Plasma Concentrations Of Omeprazole Research Articles

Prediction of Omeprazole Pharmacokinetics and its Inhibition on Gastric Acid Secretion in Humans Using Physiologically Based Pharmacokinetic-Pharmacodynamic Model Characterizing CYP2C19 Polymorphisms.

To develop a whole physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model to describe the pharmacokinetics and anti-gastric acid secretion of omeprazole in CYP2C19 extensive metabolizers (EMs), intermediate metabolizers (IMs), poor metabolizers (PMs) and ultrarapid metabolizers (UMs) following oral or intravenous administration. A PBPK/PD model was built using Phoenix WinNolin software. Omeprazole was mainly metabolized by CYP2C19 and CYP3A4 and the CYP2C19 polymorphism was incorporated using in vitro data. We described the PD by using a turn-over model with parameter estimates from dogs and the effect of a meal on the acid secretion was also implemented. The model predictions were compared to 53 sets of clinical data. Predictions of omeprazole plasma concentration (72.2%) and 24h stomach pH after administration (85%) were within 0.5-2.0-fold of the observed values, indicating that the PBPK-PD model was successfully developed. Sensitivity analysis demonstrated that the contributions of the tested factors to the plasma concentration of omeprazole were Vmax,2C19 ≈ Papp > Vmax,3A4 > Kti, and contributions to its pharmacodynamic were Vmax,2C19 > kome > kms > Papp > Vmax,3A4. The simulations showed that while the initial omeprazole dose in UMs, EMs, and IMs increased 7.5-, 3- and 1.25-fold compared to those of PMs, the therapeutic effect was similar. The successful establishment of this PBPK-PD model highlights that pharmacokinetic and pharmacodynamic profiles of drugs can be predicted using preclinical data. The PBPK-PD model also provided a feasible alternative to empirical guidance for the recommended doses of omeprazole.

Evaluation of the relationship between polymorphisms in CYP2C19 and the single-dose pharmacokinetics of omeprazole in healthy Chinese volunteers: A multicenter study.

The aim of this study was to evaluate the relationship between polymorphisms in CYP2C19 and the single‐dose pharmacokinetics (PKs) of omeprazole in healthy Chinese volunteers. A 20 mg single dose of omeprazole (Losec) enteric‐coated capsules or tablets was orally administered to 656 healthy subjects from eight subcenters. The polymorphic alleles of CYP2C19*2, *3, and *17 were determined by Sanger sequencing and Agena mass array. Plasma concentrations of omeprazole were determined by high‐performance liquid‐chromatography tandem mass spectrometry. PK parameters of area under the concentration versus time curve (AUC)0‐t, AUC from zero to infinity (AUC0‐∞), maximum plasma concentration (Cmax), and terminal half‐life (t1/2) were significantly influenced by CYP2C19 phenotype (all p < 0.001) and diplotype (all p < 0.001), and the same results were obtained in the subgroup analysis of the effects of diet and dosage form. The polymorphisms of CYP2C19*2(rs4244285; all PK parameters p < 0.001) and *3(rs4986893; p Cmax = 0.020, and the p values of other PK parameters were less than 0.001) were significantly associated with the PKs of omeprazole. For CYP2C19*17 (rs12248560), only t1/2 showed a significant correlation (p = 0.032), whereas other PK parameters did not. The present study demonstrated that the Pks of omeprazole is greatly influenced by CYP2C19.

Effect of Sijunzi Pills on Pharmacokinetics of Omeprazole in Beagle Dogs by HPLC-UV: A Herb-Drug Interaction Study.

A sensitive high-performance liquid chromatography (HPLC-UV) method for determination of omeprazole in beagle dog plasma was developed and to investigate the effect of Sijunzi pills (SJZPs) on the pharmacokinetics of omeprazole in beagle dogs. The beagle dog plasma was extracted with ethyl acetate and n-hexane under alkaline conditions. Omeprazole and internal standard (IS, fluconazole) were separated on an XDB-C18 column, and acetonitrile and 0.1% trifluoroacetic acid were used as the mobile phase. Omeprazole and IS were detected by using a diode array detector. This experiment adopts the experimental design of double-cycle self-control. In the first cycle (group A), six beagle dogs were given omeprazole 0.67 mg/kg orally in a single dose. In the second period (group B), the same six beagle dogs were orally given SJZPs 0.2 g/kg twice a day for 7 consecutive days, and then, omeprazole was orally given. At the different time points after omeprazole was given in the two periods, the blood samples were collected. The concentration of omeprazole was detected by the developed HPLC method. DAS 2.0 was used to calculate the pharmacokinetic parameters of omeprazole. Under the current experimental conditions, this UPLC method showed good linearity in the detection of omeprazole. Interday and intraday precision did not exceed 10%, and the range of accuracy values were from −1.43% to 2.76%. The results of extraction recovery and stability met the requirements of FDA approval guidelines of bioanalytical method validation. The Cmax of omeprazole in group B was 61.55% higher than that in group A, and the AUC(0−t) and AUC(0−∞) of omeprazole in group B were 63.96% and 63.65% higher those that in group A, respectively. At the same time, the clearance (CL) and apparent volume of distribution (Vd) decreased in group B. In this study, an HPLC method for the determination of plasma omeprazole concentration was established. SJZPs could inhibit the metabolism of omeprazole and increase the concentration of omeprazole in beagle dogs. It is suggested that when SJZPs are combined with omeprazole, attention should be paid to the herb-drug interactions and possible adverse reactions.

Comparison of Outcomes in Patients with Obesity Between Two Administration Routes of Omeprazole After Laparoscopic Sleeve Gastrectomy: An Open-Label Randomized Clinical Trial

BackgroundThe effect of different administration routes of omeprazole remains unclear on the recovery in patients with obesity after laparoscopic sleeve gastrectomy (LSG).MethodsWe designed a randomized clinical trial enrolling 120 patients with a BMI≥32.5 kg/m2 after LSG. They were randomized into two groups to be administered with omeprazole by rapid intravenous injection (group A) or by continuous micropump infusion (group B). The plasma concentration of omeprazole was monitored upon initiating administration. Change in intragastric pH and gastrointestinal symptoms during follow-up served as indicators for therapeutic evaluation.ResultsPatients in the two groups showed no difference in the AUC curves (P=0.25), but group A had significantly higher peak concentration (P<0.001), and shorter time to reach peak concentration after administration (P<0.001), compared to group B. Before and after the administration of omeprazole, the average change in intragastric pH was much lower in group A (0.031 ± 0.61) than in group B (0.48 ± 0.74) (P=0.004). The incidence of gastrointestinal symptoms was similar between the two groups (P=0.85); however, the average duration of remaining symptoms was longer in group A (3.97 months; 95% CI, 2.90–5.04) than in group B (2.82 months; 95% CI, 2.01–3.63) (P=0.04).ConclusionContinuous micropump infusion of omeprazole may improve the outcomes in patients with obesity after LSG.Trial registrationChina Clinical Trial Registration Center (ChiCTR), ChiCTR-IPR-17013365. Registered 13 November 2017. http://www.chictr.org.cn/showproj.aspx?proj=22892.

Pharmacokinetic and pharmacodynamic effects of 2 registered omeprazole preparations and varying dose rates in horses.

BackgroundOmeprazole preparations vary in bioavailability in horses.Hypothesis/ObjectivesTo characterize the pharmacokinetics and pharmacodynamics of an existing enteric‐coated oral omeprazole paste (REF) and a novel, in‐feed, enteric‐coated dry granule preparation (NOV).AnimalsTwelve Standardbred/Thoroughbred mares free from clinical disease.MethodsA prospective, blinded randomized interventional study was trial, conducted in 3 parts: (a) bioavailability study, (b) dose titration study, and (c) comparative clinical pharmacodynamic study, each using a blocked crossover design.ResultsConsistent with the larger dose administered, Cmax (median, 1032 ng/mL; range, 576‐1766) and AUC0‐24 (median, 63.9 μg/mL*min; range, 42.4‐152.4) were greater after single oral administration of NOV than REF (282.7 ng/mL; range, 94.8‐390.2, and 319 23.8 μg/mL*min; range, 8.2‐42.3, respectively; both P = .004). No differences were observed between products for absolute oral bioavailability (NOV 55% range, 15‐88; REF 17% range, 10‐77; P = .25). Treatment with both preparations was associated with reduced gastric squamous ulcer scores and increased pH of gastric fluid. Bioequivalence was demonstrated for pharmacodynamic measures with the exception of % time pH <4, despite differences in dose rate and subsequent plasma omeprazole concentrations.Conclusions and Clinical ImportanceThe findings of this study indicate that the NOV product would be a suitable alternative to the reference product, and confirm that plasma concentrations of omeprazole and omeprazole dose do not predict drug pharmacodynamics in horses.

Has the Time Come to Employ Population and Individual Bioequivalence for the Evaluation of Generics?

Bioequivalence studies are a vital part of drug development. The average bioequivalence approach is the standard method of assessment to conclude whether the generic product is bioequivalent to the innovator product. Of late, debates are on whether the average bioequivalence approach adequately addresses drug interchangeability as it considers only population mean for the evaluation especially when highly variable drug products and narrow therapeutic index drugs are dealt with. Hence, the alternative approaches like population bioequivalence and individual bioequivalence assessment approaches emerge as they consider inter/intra-subject variance and subject- by-formulation variance along with population mean. The objective of the study was to apply different bioequivalence assessment approaches in a replicate bioequivalence study to evaluate the drug interchangeability. This was an open-label, single-dose, randomized, balanced, two-treatment, three-period, three-sequence, partial replicate crossover bioequivalence study of omeprazole enteric-coated tablet 20 mg conducted on 48 normal healthy subjects under fed conditions. The plasma concentration of omeprazole was analyzed by a validated bioanalytical method to determine the pharmacokinetic and statistical parameters to assess average bioequivalence, population bioequivalence, and individual bioequivalence. In this study, test formulation was shown to be bio-inequivalent to the reference formulation by average bioequivalence, population bioequivalence, and individual bioequivalence approaches. The outcome of the evaluation clearly states that the bioequivalence outcome of all these approaches are the same. Obviously, it does not mean that these three approaches provide the same outcome though the consideration of variances varies. Certainly, population bioequivalence and individual bioequivalence approach will be more accurate for the assessment of drug interchangeability.

Pharmacokinetics of omeprazole in rats with dextran sulfate sodium–induced ulcerative colitis

Omeprazole is a commonly used drug in patients with ulcerative colitis (UC). This study investigated the pharmacokinetics of omeprazole in rats with UC induced by dextran sulfate sodium (DSS). The pharmacokinetics of intravenously administered omeprazole (20 mg/kg) was investigated in normal and UC rats using LC-MS/MS. The formation of 5-OH omeprazole, a main metabolite of omeprazole, in rat liver microsomes (RLMs) from normal and UC rats was compared. The protein levels of CYP1A2, CYP2D1, and CYP3A1 in the liver were measured by Western blot. Compared with normal rats, UC rats had increased plasma concentrations of omeprazole, resulting in an increased AUC0–240 min and decreased CL. DSS treatment decreased the formation rate of 5-OH omeprazole in RLMs but did not change the affinity of the enzymes. The Vmax and CLint of RLMs from UC rats were 62% and 48% those of RLMs from normal rats, respectively. The hepatic CYP1A2 and CYP3A1 protein levels in UC rats were 42.6 and 45.2% lower than those in normal rats, respectively; however, the protein levels of CYP2D1 in the two groups were similar. The activity and expression of some hepatic CYP450 isoforms were decreased by UC, leading to changes in the pharmacokinetics of omeprazole.

Pharmacokinetic and pharmacodynamic effects of two omeprazole formulations on stomach pH and gastric ulcer scores.

Limited data are available on the relative pharmacokinetics and pharmacodynamics of different omeprazole formulations. To compare pharmacokinetic and pharmacodynamic effects of a novel omeprazole formulation against a currently registered product. Masked 2 period, 2 treatment crossover. Twelve clinically healthy horses were studied over two 6-day treatment periods. Horses were randomly assigned to receive a novel omeprazole paste (Ulcershield: ULS) or a currently registered reference omeprazole product (OMO). Gastric pH was measured continuously for 10 h on the day prior to commencing treatment (Day -1) and after 6 days of oral treatment (Day 5) using in situ antimony pH probes within an indwelling nasogastric tube. Plasma pharmacokinetics were determined on Days 0 and 6. Treatment significantly (P<0.005) increased gastric pH on Day 5, compared to results obtained prior to treatment (Day -1) and there was no significant difference between products (P = 0.773). Similarly, comparison of median hourly gastric pH (P = 0.593), mean gastric pH (P = 0.154), percentage time pH<4 (P = 0.259) and area under the time-gastric pH response curve (P = 0.734) did not discriminate between products. Both treatments resulted in significantly lower gastric ulcer severity scores (both P = 0.004), with no difference between treatments (P = 0.688). Comparison of mean log area under time-plasma concentration curves demonstrated that, although the lower limit of the 90% confidence interval was within the -20% limit for bioequivalence, the upper limit was exceeded, suggesting that the test product could have greater bioavailability than the reference product. The small sample size, large interhorse plasma omeprazole concentrations, and low bioavailability of omeprazole impacted the sensitivity of the bioequivalence analysis. ULS matched or slightly exceeded OMO plasma concentrations. Both products resulted in equivalent increases in gastric pH, gastric pH profiles and decrease in gastric ulcer scores. Thus, ULS was pharmacodynamically equivalent to OMO and was associated with an equivalent beneficial effect on gastric squamous mucosal ulceration.

Effects of CYP2C19 Genetic Polymorphisms on PK/PD Responses of Omeprazole in Korean Healthy Volunteers.

The aim of this study was to examine the effects of CYP2C19*2 and *3 genetic polymorphisms on omeprazole pharmacokinetic (PK) and pharmacodynamic (PD) responses. Twenty-four healthy Korean volunteers were enrolled and given 20 mg omeprazole orally once daily for 8 days. The genotypes of CYP2C19 single nucleotide polymorphisms (SNPs) (*2, *3, and *17) were screened. The plasma concentrations of omeprazole, omeprazole sulfone, and 5-hydroxy (5-OH) omeprazole were determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The noncompartmental method was used for the determination of PK parameters. Change of mean pH and proportion (%) of time of gastric pH above 4.0 were estimated. The poor metabolizer (PM) group had the lowest metabolic ratio and exhibited the highest area under the curve (AUC) for omeprazole among the CYP2C19 phenotype groups. The PM group showed the greatest change of mean pH and the highest % time of gastric pH above 4.0. The relationship between AUC of omeprazole and % time of gastric pH above 4.0 was confirmed. The study demonstrates that CYP2C19*2 and *3 influence the PKs and PDs of omeprazole in Korean healthy volunteers. Clinical trial registry at the U.S. National Institutes of Health (https://clinicaltrials.gov), number NCT02299687.

The effects of dose and diet on the pharmacokinetics of omeprazole in the horse.

This study aimed to investigate the effect of diet and dose on the pharmacokinetics of omeprazole in the horse. Six horses received two doses (1 and 4mg/kg) of omeprazole orally once daily for 5days. Each dose was evaluated during feeding either a high-grain/low-fibre (HG/LF) diet or an adlibitum hay (HAY) diet in a four-way crossover design. Plasma samples were collected for pharmacokinetic analysis on days 1 and 5. Plasma omeprazole concentrations were determined by ultra-high pressure liquid chromatography-mass spectrometry. In horses being fed the HG/LF diet, on day 1, the area under the curve (AUC) and maximal plasma concentration (Cmax ) were higher on the 4mg/kg dose than on the 1mg/kg dose. The AUC was higher on day 5 compared to day 1 with the 4mg/kg dose on the HG/LF diet. On days 1 and 5, the AUC and Cmax were higher in horses being fed the HG/LF diet and receiving the 4mg/kg dose than in horses being fed the HAY diet and receiving the 1mg/kg dose. These findings suggest that both dose and diet may affect pharmacokinetic variables of omeprazole in the horse.

Evaluation of predictive CYP2C19 genotyping assays relative to measured phenotype in a South African cohort.

To align predicted and measured CYP2C19 phenotype in a South African cohort. Genotyping of CYP2C19*2, *3, *9, *15, *17, *27 and *28 was performed using PCR-RFLP, and an activity score (AS) system was used to predict phenotype. True phenotype was measured using plasma concentrations of omeprazole and its metabolite 5'-hydroxyomperazole. Partial genotype-phenotype discrepancies were reported, and an adapted AS system was developed, which showed a marked improvement in phenotype prediction. Results highlight the need for a more comprehensive CYP2C19 genotyping approach to improve prediction of omeprazole metabolism. Evidence for the utility of a CYP2C19 AS system is provided, for which the accuracy can be further improved by means of comprehensive genotyping and substrate-specific modification.

Pharmacokinetics and bioequivalence testing of five commercial formulations of omeprazole in the horse.

Omeprazole is widely used in the treatment of equine gastric ulcer syndrome. To date, little is known about the relative pharmacokinetics of the different formulations making comparisons between products difficult. The objectives of the study were to investigate the relative pharmacokinetics of five commercially available formulations of omeprazole in the horse and to test for bioequivalence of four of the formulations using one of the formulations as a reference standard. Twelve mature Thoroughbred horses were fasted for 16 h then administered 2 g of each formulation in a cross-over design. Serial blood samples were collected and plasma omeprazole concentration was determined by ultra high-performance liquid chromatography-mass spectrometry (UHPLC-MS). No significant differences were present between three of the formulations and the reference formulation, while the fourth formulation had a lower Cmax and longer Tmax than the reference formulation. Bioequivalence against the reference formulation could not be demonstrated for any of the formulations tested. The findings of the study suggested that the method of protection utilised by different formulations of omeprazole (enteric-coated granules vs. buffering) does not significantly alter the pharmacokinetics of the drug. Further work to establish bioequivalence is needed before direct comparisons can be drawn between different formulations.

The effect of feeding on the pharmacokinetic variables of two commercially available formulations of omeprazole

The objectives of this study were to investigate the impact of formulation (enteric coated and buffered) and feeding on pharmacokinetic variables associated with the oral administration of omeprazole in the horse. Six thoroughbred racehorses were studied in a crossover design. Each received 2 g of an enteric coated or buffered formulation in both the fed and fasted state. Plasma omeprazole concentrations were determined by UHPLC-MS. The effects of feeding or formulation on AUC0-inf_obs, half-life, Tmax or Cmax were not statistically significant. However, a wider-than-expected degree of variation was present and examination of the raw data suggests that an effect of feeding, wherein the bioavailability of omeprazole may be reduced in the fed animal, may be present. Further investigation in a larger population of animals to assess the factors that contribute to the wide degree of absorption observed is warranted.

Evaluation of the effect of orally administered acid suppressants on intragastric pH in cats.

BackgroundAcid suppressant drugs are a mainstay of treatment for cats with gastrointestinal erosion and ulceration. However, clinical studies have not been performed to compare the efficacy of commonly PO administered acid suppressants in cats.Hypothesis/ObjectivesTo compare the effect of PO administered famotidine, fractionated omeprazole tablet (fOT), and omeprazole reformulated paste (ORP) on intragastric pH in cats. We hypothesized that both omeprazole formulations would be superior to famotidine and placebo.AnimalsSix healthy adult DSH colony cats.MethodsUtilizing a randomized, 4‐way crossover design, cats received 0.88–1.26 mg/kg PO q12h fOT, ORP, famotidine, and placebo (lactose capsules). Intragastric pH monitoring was used to continuously record intragastric pH for 96 hours beginning on day 4 of treatment. Plasma omeprazole concentrations at steady state (day 7) were determined by high performance liquid chromatography (HPLC) with ultraviolet detection. Mean percentage time that intragastric pH was ≥3 and ≥4 were compared among groups using ANOVA with a posthoc Tukey‐Kramer test (α = 0.05).ResultsThe mean percentage time ± SD that intragastric pH was ≥3 was 68.4 ± 35.0% for fOT, 73.9 ± 23.2% for ORP, 42.8 ± 18.6% for famotidine, and 16.0 ± 14.2% for placebo. Mean ± SD plasma omeprazole concentrations were similar in cats receiving fOT compared to those receiving ORP and in a range associated with acid suppression reported in other studies.Conclusions and Clinical ImportanceThese results suggest that both omeprazole formulations provide superior acid suppression in cats compared to famotidine or placebo. Fractionated enteric‐coated OT is an effective acid suppressant despite disruption of the enteric coating.

Pharmacokinetics of intravenous, plain oral and enteric-coated oral omeprazole in the horse.

The objectives were to document the pharmacokinetics of intravenous, enteric-coated oral and plain oral omeprazole in fasted horses and to investigate the impact of feeding on the bioavailability of an enteric-coated omeprazole. Twelve horses received four treatments: intravenous omeprazole (0.5mg/kg) in the fasted state (IV-Fasted), enteric-coated omeprazole (4mg/kg) orally in the fasted state (ECO-Fasted), enteric-coated omeprazole (4mg/kg) orally in the fed state (ECO-Fed) and plain omeprazole (4mg/kg) orally in the fasted state (PL-Fasted). Plasma omeprazole concentrations were determined by UHPLC-MS. Bioavailability was higher (P=0.038) in the ECO-Fasted group (21.5 [9.0-27.7]%) than the PL-Fasted group (10.1 [7.7-13.3]%). Similarly, AUC0-∞ was higher in the ECO-Fasted group than the PL-Fasted group (P=0.027). No significant differences were present between the ECO-Fasted and ECO-Fed groups with regards to bioavailability, Cmax , Tmax or AUC0-∞ . When the half-life data from the oral formulations was pooled, it was longer than that observed in the IV-Fasted group (100 [73-118] min) and 35 [34-39] min, respectively; P<0.0001). Bioavailability of enteric-coated omeprazole was higher than previously reported and feeding had minimal impact. Bioavailability of plain omeprazole was approximately half that of enteric-coated omeprazole. The longer half-life observed following oral administration was consistent with the flip-flop effect and has not previously been described for omeprazole in the horse.

Pharmacokinetics and Bioequivalance of Five Commercially Available Formulations of Omeprazole: A Preliminary Report

Reasons for performing studyThe pharmacokinetics and bioequivalence of different formulations of omeprazole have not been published.ObjectivesTo compare the pharmacokinetics and bioavailability of 4 commercially available formulations of omeprazole to an existing reference formulation.Study designA single dose cross‐over bioequivalence study.MethodsSix adult Thoroughbred horses were used. Two generic buffered formulations (OG and AG), one commercial enteric coated formulation (GZ) and one compounded enteric coated formulation (BO) were compared to the reference buffered formulation (GG). Each formulation was administered at a total dose of 2 g (equivalent to 4 mg/kg bwt for a 500 kg horse) in a cross‐over design. Blood samples were collected at 0, 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210, 240, 300 and 360 min, the plasma was separated and frozen. Plasma omeprazole concentrations were determined by UPLC‐MS. Noncompartmental pharmacokinetic analyses were performed using PK Solver.ResultsThe mean (± s.d.) area‐under‐the‐curve (AUC0‐t/0‐inf_obs) (μg/ml*min), Cmax (μg) and Tmax (min) for each formulation was; OG – 59.4 ± 20.1, 0.37 ± 0.12, 87.5 ± 38.4; AG – 77.3 ± 53.7, 0.34 ± 0.24, 170.0 ± 62.0; GZ – 102.9 ± 51.1, 0.86 ± 0.68, 67.5 ± 29.6; BO – 88.0 ± 37.4, 0.59 ± 0.39, 95.0 ± 47.1; GG – 57.5 ± 35.3, 0.41 ± 0.22, 57.5 ± 19.9.ConclusionsThe results of this study suggest that differences are present between commercially available formulations of omeprazole. Caution should be exercised in extrapolating results of clinical studies from one formulation to another.Ethical animal research: This study was performed under an ethics permit issued by the NSW Department of Primary Industries and in accordance with relevant state laws and legislation. Explicit owner informed consent for participation in this study was not stated. Sources of funding: This study was funded by a grant from the Grayson‐Jockey Club Research Foundation. Competing interests: The manufacturers of Gastrozol (GZ), Abgard (AG) and BOVA (BO) have previously funded research by B.W. Sykes. None of the companies contributed to the present study.

Efficacy of Omeprazole Powder Paste or Enteric‐Coated Formulation in Healing of Gastric Ulcers in Horses

BackgroundGastroGard, an omeprazole powder paste formulation, is considered the standard treatment for gastric ulcers in horses and is highly effective. Gastrozol, an enteric‐coated omeprazole formulation for horses, has recently become available, but efficacy data are controversial and sparse.ObjectivesTo investigate the efficacy of GastroGard and Gastrozol at labeled doses (4 and 1 mg of omeprazole per kg bwt, respectively, PO q24h) in healing of gastric ulcers.Animals40 horses; 9.5 ± 4.6 years; 491 ± 135 kg.MethodsProspective, randomized, blinded study. Horses with an ulcer score ≥1 (Equine Gastric Ulcer Council) were randomly divided into 2 groups and treated for 2 weeks each with GastroGard followed by Gastrozol (A) or vice versa (B). After 2 and 4 weeks, scoring was repeated and compared with baseline. Plasma omeprazole concentrations were measured on the first day of treatment after administration of GastroGard (n = 5) or Gastrozol (n = 5).ResultsCompared with baseline (squamous score (A) 1.65 ± 0.11, (B) 1.98 ± 0.11), ulcer scores at 2 weeks ((A) 0.89 ± 0.11, (B) 1.01 ± 0.11) and 4 weeks ((A) 1.10 ± 0.12, (B) 0.80 ± 0.12) had significantly decreased in both groups (P < .001), independent of treatment (P = .7). Plasma omeprazole concentrations were significantly higher after GastroGard compared with Gastrozol administration (AUCGG = 2856 (1405‐4576) ng/mL × h, AUCGZ = 604 (430‐1609) ng/mL × h; P = .03). The bioavailability for Gastrozol was 1.26 (95% CI 0.56–2.81) times higher than for GastroGard.Conclusions and Clinical ImportanceBoth Gastrozol and GastroGard, combined with appropriate environmental changes, promote healing of gastric ulcers in horses. However, despite enteric coating of Gastrozol, plasma omeprazole concentrations after single labeled doses were significantly higher with GastroGard.

Variation in omeprazole pharmacokinetics in a random Iranian population: a pilot study

Omeprazole is metabolized in the liver mainly by the polymorphic CYP2C19 enzyme. Considerable ethnic differences have been reported in the pharmacokinetics of omeprazole. The present study was conducted to evaluate the pharmacokinetic parameters of omeprazole after a single oral administration to a random Iranian population. Thirty healthy male subjects, aged 24-31 years, weighing 60-98 kg completed the study. Plasma concentrations of omeprazole were measured over a 12 h period after administration of a single oral dose of 20 mg omeprazole. The pharmacokinetic parameters were calculated from the plasma concentration-time profiles. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was used to quantify 5-hydroxyomeprazole. The mean area under the concentration-time curve (AUC) from time zero to infinity (AUC(∞) ) values of omeprazole and the corresponding coefficient of variation (CV%) was 987.3 ng h/ml (65%). In general, most subjects showed a normal distribution. Only one subject showed a very high AUC compared with the corresponding mean AUC level. This subject had the highest half-life and the lowest rate of elimination. The omeprazole metabolic ratio for this subject was 2.9, while for the others it was in the range 0.12-0.56. These results are consistent with previous literature that showed the existence of interindividual variability in omeprazole pharmacokinetics, even within a single ethnic group. Differences in the pharmacokinetics could be due to differences in the genetic make-up of subjects as found in their omeprazole metabolic ratios.

Bioequivalence Assessment of Two Capsule Formulations of Omeprazole in Healthy Volunteers

A randomized, single-dose, crossover study was conducted to assess the bioavailability of two omeprazole (CAS 73590-58-6) capsule formulations, Emilok (test) and a commercially available original preparation (reference), under fasting conditions. A 20 mg dose of each formulation was administered to 36 healthy male volunteers with one-week washout period, 17 blood samples were collected over 12 h, plasma omeprazole concentrations were determined by a locally validated high performance liquid chromatography (HPLC) assay, and omeprazole pharmacokinetic parameters were analyzed by the standard non-compartmental method. Mean +/- SD of Cmax, Tmax, AUC(0 --> t), AUC(0 --> infinity), and t1/2 were 0.41 +/- 0.21 and 0.48 +/- 0.27 microg/ml, 1.98 +/- 1.02 and 1.63 +/- 0.78 h, 0.95 +/- 0.78 and 1.00 +/- 0.90 microg x h/ml, 0.99 +/- 0.81 and 1.04 +/- 0.95 microg x h/ml, and 1.30 +/- 0.64 and 1.14 +/- 0.61 h for the test and reference formulations, respectively. The parametric 90% confidence intervals on mean difference between log-transformed values of the two formulations were within the acceptable bioequivalence range of 80% to 125% for AUC(0 --> t) and AUC(0 --> infinity) (88.63% to 104.98%, and 91.71% to 106.86%, respectively) but not for Cmax (76.27% to 103.63%). ANOVA revealed significant subject's effect for AUC(0 --> t), AUC(0 --> infinity), Cmax, and t1/2 with a ratio of the inter-subject to intra-subject coefficient of variation of 3.66, 3.92, 1.25, and 1.46, respectively. The results confirm the presence of marked individual variations in the pharmacokinetics of omeprazole and indicate that the two formulations are equivalent in relation to the extent but not the rate of absorption.

Omeprazole limited sampling strategies to predict area under the concentration–time curve ratios: implications for cytochrome P450 2C19 and 3A phenotyping

To develop a limited sampling strategy (LSS) to predict area under the concentration-time curve (AUC) ratios of omeprazole (AUC(OPZ)) to its metabolites 5-hydroxyomeprazole (AUC(5OH)) and omeprazole sulfone (AUC(SUL)) as phenotyping parameters for cytochrome P450 (CYP) 2C19 and 3A. Data were obtained from 37 (4 women) Caucasian, Chinese, and Korean healthy adults from three published studies. The AUC(OPZ), AUC(5OH), and AUC(SUL) were calculated via noncompartmental analysis. Observed AUC(OPZ, OBS)/AUC(5OH, OBS) and AUC(OPZ, OBS)/AUC(SUL, OBS) were determined. Plasma concentrations of omeprazole, 5-hydroxyomeprazole, and omeprazole sulfone at 1, 1.5, 2, 3, 4, 6, and 8 h post-dose were used to generate limited sampling strategy (LSS) models to predict AUC(OPZ,PRE)/AUC(5OH,PRE) and AUC(OPZ,PRE/)AUC(SUL,PRE). Bias and precision were assessed via percentage mean prediction error (%MPE) and percentage mean absolute error (%MAE), with acceptable limits being <15%. For CYP2C19, the AUC(OPZ,OBS)/AUC(5OH,OBS) was [mean ± standard deviation (SD)] 2.10 ± 1.63. Five LSS models of AUC(OPZ,PRE)/AUC(5OH,PRE) were generated, but none met the bias or precision criteria. Upon stratification by CYP2C19 genotype and ethnicity, a three-timepoint (at 1, 2, and 4h) LSS model accurately predicted AUC(OPZ)/AUC(5OH) in Caucasian CYP2C19*1/*1 subjects. For CYP3A, AUC(OPZ,OBS)/AUC(SUL,OBS) (mean ± SD) was 1.79 ± 0.67. All LSS models had unacceptable %MAE, even when stratified by CYP2C19 genotype and ethnicity. A LSS model to predict AUC(OPZ)/AUC(5OH), and thus CYP2C19 activity, was generated for Caucasian CYP2C19*1/*1 subjects. However, additional model validation is needed prior to general use. LSS models to predict AUC(OPZ)/AUC(SUL), and thus CYP3A activity, were not possible, even upon stratification by CYP2C19 genotype and ethnicity.