Differential stereoselective pharmacokinetics of pantoprazole,a proton pump inhibitor in extensive and poor metabolizers of pantoprazole—a preliminary study

Pantoprazole (PAN) is a proton pump inhibitor that is administered as a racemic mixture. The pharmacokinetics of PAN enantiomers were investigated in extensive metabolizers (EMs) and apparent poor metabolizers (PMs) of PAN who received a single 40, 60, or 80 mg oral dose of racemic PAN as enteric-coated formulation. In the EMs, the serum concentrations of (−)-PAN were slightly higher than those of (+)-PAN at each dose level. The (+)/(−) ratios for the area under the concentration-time curve (AUC) and the half-life were 0.58–0.89 and 0.62–0.88, respectively. In the PMs, the serum concentrations of both enantiomers were much higher than those in the EMs at each dose level and significant differences in pharmacokinetics of (+)- and (−)-PAN were observed. The half-lives for (+)-PAN were 2.67–3.77 times longer than those for (−)-PAN. The AUCs for (+)-PAN were 2.65–3.45 times greater than those for (−)-PAN. Therefore, the metabolism of (+)-PAN is impaired to a greater extent than (−)-PAN in the PMs, which resulted in the stereoselective disposition of PAN in the PMs. It has been suggested that the EMs and the PMs of PAN could be differentiated by determining the (+)/(−) enantiomer ratio in serum at one time point, possibly 2–6 h after oral dosing, because the (+)/(−) enantiomer ratios in the PMs were opposite those in the EM subjects. Chirality 9:17–21, 1997 © 1997 Wiley-Liss, Inc.     

Pharmacokinetics of ketoprofen enantiomers in monkeys following single and multiple oral administration

Pharmacokinetic studies are reported after single oral administration of 3 mg/kg of stereochemically pure (S)-ketoprofen [(S)-KP] and (R)-ketoprofen [(R)-KP] to three male Cynomolgus monkeys and after repeated administration for 6 months of 3, 15 and 75 mg/kg/day of (S)-KP to both male and female monkeys. A high-performance liquid chromatographic (HPLC) analysis was performed without derivatization of the samples, using a chiral column. The pharmacokinetic parameters for (S)-KP after administration of (S)-KP and for (R)-KP after administration of (R)-KP were, respectively, elimination half-life 2.32 ± 0.36 and 1.64 ± 0.40 h; oral clearance 3.50 ± 0.66 and 7.50 ± 3.20 ml/min/kg; apparent volume of distribution 0.74 ± 0.24 and 1.16 ± 0.76 liter/kg; mean residence time 1.79 ± 0.77 and 1.41 ± 0.65 h; area under the concentration/time curve 14.16 ± 2.93 and 7.31 ± 2.98 μg·h/ml. Forty-nine percent unidirectional bioinversion of (R)-KP to (S)-KP was observed in this species and the pharmacokinetic parameters for the (S)-KP resulting from this inversion were also calculated. In the study of 6-month repeated administration of (S)-KP, linear pharmacokinetic behavior and no evidence of drug accumulation were observed at the three dose levels. © 1994 Wiley-Liss, Inc.     

Reversed-phase HPLC enantioseparation of pantoprazole using a teicoplanin aglycone stationary phase—Determination of the enantiomer elution order using HPLC-CD analyses

A direct HPLC method was developed for the enantioseparation of pantoprazole using macrocyclic glycopeptide-based chiral stationary phases, along with various methods to determine the elution order without isolation of the individual enantiomers. In the preliminary screening, four macrocyclic glycopeptide-based chiral stationary phases containing vancomycin (Chirobiotic V), ristocetin A (Chirobiotic R), teicoplanin (Chirobiotic T), and teicoplanin-aglycone (Chirobiotic TAG) were screened in polar organic and reversed-phase mode. Best results were achieved by using Chirobiotic TAG column and a methanol-water mixture as mobile phase. Further method optimization was performed using a face-centered central composite design to achieve the highest chiral resolution. Optimized parameters, offering baseline separation (resolution = 1.91 ± 0.03) were as follows: Chirobiotic TAG stationary phase, thermostated at 10°C, mobile phase consisting of methanol/20mM ammonium acetate 60:40 v/v, and 0.6 mL/min flow rate. Enantiomer elution order was determined using HPLC hyphenated with circular dichroism (CD) spectroscopy detection. The online CD signals of the separated pantoprazole enantiomers at selected wavelengths were compared with the structurally analogous esomeprazole enantiomer. For further verification, the inline rapid, multiscan CD signals were compared with the quantum chemically calculated CD spectra. Furthermore, docking calculations were used to investigate the enantiorecognition at molecular level. The molecular docking shows that the R-enantiomer binds stronger to the chiral selector than its antipode, which is in accordance with the determined elution order on the column—S- followed by the R-isomer. Thus, combined methods, HPLC-CD and theoretical calculations, are highly efficient in predicting the elution order of enantiomers.     

Influence of the route of administration on the pharmacokinetics of pirprofen enantiomers in the rat

The pharmacokinetics of the enantiomers of the non-steroidal anti-inflammatory drug pirprofen were studied in male Sprague-Dawley rats after oral and intravenous (iv) doses of the racemate. No significant differences were detected between the enantiomers after oral or iv dosing in t_½, Vd, or ∑Xu. However, the R:S area under the plasma concentration (AUC) ratio after oral doses (0.92 ± 0.13) was slightly but significantly lower than after matching iv doses (1.05 ± 0.036). The absolute bioavailability of the active S-enantiomer (78.5%) after oral doses was higher than the inactive R-enantiomer (69.3%). The plasma protein binding of both enantiomers was saturable over a fivefold range of plasma concentrations. At higher plasma concentrations, the S-enantiomer was less bound than the R-enantiomer. In an in vitro experiment using everted rat jejunum, no chiral inversion was discernible. The dependency of the AUC ratio of the enantiomers on the route of administration may be due to stereoselective first-pass metabolism. © 1993 Wiley-Liss, Inc.     

Recent use of proton pump inhibitor-based triple therapies for the eradication of H pylori: a broad data review

Introduction. For the eradication of Helicobacter pylori a 1‐week triple therapy combining proton pump inhibitors with two antibiotics has been recommended as a gold standard therapy. However, a recent broad data review on the efficacy of the different regimens is missing. Therefore, the aim of this study was to systematically review the recent literature. Methods. We undertook a broad data review of the efficacy of nine different 7‐day triple therapies consisting of a proton pump inhibitor (lansoprazole, pantoprazole, omeprazole) in its standard dosage and two antibiotics. Relevant original papers on H. pylori eradication in adults, published in English or German between 1995 and 2000, were identified from MEDLINE searches. Studies were reviewed and selected according to predefined criteria. Results. Our predefined criteria were fulfilled by 79 full paper articles including 112 study arms with 8383 patients on intention‐to‐treat, or 6787 patients on per‐protocol basis, respectively. The mean eradication rates unweighted or weighted by the number of patients in the study arm vary from 71.9% to 83.8% for intention‐to‐treat analysis and from 78.5% to 91.2% for per‐protocol analysis. Conclusions. All nine PPI based triple therapy regimens are very effective in H. pylori eradication. The current literature review underlines that the use of either lansoprazole, omeprazole, or pantoprazole combined with two antibiotics yield similar high eradication rates.     

Direct HPLC separation of enantiomers of pantoprazole and other benzimidazole sulfoxides using cellulose-based chiral stationary phases in reversed-phase mode

A direct, isocratic, and simple reversed-phase HPLC method was described for the separation of enantiomers of the proton pump inhibitor, rac-pantoprazole (PAN) using cellulose-based chiral stationary phases (Chiralcel OD-R and Chiralcel OJ-R). Some structurally related chiral benzimidazole sulfoxides, rac-omeprazole (OME) and raclansoprazole (LAN), were also studied. Chiralcel OJ-R was successful in the resolution of enantiomers of rac-PAN and rac-OME, while Chiralcel OD-R was most suitable for resolving the enantiomers of rac-LAN. Highest enantioselectivity to rac-PAN and rac-OME was achieved on Chiralcel OJ-R by using acetonitrile as an organic modifier, whereas methanol afforded better resolution of rac-LAN on Chiralcel OD-R than acetonitrile. Increases in buffer concentration and column temperature decreased retention and did not improve the resolution of the enantiomers on both columns. Using a mixture of 50 mM sodium perchlorate solution and acetonitrile as a mobile phase at a flow rate of 0.5 ml/min, maximum separation factors of 1.26 and 1.13 were obtained for the enantiomers of rac-PAN and rac-OME using a Chiralcel OJ-R column, while maximum separation factor of 1.16 was obtained for the enantiomers of rac-LAN using a Chiralcel OD-R column. © 1995 Wiley-Liss, Inc.     

Stereoselectivity of biliary excretion of 2-arylpropionates in rats

To examine the stereoselectivity of biliary excretion, the optically pure enantiomers of ketoprofen (KT), ibuprofen (IBU), and flurbiprofen (FLU) were intravenously administered to normal and bile duct-cannulated rats at 10 mg/kg. The recovery of total KT in bile was significantly higher after administration of (S)-KT than after (R)-KT [90.1 ± 3.5% vs 68.8 ± 8.2%, n =3, P < 0.05]. In normal rats the terminal half-life of (R)-KT was significantly shorter than that of (S)-KT after administration of (R)-KT (2.2 ± 0.6 h vs 14.3 ± 4.9 h, n = 3, P < 0.05). The terminal half-life of both enantiomers was significantly shorter in rats with continuous bile drainage as compared to normal rats. No significant differences in pharmacokinetic parameters could be found between both enantiomers in bile duct-cannulated animals. The total amount of IBU in bile was slightly higher after administration of (S)-IBU than after (R)-IBU administration. The percentage of (R)-IBU after (R)-IBU administration, however, was very low [(R)-IBU: 1.5 ± 0.9%, (S)-IBU: 23.4 ± 5.8%]. In normal rats the clearance of (R)-IBU was significantly higher as compared to (S)-IBU. Differences in pharmacokinetic parameters between normal and bile duct-cannulated rats were not statistically significant due to high interindividual variability. The total recovery of FLU, which was excreted in bile to a lower extent than either KT or IBU, also tended to be greater after S-enantiomer administration. Only small amounts of (S)-FLU could be recovered in bile after (R)-FLU administration. The pharmacokinetic parameters did not differ significantly between (R)- and (S)-FLU or between normal and bile duct-cannulated rats due to its low inversion rate and low excretion via bile. © 1993 Wiley-Liss, Inc.     

Chirality and Drugs Used in Psychiatry: Nice to Know or Need to Know?

1. Many drugs used to treat psychiatric disorders contain a chiral center or a center of unsaturation and are marketed as a mixture of the resultant enantiomers or geometric isomers, respectively. These enantiomers or geometric isomers may differ markedly with regard to their pharmacodynamic and/or pharmacokinetic properties.2. Examples of the effects of chiral centers or geometric centers on such properties are given for drugs from the following classes: antidepressants (tricyclics, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, viloxazine, bupropion, trazodone, mianserin, venlaflaxine); benzodiazepines, zoplicone, and antipsychotics.3. As described in this review, there are several notable examples of psychiatric drugs currently available where the individual enantiomers or geometric isomers differ considerably with regard to factors such as effects on amine transport systems, interactions with receptors and metabolizing enzymes, and clearance rates from the body. Indeed, relatively recent developments in analytical and preparative resolution of racemic and geometric drug mixtures and increased interest in developing new drugs which interact with specific targets, which have been described in detail at the molecular level, have resulted in increased emphasis on stereochemistry in drug development.     

Pharmacokinetics of ibuprofen enantiomers in dogs

Inversion of inactive (R)-ibuprofen to active (S)-ibuprofen has been suggested to occur presystemically only. In order to investigate the site of inversion in dogs we administered both enantiomers either intravenously or intraduodenally (10 mg/kg) to adult, male beagle dogs (n = 3) in a crossover design. Plasma, urine, and bile were collected for up to 6 h and analyzed stereospecifically by HPLC, according to a previously published method. Pharmacokinetic parameters were calculated using a linear computer program. Absorption after intraduodenal administration occurred rapidly, resulting in maximum plasma concentrations 0.2 h after giving the enantiomer. Approximately 70% of the (R)-enantiomer (according to AUC) was inverted to the S-enantiomer independent of route of administration. No R-ibuprofen could be detected in plasma after (S)-ibuprofen administration. Mean residence time was found to be 2 to 3 times longer for (S)- than for (R)-ibuprofen. Total systemic clearance from plasma was twice as high for (R)- than for (S)-ibuprofen. There were no differences between plasma clearances after intravenous and intraduodenal administration. Between 8 and 17% of dose was recovered in bile [especially as free and conjugated (S)-ibuprofen] and 3-12% in urine [as (S)-ibuprofen, hydroxy- and carboxyibuprofen, free and conjugated forms]. Small amounts of (R)-ibuprofen were detected in bile after intraduodenal administration of (R)-ibuprofen only (1.8% of dose). In short, the unidirectional inversion of R-ibuprofen appears to occur systemically rather than presystemically in dogs.     

The disposition of venlafaxine enantiomers in dogs, rats, and humans receiving venlafaxine.

A stereospecific high-performance liquid chromatographic (HPLC) method was developed for the quantitation of the enantiomers of venlafaxine, an antidepressant, in dog, rat, and human plasma. The procedure involves derivatization of venlafaxine with the chiral reagent, (+)-S-naproxen chloride, and a postderivatization procedure. The method was linear in the range of 50 to 5,000 ng of each enantiomer per ml of plasma. No interference by endogenous substances or known metabolites of venlafaxine occurred. Studies to characterize the disposition of the enantiomers of venlafaxine were conducted in dog, rat, and human, following oral administration of venlafaxine. The Cmax, area under the curve (AUC) and (S)/(R) concentration ratios of the (R)- and (S)-enantiomers were compared. In rats, the mean plasma ratio of (S)-venlafaxine to that of (R)-venlafaxine over 0.5 to 6.0 h varied from 2.97 to 8.50 with a mean value of 5.51 +/- 2.45. The Cmax, AUC0-infinity, and t 1/2 values of the (R)- and (S)-enantiomers in dogs were not significantly different from one another (P greater than 0.1). The mean ratios [(S)/(R)] of enantiomers of venlafaxine in human over a 2 to 6 h interval ranged from 1.33 to 1.35 with an overall ratio of 1.34 +/- 0.26 (n = 12). These ratios of the enantiomers [(S)/(R)] were not statistically different from unity (P greater than 0.1) indicating that the disposition of venlafaxine enantiomers in humans is not stereoselective and is more similar to that in dogs than that in rats.     

Double-dose, new-generation proton pump inhibitors do not improve Helicobacter pylori eradication rate

BACKGROUND: Up to present, omeprazole plus two antibiotics are used for Helicobacter pylori eradication therapy . Few studies have compared double-dose new-generation, proton pump inhibitors (PPI) with omeprazole. Therefore, we conducted a randomized, prospective study to evaluate differences in H. pylori eradication rates by PPI type. MATERIAL AND METHODS: Between January 2006 and December 2006, 576 consecutive patients with proven H. pylori infection were enrolled prospectively. Four different PPIs [omeprazole 20 mg b.i.d. (old generation), or pantoprazole 40 mg b.i.d., rabeprazole 20 mg b.i.d., or esomeprazole 40 mg b.i.d. (new generation)] were added to clarithromycin (500 mg b.i.d.) and amoxicillin (1 g b.i.d.) for 1 week. RESULTS: By intention-to-treat analysis, no difference was found between the eradication rates of these four PPIs: 64.9% (omeprazole, n = 148), 69.3% (pantoprazole, n = 140), 69.3% (rabeprazole, n = 140), and 72.9% (esomoprazole, n = 148). When eradication rates were analyzed according to whether patients had an ulcer or not on a per-protocol basis, no difference was found between the eradication rates of the four PPIs. However, side-effects were more common in the esomeprazole-based triple therapy group than in the other groups (p < .05). CONCLUSIONS: No convincing evidence was obtained that double-dose new-generation PPIs have better H. pylori eradication rates and tolerability than omeprazole.