were evaluated 6, 24 and 48 h post-operatively using the Rhodes index of nausea, vomiting and retching (RINVR). Administration of rescue anti-emetics and adverse events were evaluated. RESULTS: The pharmacokinetic parameter estimates were V1 (l) = 5.12, V2 (l) = 108, CL (l⋅min(-1) ) = 0.08 + (59⋅age(-1) ) × 0.09, Q (l⋅min(-1) ) = 1.42. The incidences of PONV in the ramosetron and ondansetron groups were 77 (13.9%) and 113 (20.6%) and 44 (7.9%) and 66 (12.0%) at 24 and 48 h post-operatively, respectively (P = 0.004, 0.030). RINVR was significantly lower in the ramosetron than the ondansetron group 24 and 48 h post-operatively (P = 0.003, 0.025). Use of rescue anti-emetics and incidence of adverse events were comparable. CONCLUSIONS: A two compartment mammillary model was used to describe ramosetron pharmacokinetics. Prophylactic anti-emetic efficacy of ramosetron was significantly better 24 and 48 h post-operatively than that of ondansetron, particularly when the Apfel score was ≥ 3.

Flavored Intravenous Ondansetron Administered Orally for the Treatment of Persistent Vomiting in Children.

OBJECTIVE: To study the serum level of ondansetron after oral administration of intravenous ondansetron, and test the palatability of the drug after being flavored. METHOD: This is a single-center prospective study enrolling children aged 3-8 years with gastroenteritis treated for persistent vomiting; patients received single dose of flavored intravenous ondansetron orally. The primary outcome was ondansetron serum level at 4 hours. Secondary outcome was palatability of the drug. RESULTS: Forty previously healthy patients presenting with acute gastroenteritis were enrolled. The mean age was 4.86±1.37 years. Serum level at 4 h had a median of 26.23 ng/ml, range (8.3-52 ng/ml). Palatability of the drug had a mean of 3.23 (of 5) ± 0.80, based on score from visual analog scale. CONCLUSIONS: Flavored intravenous ondansetron administered orally is a safe and an effective option and can be considered in the absence of the oral forms of the drug.

Effect of Ondansetron on Metformin Pharmacokinetics and Response in Healthy Subjects.

The 5-hydroxytryptamine-3 (5-HT3) receptor antagonists such as ondansetron have been used to prevent and treat nausea and vomiting for over 2 decades. This study was to determine whether ondansetron could serve as a perpetrator drug causing transporter-mediated drug-drug interactions in humans. Twelve unrelated male healthy Chinese volunteers were enrolled into a prospective, randomized, double-blind, crossover study to investigate the effects of ondansetron or placebo on the pharmacokinetics of and the response to metformin, a well-characterized substrate of organic cation transporters and multidrug and toxin extrusions (MATEs). Ondansetron treatment caused a statistically significantly higher Cmax of metformin compared with placebo (18.3 ± 5.05 versus 15.2 ± 3.23; P = 0.006) and apparently decreased the renal clearance of metformin by 37% as compared with placebo (P = 0.001). Interestingly, ondansetron treatment also statistically significantly improved glucose tolerance in subjects, as indicated by the smaller glucose area under the curve in the oral glucose tolerance test (10.4 ± 1.43) as compared with placebo (11.5 ± 2.29 mmol∙mg/l) (P = 0.020). It remains possible that ondansetron itself may affect glucose homeostasis in human subjects, but our clinical study, coupled with our previous findings in cells and in animal models, indicates that ondansetron can cause a drug-drug interaction via its potent inhibition of MATE transporters in humans.

Limited sampling pharmacokinetics of subcutaneous ondansetron in healthy geriatric cats, cats with chronic kidney disease, and cats with liver disease.

Ondansetron, a 5-HT3 receptor antagonist, is an effective anti-emetic in cats. The purpose of this study was to compare pharmacokinetics of subcutaneous (SQ) ondansetron in healthy geriatric cats to cats with chronic kidney disease (CKD) or liver disease using a limited sampling strategy. 60 cats participated; 20 per group. Blood was drawn 30 and 120 min following one 2 mg (mean 0.49 mg/kg, range 0.27-1.05 mg/kg) SQ dose of ondansetron. Ondansetron concentrations were measured by liquid chromatography coupled to tandem mass spectrometry. Drug exposure represented as area under the curve (AUC) was predicted using a limited sampling approach based on multiple linear regression analysis from previous full sampling studies, and clearance (CL/F) estimated using noncompartmental methods. Kruskal-Wallis anova was used to compare parameters between groups. Mean AUC (ng/mL·h) of subcutaneous ondansetron was 301.4 (geriatric), 415.2 (CKD), and 587.0 (liver). CL/F (L/h/kg) of SQ ondansetron was 1.157 (geriatric), 0.967 (CKD), and 0.795 (liver). AUC was significantly higher in liver and CKD cats when compared to geriatric cats (P < 0.05). CL/F in liver cats was significantly decreased (P < 0.05) compared to geriatric cats. In age-matched subset analysis, AUC and CL/F in liver cats remained significantly different from geriatric cats.

Pharmacokinetics and bioavailability study of two ondansetron oral soluble film formulations in fasting healthy male Chinese volunteers.

BACKGROUND: Ondansetron oral soluble film is designed to be applied on top of the tongue without requiring water to aid dissolution or swallowing, which is especially fitting for nausea and vomiting patients. PURPOSE: This study was conducted to compare the bioavailability of two 8 mg ondansetron oral soluble film formulations. PATIENTS AND METHODS: This randomized, open-label, two-period crossover study was performed under fasting conditions. A total of ten eligible subjects were randomly assigned at a 1:1 ratio to receive a single 8 mg dose of the test and reference ondansetron oral soluble film formulations, followed by a 1-week washout period and administration of the alternate formulation. The concentrations of ondansetron were assayed using an liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS) method. For analysis of pharmacokinetic properties, including the peak concentration of T max (C max), AUC from time 0 (baseline) to t hours (AUC0- t ), and AUC from baseline to infinity (AUC0-∞), blood samples were obtained at intervals over the 24-hour period after studying drug administration. Tolerability was assessed by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis) and by questioning subjects about adverse events. RESULTS: The mean (standard derivation [SD]) relative bioavailability was 96.5 (23.7%). The 90% confidence intervals (CIs) for the log-transformed ratios of C max and AUC0- t were 84.71%-103.28% and 91.38%-108.60%, respectively (P>0.05). Similar results were found for the data without log-transformation. No statistically significant differences were found based on analysis of variance. No significant adverse events occurred or were reported during the study. CONCLUSION: As the 90% CIs based on the differences between the test and reference formulation were within the 80%-125% range for both the C max and AUC0- t , we concluded that the two formulations were bioequivalent with respect to the rate or the extent of absorption. Both formulations are well tolerated.

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.

Multi-walled carbon nanotubes/Nafion composite film modified electrode as a sensor for simultaneous determination of ondansetron and morphine.

The electrochemical behavior of ondansetron was studied on the multi-walled carbon nanotubes/Nafion polymer composite modified glassy carbon electrode (MWCNTs-Nafion/GCE). The oxidation peak potential was shifted from 1.32 V to 1.18 V compared to the bare electrode indicating excellent electrocatalytic activity of immobilized film toward drug molecule. The modified electrode exhibited a remarkable enhancement effect on voltammetric response due to the synergistic effect of nanomaterial and cation-exchange polymer on the electron transfer rate, the effective electrode area and the accumulation capability. After optimizing the experimental parameters, adsorptive stripping procedure was used for the determination of ondansetron in pharmaceutical formulation. The results were satisfactory in comparison with those obtained by high-performance liquid chromatography. In addition, the MWCNTs-Nafion/GCE exhibited high selectivity in the voltammetric measurements of ondansetron and co-administrated drug morphine with potential difference of 430 mV. The response peak currents had linear relationship with drug concentration in the range of 1.0 × 10(-7)-5.0 × 10(-6)M and 1.0 × 10(-7)-4.0 × 10(-6)M with detection limits 3.1 × 10(-8) and 3.2 × 10(-8)M for ondansetron and morphine, respectively. The electrode was successfully applied for simultaneous electrochemical sensing of both drugs in human serum samples after selective accumulation at the electrode surface.

Development of chitosan-based ondansetron buccal delivery system for the treatment of emesis.

BACKGROUND: For the buccal drug delivery, chitosan (CS) can be used to improve drug absorption and reduce application frequency and drug amount. The aim of this study is to develop and evaluate mucoadhesive ondansetron buccal films for the treatment of emesis using CS as a mucoadhesive polymer. METHODS: The film prepared by solvent casting method was comprised of ondansetron (approximately 65 µg)-loaded mucoadhesive gels containing 1, 2 or 3% CS and impermeable backing layer. Rheological property of the gels, physiochemical properties of the films (weight, thickness, drug content, swelling ratio, adhesion time and mucoadhesive force) and in vitro ondansetron release profile from the films were determined to evaluate the formulation. The films containing 3% CS (diameter: 0.5 cm; thickness: 170 µm) was selected as the novel formulation, and were used for the in vivo study. Comparative pharmacokinetic studies of ondansetron with this film and oral solution were performed at the same dose in hamsters. RESULTS: The mean values of T(max) and C(max) of the film and oral solution were similar. However, the half-life, mean residence time and AUC(0-24 h) of the film were about 1.7, 1.4 and 2.0-fold higher than those of the oral solution, respectively. The film showed enhanced bioavailability and prolonged efficacy compared to the oral solution. CONCLUSIONS: The mucoadhesive ondansetron buccal film may be a potential alternative to the marketed oral formulation, parenterals and solid suppositories with better patient compliance and higher bioavailability for the treatment of emesis.

Effects of OCT1 polymorphisms on the cellular uptake, plasma concentrations and efficacy of the 5-HT(3) antagonists tropisetron and ondansetron.

After uptake into liver cells, the antiemetic drugs tropisetron and ondansetron undergo metabolic inactivation by cytochrome P450 2D6 (CYP2D6). We investigated whether the hepatic organic cation transporter 1 (OCT1; SLC22A1) mediates cellular uptake and whether common OCT1 loss-of-function polymorphisms affect pharmacokinetics and efficacy of both drugs. Both tropisetron and ondansetron inhibited ASP(+) uptake in OCT1-overexpressing HEK293 cells. Overexpression of wild-type, but not OCT1 loss-of-function variants, significantly increased tropisetron uptake. Correspondingly, patients with two loss-of-function OCT1 alleles had higher tropisetron plasma concentrations (n=59, P<0.04) and higher clinical efficacy (n=91, P=0.009) compared with carriers of fully active OCT1. Overexpression of OCT1 did not increase ondansetron uptake. Nevertheless, OCT1 genotypes correlated with pharmacokinetics (n=45, P<0.05) and clinical efficacy (n=222, P<0.02) of ondansetron, the effect size of OCT1 genotypes on pharmacokinetics and efficacy was greater for tropisetron than for ondansetron. In conclusion, in addition to the known effects of CYP2D6, OCT1 deficiency may increase efficacy of tropisetron and potentially of ondansetron by limiting their hepatic uptake.

CYP2D6- and CYP3A-dependent enantioselective plasma concentrations of ondansetron in postanesthesia care.

BACKGROUND: An influence of polymorphic cytochromes P450 (CYP) 2D6 genetic variants on antiemetic efficacy of ondansetron has been suggested. However, the role of CYP3A in ondansetron metabolism and efficacy has been unclear. In this study, we evaluated the hypothesis that genotype-dependent CYP2D6 and CYP3A activity selectively influences plasma concentrations of ondansetron enantiomers. Additionally, the effects of doubling the ondansetron dose on genotype-dependent plasma concentrations were investigated. METHODS: Patients received IV ondansetron 4 or 8 mg for emesis prophylaxis before emergence from anesthesia. The CYP2D6-dependent activity score representing no, decreased, normal, or increased CYP2D6 enzyme activity as well as CYP3A low (CYP3A5*3/*3) and high expressor status (CYP3A5 wt/wt or wt/*3) were determined. Plasma concentrations of R- and S-ondansetron enantiomers were measured by liquid chromatography-tandem mass spectrometry. Area under the plasma concentration-time curves (AUCs) of R- and S-ondansetron were associated with CYP2D6 and CYP3A5 genotype-dependent enzyme activity. RESULTS: Complete data of 141 subjects were analyzed. Concentrations of S-ondansetron differed between CYP2D6 activity groups (P = 0.01) with highest values in patients with no CYP2D6 activity (mean [95% confidence interval]: 362.5 [238.3/486.7] h · ng/mL) and lowest values in those with increased activity (149.6 [114.5/184.8] h · ng/mL) compared with subjects displaying genotypes resulting in reduced or normal CYP2D6 activity (263.6 [228.8/298.8], 255.4 [228.2/282.7] h · ng/mL). AUC of R-ondansetron was 2 times higher in CYP3A5 low expressors compared with high expressors (281.5 [248.6/314.3] vs 142.5 [92.4/192.7] h · ng/mL; P = 0.003). Doubling the ondansetron dose increased plasma concentrations only in individuals with low CYP3A activity, but not in individuals with high enzyme activity (P < 0.001). CONCLUSIONS: The metabolism of ondansetron seems to be enantioselective. In this postoperative setting, CYP2D6 activity scores correlated with concentrations of S-ondansetron, whereas CYP3A5 expressor status mainly influenced concentrations of R-ondansetron. Genetically and environmentally determined CYP2D6 and CYP3A enzyme activity might have implications for antiemetic efficacy.

Human plasma quantification of droperidol and ondansetron used in preventing postoperative nausea and vomiting with a LC/ESI/MS/MS method.

An analytical method based upon liquid chromatography coupled to ion trap mass spectrometry (MS) detection with electrospray ionization interface has been developed for the simultaneous identification and quantification of droperidol and ondansetron in human plasma. The two drugs were isolated from 0.5 mL of plasma using a basic liquid-liquid extraction with diethyl ether/heptane (90/10, v/v) and tropisetron and haloperidol as internal standards, with satisfactory extraction recoveries. They were separated on a 5-µm C(18) Highpurity column (150 mm×2.1 mm I.D.) maintained at 30°C. The elution was achieved isocratically with a mobile phase of 2 mM HCOONH(4) pH 3.8 buffer/acetonitrile (60/40, v/v) at a flow rate of 200 µL/min. Data were collected either in full-scan MS mode at m/z 100-450 or in full-scan MS-MS mode, selecting the [M+H] (+) ion at m/z=294.0 for ondansetron, m/z=285.2 for tropisetron, m/z=380.0 for droperidol and m/z=376.0 for haloperidol. The most intense daughter ion of ondansetron (m/z=212.0) and droperidol (m/z=194.0) were used for quantification. Retention times for tropisetron, ondansetron, droperidol and haloperidol were 2.50, 2.61, 3.10 and 4.68 min, respectively. Calibration curves were linear for both compounds in the 0.50-500 ng/mL range. The limits of detection and quantification were 0.10 ng/mL and 0.50 ng/mL, respectively. The intra- and inter-assay precisions were lower than 6.4% and intra- and inter-assay recoveries were in the 97.6-101.9% range for the three 3, 30 and 300 ng/mL concentrations. This method allows simultaneous and rapid measurement of droperidol and ondansetron, which are frequently co-administrated for the prevention of postoperative nausea and vomiting.

Enantioselective determination of ondansetron and 8-hydroxyondansetron in human plasma from recovered surgery patients by liquid chromatography-tandem mass spectrometry.

A liquid chromatographic-mass spectrometric assay with atmospheric pressure chemical ionization for quantification of ondansetron and its main metabolite 8-hydroxyondansetron in human plasma was presented. The enantiomeric separation was achieved on a Chiralcel OD-R column containing cellulose tris-(3,5-dimethylphenylcarbamate). The validation data were within the required limits. The assay was successfully applied to authentic plasma samples. Quantitative results from postoperative patients receiving ondansetron demonstrated a great interindividual variability in postoperative plasma drug concentrations, the metabolites were not detected in their unconjugated form. A wide variation in the S-(+)-/R-(-)-ondansetron concentration ratio between 0.14 and 7.18 is indicative for a stereoselective disposition or metabolism. In further studies CYP2D6 and CYP3A4 genotype dependent metabolism of ondansetron enantiomers as well as of co-administered drugs and clinical efficacy of the medication should be tested.