Pharmacokinetic differences between lansoprazole enantiomers in rats

Because limited information is available about potential differences between the pharmacokinetics and pharmacodynamics of the enantiomers of lansoprazole, the enantioselective pharmacokinetics of the compound have been investigated in rats. There was a noticeable difference between the serum levels of the enantiomers of lansoprazole and of their metabolites, 5-hydroxylansoprazole enantiomers, after oral administration of the racemate (50 mg kg(-1)) to rats. Cmax (maximum serum concentration) and AUC (area under the serum concentration-time curve) for (+)-lansoprazole were 5-6 times greater than those for (-)-lansoprazole, whereas for (+)-5-hydroxylansoprazole both values were significantly smaller than those for the (-) enantiomer. CLtot/F values (where CLtot is total clearance and F is the fraction of the dose absorbed) for (+)-lansoprazole were significantly smaller than those for the (-) enantiomer. There was no significant difference between the absorption rate constants of the lansoprazole enantiomers in the in-situ absorption study. The in-vitro protein-binding study showed that binding of (+)-lansoprazole to rat serum proteins was significantly greater than for the (-) enantiomer. The in-vitro metabolic study showed that the mean metabolic ratio (45.9%) for (-)-lansoprazole was significantly greater than that (19.8%) for the (+) enantiomer in rat liver microsomes at 5.6 microM lansoprazole. These results show that the enantioselective disposition of lansoprazole could be a consequence of the enantioselectivity of plasma-protein binding and the hepatic metabolism of the enantiomers.     

In vitro ammonia utilization and urea synthesis by rat liver after portacaval shunt

AIMS: To investigate the transplacental distribution of salbutamol enantiomers after administration of racemate to women prior to Caesarian section. METHODS: Five women about to undergo elective Caesarian section were administered a single 0.25 mg bolus intravenous dose of (R,S)-salbutamol. The time from drug administration to delivery was different for each woman (27-105 min). Maternal and foetal umbilical cord venous blood samples were collected immediately after delivery and the plasma fraction analysed for salbutamol enantiomer concentrations by enantioselective high pressure liquid chromatography. RESULTS: The concentrations (mean +/- s.d.) of the active (R) enantiomer of salbutamol in cord and maternal plasma were 0.46 +/- 0.35 and 0.89 +/- 0.50 ng ml-1, respectively, and the difference was statistically significant (95% confidence interval (CI) of the difference: 0.12-0.74 ng ml-1). The corresponding concentrations of the (S) enantiomer of 0.92 +/- 0.45 and 1.11 +/- 0.67 ng ml-1, respectively, were not significantly different (95% CI of the difference -0.08-0.48 ng ml-1). The ratio of (R):(S) in cord plasma was significantly less than that in maternal plasma (P=0.016). CONCLUSIONS: Transplacental distribution of salbutamol enantiomers at Caesarian section after prior administration of racemate to mothers leads to concentrations in cord plasma that are significantly less for the active (R) enantiomer and not significantly different for the (S) enantiomer than in maternal plasma presumably due to enantioselective placental-foetal metabolism.     

Stereoselective hydrolysis of O-isovaleryl propranolol and its influence on the clearance of propranolol after oral administration

The stereoselective hydrolysis of O-isovaleryl propranolol (isovaleryl-PL) was studied using phosphate and Tris-HCl buffers (pH 7.4), dog plasma, and liver preparations. The 10000g supernatant, microsomes, and cytosol were prepared from the liver homogenate. The hydrolysis rate of isovaleryl-PL was accelerated in the order Tris buffer < plasma = phosphate buffer < 10000g supernatant of liver = liver cytosol < liver microsomes. The high plasma protein binding of the prodrug brought about the extremely slow hydrolysis rate of isovaleryl-PL in plasma. No difference was observed in the hydrolysis rate between the isomers of isovaleryl-PL in buffers. The hydrolysis rate was 2-3 times faster with the (R)-isomer than with the (S)-isomer using racemate in dog plasma and liver preparations. The hydrolysis of each enantiomer was inhibited by the other enantiomer. For hydrolysis in microsomes the Km values of (R)- and (S)-isomers were same, and the Vmax of the (R)-isomer was 3 times greater than that of the (S)-isomer. These data suggested the mutual interaction of (R)- and (S)-isomers during the hydrolysis process and the rapid hydrolysis of isovaleryl-PL in liver after absorption. The AUC of PL enantiomers after oral administration of racemic isovaleryl-PL was about 2 times higher compared to 2 mg/kg equivalent molar dose of racemic PL in beagle dogs, and the corresponding plasma levels were not stereoselective from both PL and prodrug. The amount of (R)-PL absorbed after administration of a 5 mg/kg dose of racemic PL was 2-fold greater than (S)-PL, because of the stereoselective oxidation and glucronidation of (S)-PL.(ABSTRACT TRUNCATED AT 250 WORDS)     

Is the inversion from R- to S-ketoprofen concentration dependent? Investigations in rats in vivo and in vitro

The effects of dose on the pharmacokinetics of ketoprofen (KT) enantiomers were investigated in rats in vivo and in hepatoma cells in continuous culture in vitro following administration of the optically pure enantiomers and the racemate of KT. With the exception of AUC (area under the curve) no pharmacokinetic differences could be found following i.v. administration of various doses of KT enantiomers (2.5, 5 and 10 mg/kg) and of racemic KT (5, 10 and 20 mg/kg) and between single enantiomer and racemate administration in rats in vivo. Independent of the dose administered the fraction inverted was about 66%. In line with the findings in vivo good correlation between incubation concentration and AUC of R- and S-KT was found in the hepatoma cells in vitro. The ratios of AUC(S)/AUC(R) were not significantly affected by concentration after R-KT (2.5-20 micrograms/mL) and racemate incubation (5-40 micrograms/mL) in the concentration ranges investigated. However, unlike in rats in vivo enhanced inversion was observed following racemate as compared to single enantiomer incubation in vitro.     

Enantioselective determination of isradipine in human serum using chiral stationary phase liquid chromatography and gas chromatography with nitrogen selective detection

rac-Isradipine is a dihydropyridine type calcium antagonist. Its calcium entry blocking effect is due primarily to the (+)-(S)-enantiomer. This study describes a sensitive enantioselective method for the determination of isradipine in human serum. Following alkaline extraction into hexane, the enantiomers of isradipine are separated quantitatively by high-performance liquid chromatography on a Chiralcel OJ column at 39 degrees C. The collected fractions were evaporated and assayed using capillary gas chromatography on a HP 50+ column with nitrogen selective detection. Using 2.0 ml of serum, 0.7 nmol/1 (0.26 ng/ml) of each enantiomer could be determined with acceptable precision. The method has successfully been used to measure (+)-(S)- and (-)-(R)-isradipine concentrations in samples from volunteers after intravenous and oral administration of isradipine.     

Stereoselective differences in the vasorelaxing effects of S(+) and R(-) ketamine on rat isolated aorta

BACKGROUND: S(+) ketamine, because of its higher anesthetic potency and lower risk of psychotomimetic reactions, has been suggested to be superior to presently available racemic ketamine. The racemate is a direct vasodilator in vivo, and thus the authors investigated the vasorelaxing effects of ketamine enantiomers on rat aorta. METHODS: Rat isolated aortic rings with and without endothelium were contracted with 3 x 10(-7) M norepinephrine. Then 10(-5) to 3 x 10(-3) M S(+), R(-), or racemic ketamine were added cumulatively. Vascular responses to ketamine were further studied in rings pretreated with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (NNLA), the adenosine triphosphate-sensitive K+ channel antagonist glibenclamide, and the L-type calcium channel blocking agent D888. RESULTS: Ketamine enantiomers and the racemate produced concentration-dependent vasorelaxation. The relaxing effect of S(+) ketamine was significantly weaker compared with R(-) ketamine and the racemate reflected by the half-maximum effective concentration (EC50) values of 11.6 x 10(-4), 4.8 x 10(-4), and 6 x 10(-4) M, respectively. Removal of the endothelium and NNLA or glibenclamide pretreatment did not significantly alter the vasorelaxing effect of ketamine. In contrast, D888 pretreatment significantly shifted the concentration-effect curves of both S(+) and R(-) ketamine rightward (EC50 values of 18.9 x 10(-4) and 8.5 x 10(-4) M, respectively), whereas the difference between the isomers was not affected. CONCLUSIONS: Vasorelaxation by ketamine enantiomers is quantitatively stereoselective: The effect of S(+)ketamine is significantly weaker compared with that of the racemate and R(-) ketamine. This stereoselective difference is not due to nitric oxide release, activation of adenosine triphosphate-sensitive potassium channels, or differential inhibition of L-type calcium channels.     

Stereoselective determination of unchanged and glucuroconjugated eliprodil, a new anti-ischaemic drug, in human plasma and urine by precolumn derivatization and column-switching high-performance liquid chromatography with fluorescence detection

An HPLC method was developed and validated for the determination in human plasma and urine of the enantiomers of eliprodil, (+/-)-alpha-(4-chlorophenyl)-4[(4-fluorophenyl) methyl]piperidine-1-ethanol hydrochloride, a new anti-ischaemic agent administered as a racemate. Both enantiomers are present in human plasma in unchanged and glucuroconjugated form, whereas only the glucuroconjugated form is excreted into urine; as a consequence, such metabolites in human plasma and urine should be submitted to enzymatic deconjugation with beta-glucuronidase (Escherichia coli) before being extracted. The general method involves a liquid-liquid extraction of eliprodil and internal standard from alkalinized plasma or urine with n-hexane, evaporation of the organic phase and derivatization with (S)-(+)-naphthylethyl isocyanate to give carbamate diastereoisomeric derivatives of (S)-(+)- and (R)-(-)-eliprodil and internal standard; after evaporation of the derivatizing mixture and dissolution of the residue in a small volume of phosphate buffer-acetonitrile (60:40, v/v), an aliquot is injected into a column-switching HPLC system. The derivatized sample extract is purified on a precolumn filled with C8-bonded silica material, which is flushed with acetonitrile-water, then diastereoisomers of eliprodil and the internal standard are automatically transferred by the mobile phase to the analytical column. The analytical column is a C8 type, specially deactivated for basic compounds, the mobile phase is 0.025 M phosphate buffer (pH 2.6)-methanol-acetonitrile (42:2:56) at a flow-rate of 1.2 ml min-1 and fluorimetric detector operating at lambda ex = 275 nm and lambda em = 336 nm is used. The retention times, under these conditions, are about 16 and 17 min for (S)-(+)- and (R)-(-)-eliprodil diastereoisomers, respectively, and about 19 min for the first-eluted diastereoisomer of the internal standard. During the analysis time, the precolumn, reset in a different path from that of the analytical column, is back-flushed with different solvents, then re-equilibrated with acetonitrile-water before the next injection. Linearity in plasma, for unchanged eliprodil enantiomers, was assessed in the range 0.15-10 ng ml-1 and for total eliprodil enantiomers (unchanged + conjugated) in the range 0.75-500 ng ml-1; the limit of quantitation (LOQ) is 0.15 ng ml-1 for each unchanged enantiomer and 0.75 ng ml-1 for each total enantiomer. Linearity was also assessed in urine for total (conjugated) eliprodil enantiomers in the range 50-25 000 ng ml-1; the LOQ is 50 ng ml-1 for each enantiomer. The intra- and inter-day precision and accuracy of the method were investigated in plasma and urine and found to be satisfactory for pharmacokinetic studies. The method has been extensively used in pharamcokinetic studies in man treated with a 20-mg dose of eliprodil racemate and some results of this application are reported.     

In vivo pharmacology of MDMA and its enantiomers in rhesus monkeys.

The chiral nature of the MDMA molecule gives rise to two enantiomers, each of which is biologically active. This review attempts to cover the author's research into the in vivo effects of MDMA and its enantiomers, as well as other relevant publications which pertain to this topic. No particular differences between the capacities of racemic MDMA and its enantiomers to maintain behavior were noted, but antagonism of the 5-HT2A receptor produces a parallel rightward shift in the dose-effect function for the S(+)-enantiomer, but insurmountably reduces the reinforcing effects of R(-)-MDMA. Long-term self-administration of MDMA may lead to the development of chronic tolerance to the reinforcing effects of MDMA, but S(+)-MDMA is somewhat less susceptible to this effect than the racemate or the R(-)-enantiomer. Using PET neuroimaging, negligible occupancy at the dopamine transporter (DAT) was observed following administration of R(-)-MDMA, but reasonable DAT interaction was quantified following injection of S(+)-MDMA. The non-human primate studies reviewed herein caution that any results obtained in vivo with the MDMA enantiomers may not be particularly informative with regards to the racemate and vice versa. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The enantiomers of phenprocoumon: pharmacodynamic and pharmacokinetic studies

The pharmacodynamics and pharmacokinetics of the optical enantiomers of phenprocoumon were studied in 5 normal subjects and compared to the racemic mixture. Each subject received a single oral dose of 0.6 mg/kg of racemic, S(-), and R(+) phenprocoumon. S(-) phenprocoumon was 1.6 to 2.6 times as a potent as R(+) phenprocoumon when the area under the effect/time curve was used to quantify the total anticoagulant effect per dose. Comparing the plasma concentrations that elicited the same anticoagulant effect, S(-) phenprocoumon was 1.5 to 2.5 times as potent as R(+) phenprocoumon. The anticoagulant activity of the racemic mixture was between that of the enantiomers. There was no distinct difference in the rate of elimination between the enantiomers. The apparent volume of distribution and the plasma clearance for S(-) phenprocoumon were less than those for R(+) phenprocoumon. When the binding of the enantiomers to human serum albumin was compared, S(-) phenprocoumon was more highly bound than R(+) phenprocoumon. The protein binding of racemic phenprocoumon was between that of the enantiomers. The results show that S(-) phenprocoumon is more potent anticoagulant than R(+) phenprocoumon and that the pharmacokinetic differences between the enantiomers are due mainly to differences in their distribution.     

Comparative repellency of commercial formulations of deet, permethrin and citronellal against the mosquito Aedes aegypti, using a collagen membrane technique compared with human arm tests

The plasma concentrations and urinary excretions of bisoprolol enantiomers in four Japanese male healthy volunteers after a single oral administration of 20 mg of racemic bisoprolol were evaluated. The AUC(infinity) and elimination half-life of (S)-(-)-bisoprolol were slightly larger than those of (R)-(+)-bisoprolol in all subjects. The metabolic clearance of (R)-(+)-bisoprolol was significantly (P < 0.05) larger than that of (S)-(-)-bisoprolol (S/R ratio: 0.79+/-0.03), although the difference was small. In contrast, no stereoselective in vitro protein binding of bisoprolol in human plasma was found. An in vitro metabolic study using recombinant human cytochrome P450 (CYP) isoforms indicated that oxidation of both bisoprolol enantiomers was catalyzed by the two isoforms, CYP2D6 and CYP3A4. CYP2D6 metabolized bisoprolol stereoselectively (R > S), whereas the metabolism of bisoprolol by CYP3A4 was not stereoselective. The S/R ratio of the mean clearance due to renal tubular secretion was 0.68, indicating a moderate degree of stereoselective renal tubular secretion. These findings taken together suggest that the small differences in the pharmacokinetics between (S)-(-)- and (R)-(+)-bisoprolol are mainly due to the stereoselectivity in the intrinsic metabolic clearance by CYP2D6 and renal tubular secretion.     

Stereoselective HPLC bioanalysis of atenolol enantiomers in plasma: application to a comparative human pharmacokinetic study

An enantioselective HPLC bioassay has been developed relying on extraction of (R)- and (S)-atenolol from alkalinized plasma or serum (pH > 12) into dichloromethane containing 5% (v/v) 1-butanol followed by an achiral derivatization of the drug with phosgene leading to (R)- and (S)-oxazolidine-2-one derivatives. Under these conditions there was quantitative conversion of the acetamido group to the corresponding nitrile. These stable derivatives were separated on a (R,R)-diaminocyclohexane-dinitrobenzoyl chiral stationary phase [(R,R)-DACH-DNB] using dichloromethane/methanol 98/2 as mobile phase. Determination limits of 0.5 ng for (R)- and 0.6 ng for (S)-atenolol could be achieved using fluorimetric detection. The assay was applied to a human pharmacokinetic study which was performed in a randomized cross-over, double-blind fashion in 12 healthy volunteers, administering single oral doses of 100 mg (R,S)-, 50 mg (R)-, and 50 mg (S)-atenolol. AUC0-24 and Cmax values of (R)-atenolol were slightly but significant higher than those of (S)-atenolol. The R/S ratios were 1.09 for AUC(R)/AUC(S) and 1.03 for Cmax (R)/Cmax(S) (P < 0.01) respectively after administration of the racemic drug. However, there were no difference between AUC, Cmax, and t1/2 values of each enantiomer, whether they were administered as single enantiomers or in the form of its racemic mixture.     

Pharmacokinetics of pirmenol enantiomers and pharmacodynamics of pirmenol racemate in patients with premature ventricular contractions

The pharmacokinetics and pharmacodynamics of pirmenol were investigated in 12 patients with premature ventricular contractions (PVCs) after oral administration of racemic pirmenol, 100 mg and 200 mg every 12 hours. Holter monitoring was performed and serial blood samples were collected after the seventh doses. Plasma concentrations of pirmenol enantiomer were determined using a stereospecific liquid chromatographic assay. Clearance of total (-)-pirmenol was 20% higher than that of total (+)-pirmenol, and the difference in unbound clearance was 45% between enantiomers. Total pirmenol showed a smaller difference because of stereoselective protein binding, with 25% (100-mg dose) or 27% (200-mg dose) higher fraction unbound for (+)-pirmenol than for (-)-pirmenol. Distribution volume was similar for both enantiomers. Dose-dependent clearance was observed for unbound pirmenol enantiomers, as both enantiomers showed 20% lower unbound clearance at the higher dose. Antiarrhythmic effect (% reduction in PVCs from baseline) was correlated with plasma concentrations of pirmenol using a sigmoid maximum drug effect model, and patients showed a large variability in their antiarrhythmic response to plasma concentrations of pirmenol. The median value for minimum effective plasma concentration of racemic pirmenol was 1.5 micrograms/mL.     

Arterial and pulmonary arterial concentrations of the enantiomers of bupivacaine after epidural injection in elderly patients

Bupivacaine HCl is a 50:50 racemic mixture of the levo [S(-)] and dex [R(+)] enantiomers. The R(+) enantiomer exhibits greater cardiac tissue binding and toxicity. To determine whether the lung exhibits selective uptake of one of the enantiomers of bupivacaine, we measured pulmonary artery and radial artery blood concentrations of the two enantiomers after a lumbar epidural injection of 20 mL of 0.75% bupivacaine in 10 elderly patients undergoing one-stage bilateral total knee arthroplasty. Significantly lower concentrations of R(+) than S(-) were noted in both pulmonary artery and arterial blood. Both enantiomers were absorbed by the lung to a similar extent within the first 5 min after epidural injection (extraction ratio approximately equal to 0.1 or 10%). Mean time of maximal concentration (Tmax) was 6 min. In 3 of the 10 patients, Tmax occurred in 1-3 min. We conclude that the lung absorbs both the R(+) and S(-) enantiomers of bupivacaine to a similar extent after epidural injection and that this is of doubtful clinical significance. This study also suggests that peak concentrations of bupivacaine may occur earlier after epidural injection in certain elderly patients than previously believed. Implications: In the first 5 min after epidural injection, approximately 10% of the local anesthetic bupivacaine was absorbed by the lung. Absorption of the two enantiomers (mirror images) of bupivacaine were similar. Lung absorption of bupivacaine is unlikely to influence local anesthetic toxicity.     

Quantitation of trimipramine enantiomers in human serum by enantioselective high-performance liquid chromatography and mixed-mode disc solid-phase extraction

A sensitive and stereospecific method for the quantitation of trimipramine enantiomers in human serum was developed. The assay involves the use of a novel mixed-mode disc solid-phase extraction for serum sample clean-up prior to HPLC analysis and is also free of interference from the enantiomers of desmethyltrimipramine, 2-hydroxytrimipramine, and 2-hydroxydesmethyltrimipramine, the three major metabolites of trimipramine. Chromatographic resolution of trimipramine enantiomers was performed on a reversed-phase cellulose-based chiral column (Chiralcel OD-R) under isocratic conditions using a mobile phase consisting of 0.3 M aqueous sodium perchlorate-acetonitrile (58:42, v/v) at a flow-rate of 0.5 ml/min. Recoveries for R- and S-trimipramine enantiomers were in the range of 93-96% at 25-185 ng/ml levels. Intra-day and inter-day precisions calculated as R.S.D. were in the ranges of 0.30-8.00% and 1.60-10.20% for both enantiomers, respectively. Intra-day and inter-day accuracies calculated as percent error were in the 0.01-2.10% and 1.00-3.00% ranges for both enantiomers, respectively. Linear calibration curves were in the concentration range 15-250 ng/ml for each enantiomer in serum. The limit of quantification of each enantiomer was 15 ng/ml. The detection limit for each enantiomer in serum using a UV detector set at 210 nm was 10 ng/ml (S/N=2). In addition, separation of the enantiomers of desmethyltrimipramine, 2-hydroxytrimipramine, and 2-hydroxydesmethyltrimipramine were investigated. The desmethyltrimipramine enantiomers could be resolved on the Chiralcel OD-R column under the same chromatographic conditions as the trimipramine enantiomers, but the other two metabolite enantiomers required different mobile phases on the Chiralcel OD-R column to achieve satisfactory resolution with Rs values of 1.00.     

Resolution and quantitation of pentazocine enantiomers in human serum by reversed-phase high-performance liquid chromatography using sulfated beta-cyclodextrin as chiral mobile phase additive and solid-phase extraction

A sensitive and stereospecific HPLC method was developed for the analysis of (-)- and (+)-pentazocine in human serum. The assay involves the use of a phenyl solid-phase extraction column for serum sample clean-up prior to HPLC analysis. Chromatographic resolution of the pentazocine enantiomers was performed on a octadecylsilane column with sulfated-beta-cyclodextrin (S-beta-CD) as the chiral mobile phase additive. The composition of the mobile phase was aqueous 10 mM potassium dihydrogenphosphate buffer pH 5.8 (adjusted with phosphoric acid)-absolute ethanol (80:20, v/v) containing 10 mM S-beta-CD at a flow-rate of 0.7 ml/min. Recoveries of (-)- and (+)-pentazocine were in the range of 91-93%. Linear calibration curves were obtained in the 20-400 ng/ml range for each enantiomer in serum. The detection limit based on S/N=3 was 15 ng/ml for each pentazocine enantiomer in serum with UV detection at 220 nm. The limit of quantitation for each enantiomer was 20 ng/ml. Precision calculated as R.S.D. and accuracy calculated as error were in the range 0.9-7.0% and 1.2-6.2%, respectively, for the (-)-enantiomer and 0.8- 7.6% and 1.2-4.6%, respectively, for the (+)-enantiomer (n=3).     

Dose proportionality and comparison of single and multiple dose pharmacokinetics of fexofenadine (MDL 16455) and its enantiomers in healthy male volunteers

The pharmacokinetics and dose proportionality of fexofenadine, a new non-sedating antihistamine, and its enantiomers were characterized after single and multiple-dose administration of its hydrochloride salt. A total of 24 healthy male volunteers (31 +/- 8 years) received oral doses of 20, 60, 120 and 240 mg fexofenadine HCl in a randomized, complete four-period cross-over design. Subjects received a single oral dose on day 1, and multiple oral doses every 12 h on day 3 through the morning on day 7. Treatments were separated by a 14-day washout period. Serial blood and urine samples were collected for up to 48 h following the first and last doses of fexofenadine HCl. Fexofenadine and its R(+) and S(-) enantiomers were analysed in plasma and urine by validated HPLC methods. Fexofenadine pharmacokinetics were linear across the 20-120 mg dose range, but a small disproportionate increase in area under the plasma concentration-time curve (AUC) (< 25%) was observed following the 240 mg dose. Single-dose pharmacokinetics of fexofenadine were predictive of steady-state pharmacokinetics. Urinary elimination of fexofenadine played a minor role (10%) in the disposition of this drug. A 63:37 steady-state ratio of R(+) and S(-) fexofenadine was observed in plasma. This ratio was essentially constant across time and dose. R(+) and S(-) fexofenadine were eliminated into urine in equal rates and quantities. All doses of fexofenadine HCl were well tolerated after single and multiple-dose administration.     

Enantioseparation of beta-blockers labelled with a chiral fluorescent reagent, R (-)-DBD-PyNCS, by reversed-phase liquid chromatography

A fluorescent chiral tagging reagent, 4-(3-isothiocyanatopyrrolidin-1-yl)-7-(N,N-dimethylaminosulfony l)-2,1, 3-benzoxadiazole [R(-)-DBD-PyNCS], has been used for the liquid chromatographic resolution of racemic pairs of beta-blockers. The reagents reacts with beta-blockers at 65 degrees C for 90 min in aqueous acetonitrile containing 0.05% triethylamine to produce the corresponding pair of diastereomers. No racemization occurs during the tagging reaction under these conditions. From results of the time-course study of oxprenolol the reactivities of the enantiomers of beta-blockers with R(-)-DBD-PyNCS are comparable. The optimum excitation and emission wavelengths of the resulting derivatives were ca. 460 and 550 nm, respectively. The derivatives of beta-blockers were efficiently resolved by a reversed-phase column with water-acetonitrile containing 0.1% trifluoroacetic acid as the eluent. The resolution (Rs) values of the diastereomers derived from 10 beta-blockers were in the range of 1.54-4.80. The Rs value for timolol was 0.643. The detection limits (signal-to-noise ratio of 2) were one or two orders of magnitude lower with beta-blockers having the iso-propylamino structure (15-300 fmol) than with those having the tert-butylamino structure (1.25-8.00 pmol). The proposed procedure was applied to the determination of R(+)- and S(-)-propranolol in rat plasma and saliva after oral administration of R(+)-propranolol hydrochloride or S(-)-propranolol hydrochloride.     

Effect of first-pass metabolism on enantioselective pharmacokinetics after oral administration of (+)-, (-)- and racemic homochlorcyclizine to rats

The enantioselective relationship between the pharmacokinetics and hepatic metabolism of homochlorcyclizine hydrochloride (HCZ) was investigated using rats. There were no significant differences in blood concentrations between the three forms after intravenous administration (5 mg/kg) of (+)-, (-)- and racemic HCZ. On the other hand, there were significant differences in the pharmacokinetics between (-)- and (+)-HCZ and between (-)- and racemic HCZ after oral administration (50 mg/kg) of these three forms. The Cmax and AUC0-infinity of (-)-HCZ were lower than those of (+)-isomer and racemate, and its CLo was clearly higher than the others. The (+)-isomer and racemate showed no significant differences in their pharmacokinetic parameters. At a lower dose (10 mg/kg), however, no enantiomeric differences were found in the pharmacokinetic parameters of (+)- and (-)-HCZ. Also examined was the cytochrome p-450-dependent-oxidative metabolism of (+)-, (-)- and racemic HCZ in vitro using rat liver 9000 x g supernatant fraction. The in vitro metabolism of (-)-HCZ was extremely fast, compared with those of the (+)-isomer and the racemate. The Vmax in vitro showed a good correlation with the CLo in vivo after oral administration (50 mg/kg) of all three forms of HCZ. In vitro study of enantiomeric inhibition of the metabolism showed that (+)-HCZ was a competitive inhibitor of (-)-HCZ metabolism, with a Ki of 6.96 microM. (-)-HCZ was also a competitive inhibitor of (+)-HCZ metabolism, with a Ki of 20.4 microM.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vivo studies on chiral inversion and amino acid conjugation of 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid in rats and dogs

The relationship between chiral inversion and stereoselective amino acid conjugation of a new nonsteroidal anti-inflammatory agent, R, S-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid (R,S-MTPPA) was investigated in rats and dogs. Only the S-enantiomer was found in plasma after oral administration of S-MTPPA to both species. In contrast, the R- and S-enantiomers were both detected after the dosing of R-MTPPA. In rats, the area under the curve of S-MTPPA in plasma was only 9% of that of R-MTPPA when R-MTPPA was dosed, whereas in dogs it was 2.5 times larger than that of the R-enantiomer. After administration of R-MTPPA, both enantiomers appeared in the urine. In rats, a small amount of S-enantiomer was found in the urine, whereas in the case of dogs the amount of the S-enantiomer was larger than that of the R-enantiomer. It appears that R-MTPPA is chirally inverted to S-MTPPA in both rats and dogs, although the extent of chiral inversion is greater in dogs than in rats. In dogs, the taurine conjugate was detected in plasma, urine and feces as a major metabolite after oral administration of either R- or S-MTPPA. In this case, only S-MTPPA-taurine was detected in the urine after the administration of S-MTPPA, and it was also the main component after administration of R-MTPPA.     

Cardiovascular effects of verapamil enantiomer combinations in conscious dogs

We examined the systemic and coronary hemodynamic effects of five combinations of R- and S-verapamil enantiomers (R/S; 100/0, 90/10, 80/20, 50/50, and 20/80%, respectively) in conscious dogs chronically instrumented for measurement of aortic and LV pressure, +dP/dt, subendocardial segment length, coronary blood flow velocity, and aortic blood flow. Dogs received escalating doses (0.1, 0.2, and 0.4 mg kg(-1)) of each verapamil combination over 2 min at 30 min intervals on different experimental days and peak changes in hemodynamics were recorded 2 min after each dose. All verapamil combinations increased heart rate, mean aortic blood flow, and coronary blood flow velocity and decreased calculated systemic and coronary vascular resistance. Alterations in coronary hemodynamics were most pronounced with 20/80 R/S verapamil. Racemic and 20/80 R/S verapamil decreased mean arterial and left ventricular systolic pressure, in contrast to combinations with greater concentrations of the R enantiomer. Left ventricular function was unchanged during administration of 100/0, 90/10, and 80/20 R/S verapamil. Direct negative inotropic and lusitropic effects occurred with 50/50 and 20/80 R/S verapamil. The high dose of 20/80 R/S verapamil also increased left ventricular end-diastolic pressure and the regional chamber stiffness constant, consistent with diastolic dysfunction. The results indicate that combinations of R- and S-verapamil produce differential hemodynamic and left ventricular functional effects in conscious, unsedated dogs that are dependent on the relative ratio of these enantiomers.