Stereoselective features of (R)- and (S)-atenolol: Clinical pharmacological,pharmacokinetic, and radioligand binding studies

In a randomized, double-blind, cross-over study in 12 healthy volunteers, the effects of single oral doses of 100 mg rac-atenolol were compared during exercise to those of equal amounts of the optically pure enantiomers, i.e., 50 mg (R)- and 50 mg (S)-atenolol. The mean rate pressure product decreased with rac-atenolol (?37%; P < 0.01) and half-dosed (S)-atenolol (?35%; P < 0.01) to the same extent, whereas (R)-atenolol caused no effect. Radioligand binding studies in beta-adrenergic receptors of the guinea pig heart yielded a eudismic ratio of 46 for (S)- to (R)-atenolol. The mean AUCs, maximal plasma concentrations, and plasma half-lives of the enantiomers were similar regardless of whether they were administered as optically pure enantiomers or as racemic mixture. On the other hand, the AUC of (R)-atenolol was 1.08-fold greater (P < 0.01) than that of the (S)-enantiomer. The reason for this finding remains unclear. We conclude that only (S)-atenolol, but not (R)-atenolol, contributes to the beta-blocking effect of currently used rac-atenolol since the same effect can be elicited with the (S)-enantiomer alone. © 1993 Wiley-Liss, Inc.     

Pharmacokinetics of reboxetine enantiomers in the dog

Reboxetine, (RS)-2-[(RS)-α-(2-ethoxyphenoxy)benzyl]morpholine methanesulphonate, is a racemic compound and consists of a mixture of the (R,R)- and (S,S)-enantiomers. The pharmacokinetics of reboxetine enantiomers were determined in a crossover study in three male beagle dogs. Each animal received the following oral treatments, separated by 1-week washout period: 10 mg/kg reboxetine, 5 mg/kg (R,R)- and 5 mg/kg (S,S)-. Plasma and urinary levels of the reboxetine enantiomers were monitored up to 48 h post-dosing using an enantiospecific HPLC method with fluorimetric detection (LOQ: 1.1 ng/ml in plasma and 5 ng/ml in urine for each enantiomer). After reboxetine administration mean t_max was about 1 h for both enantiomers. C_max and AUC were about 1.5 times higher for the (R,R)- than for the (S,S)-enantiomer, mean values ± SD being 704 ± 330 and 427 ± 175 ng/ml for C_max and 2,876 ± 1,354 and 1,998 ± 848 ng.h/ml for AUC, respectively. No differences between the (R,R)- and (S,S)-enantiomers were observed in t½ (3.9 h). Total recovery of the two enantiomers in urine was similar, the Ae (0–48 h) being 1.3 ± 0.7 and 1.1 ± 0.7% of the enantiomer dose for the (R,R)- and the (S,S)-enantiomers, respectively. No marked differences in the main plasma pharmacokinetic parameters were found for either enantiomer on administration of the single enantiomers or reboxetine. No chiral inversion was observed after administration of the separate enantiomers, as already observed in humans. Chirality 9:303–306, 1997. © 1997 Wiley-Liss, Inc.     

Preliminary pharmacokinetic study of ibuprofen enantiomers after administration of a new oral formulation (ibuprofen arginine) to healthy male volunteers

The pharmacokinetics of ibuprofen enantiomers were investigated in a crossover study in which seven healthy male volunteers received single oral doses of 800 mg racemic ibuprofen as a soluble granular formulation (sachet) containing L-arginine (designated trade name: Spedifen®), 400 mg (-)R-ibuprofen arginine or 400 mg (+)S-ibuprofen arginine. Plasma levels of both enantiomers were monitored up to 480 minutes after drug intake using an enantioselective analytical method (HPLC with ultraviolet detection) with a quantitation limit of 0.25 mg/l. Substantial inter-subject variability in the evaluated pharmacokinetic parameters was observed in the present study. After (+)S-ibuprofen arginine, the following mean pharmacokinetic parameters ±SD were calculated for (+)S-ibuprofen: t_max 28.6 ± 28.4 min; C_max 36.2 ± 7.7 mg/l; AUC 86.4 ± 14.9 mg · h/l; t½ 105.2 ± 20.4 min. After (-)R-ibuprofen arginine, the following mean pharmacokinetic parameters were calculated for (+)S-ibuprofen and (-)R-ibuprofen, respectively: t_max 90.0 ± 17.3 and 50.5 ± 20.5 min; C_max 9.7 ± 3.0 and 35.3 ± 5.0 mg/l; AUC 47.0 ± 17.2 and 104.7 ± 27.7 mg · h/l; t_½ 148.1 ± 63.6 and 97.7 ± 23.3 min. After racemic ibuprofen arginine, the following mean pharmacokinetic parameters were calculated for (+)S- and (-)R-ibuprofen, respectively: t_max 30.7 ± 29.1 and 22.9 ± 29.8 min.; C_max 29.9 ± 5.6 and 25.6 ± 4.4 mg/l; AUC 105.1 ± 23.0 and 65.3 ± 15.0 mg · h/l; t_½ 136.6 ± 20.7 and 128.6 ± 45.0 min. T_max values of S(+)- and (-)R-ibuprofen after a single dose of 400 mg of each enantiomer did not differ significantly from the corresponding parameters obtained after a single dose of 800 mg of racemic ibuprofen arginine, indicating that the absorption rate of (-)R- and (+)S-ibuprofen is not different when the two enantiomers are administered alone or as a racemic compound. An average of 49.3 ± 9.0% of a dose of the (-)R-ibuprofen arginine was bioinverted into its antipode during the study period (480 minutes post-dosing). The percent bioinversion during the first 30 minutes after (-)R-ibuprofen arginine intake averaged 8.1 ± 3.9%. The mean AUC of (+)S-ibuprofen calculated after 800 mg racemic ibuprofen arginine (105.1 ± 23.0 mg · h/l) was lower than the mean AUC value obtained by summing the AUCs of (+)S-ibuprofen after administration of 400 mg (+)S-ibuprofen arginine and 400 mg (-)R-ibuprofen arginine (133.4 ± 26.6 mg · h/l). In conclusion, the administration of Spedifen® resulted in very rapid absorption of the (+)S-isomer (eutomer) with t_max values much lower than those observed for this isomer when conventional oral solid formulations such as capsules or tablets of racemic ibuprofen are administered. This characteristic is particularly favourable in those conditions in which a very rapid analgesic effect is required. Chirality 9:297–302, 1997. © 1997 Wiley-Liss, Inc.     

Enantioselective Pharmacokinetics of Doxazosin and Pharmacokinetic Interaction Between the Isomers in Rats

In this study, the stereoselective pharmacokinetics of doxazosin enantiomers and their pharmacokinetic interaction were studied in rats. Enantiomer concentrations in plasma were measured using chiral high‐pressure liquid chromatography (HPLC) with fluorescence detection after oral or intravenous administration of (–)‐(R)‐doxazosin 3.0 mg/kg, (+)‐(S)‐doxazosin 3.0 mg/kg, and rac‐doxazosin 6.0 mg/kg. AUC values of (+)‐(S)‐doxazosin were always larger than those of (–)‐(R)‐doxazosin, regardless of oral or intravenous administration. The maximum plasma concentration (C_max) value of (–)‐(R)‐doxazosin after oral administration was significantly higher when given alone (110.5 ± 46.4 ng/mL) versus in racemate (53.2 ± 19.7 ng/mL), whereas the C_max value of (+)‐(S)‐doxazosin did not change significantly. The area under the curve (AUC) and C_max values for (+)‐(S)‐doxazosin after intravenous administration were significantly lower, and its Cl value significantly higher, when given alone versus in racemate. We speculate that (–)‐(R)‐doxazosin increases (+)‐(S)‐doxazosin exposure probably by inhibiting the elimination of (+)‐(S)‐doxazosin, and the enantiomers may be competitively absorbed from the gastrointestinal tract. In conclusion, doxazosin pharmacokinetics are substantially stereospecific and enantiomer–enantiomer interaction occurs after rac‐administration. Chirality 27:738–744, 2015. © 2015 Wiley Periodicals, Inc.     

Evidence of absorption rate dependency of ibuprofen inversion in the rat

Ibuprofen (IB) is a chiral 2-arylpropionic acid derivative used as a nonsteroidal antiinflammatory drug (NSAID). It undergoes substantial R to S chiral inversion in humans and rats. In addition to systemic inversion, presystemic chiral inversion has been suggested for IB in humans but only after administration of formulations with slow absorption rates. In search for a suitable animal model, the absorption rate dependency of the extent of inversion was examined in male Sprague–Dawley rats given 20 mg/kg of racemic IB in aqueous solution (T_max, 0.6 h), suspension (T_max, 1 h) or as sustained release granules (T_max, 2.3 h). In addition, (R)-IB (5 mg/liter) was incubated in the presence of everted rat gut segments in an organ bath at 37°. After sustained release granules, the S:R AUC ratios (7.3 ± 1.5) were significantly higher than suspension (3.6 ± 1.1) and solution (3.5 ± 0.2). Accordingly, AUC_S and AUC_R, as percent of the total AUC (S + R), significantly increased and decreased, respectively, after administration of the sustained released granules as compared with the solution and suspension. A significant positive linear correlation was found between the S:R AUC ratios and the corresponding T_max for (R)-IB (r = 0.82). In vitro, (R)-IB was inverted by everted jejunum (12.2 ± 1.6%), ileum (14.2 ± 2.0%), and colon (4.4 ± 0.6%) segments. IB was also glucuronidated in the presence of the intestinal segments. Therefore, similar to earlier observations made in humans, in the rat, the S:R AUC ratio was positively and significantly correlated with the absorption rate from the dosage form. Rat small intestine was capable of inverting and conjugating (R)-IB. Hence, rat is a suitable model for studying the chiral inversion of IB. © 1994 Wiley-Liss, Inc.     

Enantioselective inhibitory effect of nicardipine on the hepatic clearance of propranolol in man

The influence of a single oral dose of 30 mg nicardipine on the pharmacokinetics of (R)- and (S)-propranolol, given orally as rac-propranolol 80 mg, was studied in 12 healthy volunteers. The plasma concentrations were higher for the (S)-enantiomer than for the (R)-enantiomer. The Cl_o and the Cl′_intr of (S)-propranolol were significantly lower than the Cl_o and Cl′_intr of (R)-propranolol. The unbound fraction of (R)-propranolol was significantly higher than that of (S)-propranolol. Coadministration of nicardipine significantly increased the AUC and C_max and significantly decreased the Cl_o and Cl′_intr for unbound drug of (R)- and (S)-propranolol. These changes were more important for (R)- than for (S)-propranolol. The protein binding was not altered by nicardipine. The enantioselective effect of nicardipine on the metabolic clearance of propranolol appears to be due to an interaction at the level of the metabolizing enzymes. The effect on blood pressure of rac-propranolol was little affected when nicardipine was coadministered with rac-propranolol, and its bradycardic effect was reduced. © 1994 Wiley-Liss, Inc.     

Separation and quantitation of (R)- and (S)-atenolol in human plasma and urine using an alpha 1-AGP column

A method for the determination of (R)- and (S)-atenolol in human plasma and urine is described. The enantiomers of atenolol are extracted into dichloromethane containing 3% heptafluorobutanol followed by acetylation with acetic anhydride at 60 degrees C for 2 h. The acetylated enantiomers were separated on a chiral alpha 1-AGP column. Quantitation was performed using fluorescence detection. A phosphate buffer pH 7.1 (0.01 M phosphate) containing 0.25% (v/v) acetonitrile was used as mobile phase. The described procedure allows the detection of less than 6 ng of each enantiomer in 1 ml plasma. The relative standard deviation is 4.4% at 30 ng/ml of each enantiomer in plasma. The plasma concentration of (R)- and (S)-atenolol did not differ significantly in two subjects who received a single tablet of racemic atenolol. The R/S ratio of atenolol in urine was approximately 1.     

Influence of Dose and Route of Administration on the Enantioselective Pharmacokinetics of TJ0711 Hydrochloride in Rats

The enantioselective pharmacokinetics of TJ0711 hydrochloride were studied in rats given different doses of rac‐TJ0711 hydrochloride via intravenous and oral routes. R‐ and S‐TJ0711 hydrochloride were both rapidly absorbed, and the average AUC_0‐∞ of R‐TJ0711 hydrochloride was greater than that of S‐TJ0711 hydrochloride after intragastric administration, with an R/S AUC ratio 1.11 and 1.35 for 30 and 50 mg/kg dose group, respectively. In contrast, the average AUC_0‐∞ of R‐TJ0711 hydrochloride was smaller than that of S‐TJ0711 hydrochloride after intravenous injection, with an R/S AUC ratio 0.57 and 0.73 for 10 and 20 mg/kg dose group, respectively. R‐TJ0711 hydrochloride plasma half‐lives were shorter than those of S‐TJ0711 hydrochloride for all groups. AUC_0‐4h and C_max between the two enantiomers were significantly different after oral administration of 50 mg/kg dose of the racemate, while no significant differences between the two enantiomers were found for all the pharmacokinetic parameters of the 30 mg/kg dose group. Significant differences between the two enantiomers were detected for nearly all the pharmacokinetic parameters after intravenous administration, except for the V_Z of 20 mg/kg dose group. This study suggests that dose and route of administration will influence the enantioselectivity in the pharmacokinetics of TJ0711 hydrochloride in rats. Chirality 27:53–57, 2015. © 2014 Wiley Periodicals, Inc.     

Determination of nadolol diastereomers in dog plasma using chiral derivatization and reversed-phase high-performance liquid chromatography with fluorescence detection

A stereospecific high-performance liquid chromatographic method has been developed for the determination of four diastereomers of nadolol in plasma. After the nadolol diastereomers were extracted from plasma using an Extrelut-1 solid-phase extraction cartridge, they were derivatized with (R)-(−)-1-(1-naphthyl)ethylisocyanate to form urea derivatives. These derivatives were then separated on a YMC-AM-303 ODS column using water—acetonitrile (60:40, v/v). The calibration curves of (SR)-, (RS)-, (SS)- and (RR)-nadolol were linear over the range 2.5–200 ng/ml, and the correlation coefficient (r) of the curves were higher than 0.9991 for each diastereomer. The limit of quantification was 2.5 ng/ml for each diastereomer in plasma. This method was used for a pharmacokinetic study in four dogs after oral administration of nadolol (1 mg/kg). The plasma concentrations of nadolol diastereomers showed no significant differences in C_max, T_max or AUC values. The assay appears to be readily applicable to the study of diastereoselective nadolol pharmacokinetics in animals and humans.     

Enantioselective disposition of oral amlodipine in healthy volunteers

Plasma concentrations of (R)- and (S)-amlodipine were measured after single oral administrations to 18 healthy volunteers of 20 mg amlodipine racemate. The contribution of the pharmacologically active (S)-enantiomer to the concentrations of total amlodipine (sum of enantiomers) was significantly higher than that of the inactive (R)-enantiomer, with mean values of 47% R to 53% S for the C_max and 41% R to 59% S for the AUC (range between 24% R:76% S and 50% R:50% S). The oral clearance of the active (S)-form was subject to much less intersubject variation (25% CV) than that of the inactive (R)-form (52% CV). (R)-Amlodipine was more rapidly eliminated from plasma than (S)-amlodipine, with mean terminal half-lives of 34.9 h (R) and 49.6 h (S). The terminal half-lives of total amlodipine (mean 44.2 h) were strongly correlated with—and thus highly predictive for—the half-lives of the (S)-enantiomer. It is proposed that the observed enantioselectivity of oral amlodipine is due to differences in the systemic blood clearance of the enantiomers. © 1994 Wiley-Liss, Inc.     

Enantioselectivity in the metabolism of mexiletine by conjugation in female patients with the arrhythmic form of chronic Chagas' heart disease

The phenomenon of enantioselectivity in the metabolism of mexiletine (MEX) conjugation was investigated in eight female patients with the arrhythmic form of chronic Chagas' heart disease treated with racemic mexiletine hydrochloride (two 100 mg capsules every 8 hr). Blood samples were collected up to 24 hr after the administration of the morning dose, with discontinuation of the subsequent doses during the study period. Plasma concentrations of N‐hydroxymexiletine glucuronide were calculated as the difference between the concentrations of unchanged and total (unchanged + conjugated) MEX enantiomers. Total plasma MEX concentrations were analyzed by HPLC after enzymatic hydrolysis with β‐glucuronidase, the formation of diastereomeric derivatives with the chiral reagent N‐acetyl‐l ‐cysteine/o‐phthalaldehyde, and fluorescence detection. The differences in the pharmacokinetic parameters of the enantiomers were evaluated by the paired t‐test. The plasma concentrations of the (+)‐(S)‐MEX did not differ before and after enzymatic hydrolysis. The pharmacokinetic parameters calculated for (−)‐(R)‐N‐hydroxymexiletine glucuronide are presented as means (95% confidence interval): maximum plasma concentration C_max = 194.0 ng · ml⁻¹ (154.3–233.7), time to maximum plasma concentration t_max = 1.4 hr (0.3–2.5), area under the plasma concentration versus time curve AUC^0–24 = 2099.2 ng · h · ml⁻¹ (1585.6–2612.6), elimination half‐life t_1/2β = 12.8 hr (9.9–15.6) and extent of conjugation of 31.6% (24.3–38.9%). The present data indicate stereospecific conjugation of (−)‐(R)‐N‐hydroxymexiletine in the female patients with the arrhythmic form of Chagas' heart disease. Chirality 11:29–32, 1999. © 1999 Wiley‐Liss, Inc.     

Impact of Chiral Bioanalytical Methods on the Bioequivalence of Ibuprofen Products Containing Ibuprofen Lysinate and Ibuprofen Base

The purpose was to assess the impact of the use of a chiral bioanalytical method on the conclusions of a bioequivalence study that compared two ibuprofen suspensions with different rates of absorption. A comparison of the conclusion of bioequivalence between a chiral method and an achiral approach was made. Plasma concentrations of R‐ibuprofen and S‐ibuprofen were determined using a chiral bioanalytical method; bioequivalence was tested for R‐ibuprofen and for S‐ibuprofen separately and for the sum of both enantiomers as an approach for an achiral bioanalytical method. The 90% confidence interval (90% CI) that would have been obtained with an achiral bioanalytical method (90% CI: C_max: 117.69–134.46; AUC₀^t: 104.75–114.45) would have precluded the conclusion of bioequivalence. This conclusion cannot be generalized to the active enantiomer (90% CI: C_max: 103.36–118.38; AUC₀^t: 96.52–103.12), for which bioequivalence can be concluded, and/or the distomer (90% CI: C_max: 132.97–151.33; AUC₀^t: 115.91–135.77) for which a larger difference was observed. Chiral bioanalytical methods should be required when 1) the enantiomers exhibit different pharmacodynamics and 2) the exposure (AUC or C_max) ratio of enantiomers is modified by a difference in the rate of absorption. Furthermore, the bioequivalence conclusion should be based on all enantiomers, since the distomer(s) might not be completely inert, in contrast to what is required in the current regulatory guidelines. In those cases where it is unknown if the ratio between enantiomers is modified by changing the rate of absorption, chiral bioanalytical methods should be employed unless enantiomers exhibit the same pharmacodynamics. Chirality 28:429–433, 2016. © 2016 Wiley Periodicals, Inc.     

MORNING-EVENING ADMINISTRATION TIME DIFFERENCES IN DIGOXIN KINETICS IN HEALTHY YOUNG SUBJECTS

Digoxin, frequently used in the treatment of congestive heart failure, has a very narrow therapeutic index. We studied the differences in digoxin pharmacokinetics when ingested in the morning versus evening. A single digoxin (0.25 mg) dose was given orally to the same group of 10 diurnally active healthy (6 male and 4 female) volunteers in the morning at 08:00 and evening at 20:00 in separate experiments scheduled 2 weeks apart. Blood samples were collected at specific times for 48h after each timed dose; digoxin was determined by radioimmunoassay (RIA). Maximum plasma concentration C_max; T_max, the time to reach C_max; area under plasma concentration curve AUC; and elimination half-time T_1/2 of digoxin were determined. T_max was statistically significantly shorter (54 min) following 08:00 dosing compared to 20:00 dosing (96 min). Although the C_max was higher after morning than evening dosing, it was not significantly so. No other parameter of digoxin pharmacokinetics except T_max exhibited administration time dependency. (Chronobiology International, 18(5), 841–849, 2001)     

Chronopharmacokinetics of Imipenem in the Rat

There are no studies indicating a possible modification of imipenem pharmacokinetics related to the hour (i.e., circadian time) of its administration. The aim of this study was to evaluate the influence of different times of intramuscular imipenem administration on its disposition in Wistar AF EOPS rats. Four groups of eight animals were given a single intramuscular injection of 140 mg/kg of imipenem either at 10∶00, 16∶00, 22∶00, or 04∶00 h. Blood samples were collected 0.5, 1, 2, 3, 4, 6, and 8 h after drug injection, and the main pharmacokinetic parameters determined were C_max, T_max, elimination half‐life (t_1/2), area under the concentration‐versus‐time curve (AUC), total serum clearance (CL/F), and volume of distribution (V/F). Circadian variation of C_max (49%), T_max (92%), and AUC (19%) was observed leading to variability of imipenem exposure. Clearance and volume of distribution were modified according to the circadian time of drug injection but did not reach statistical significance. The results suggest that varying the time of administration induces intra‐individual variability.     

STUDIES ON THE KINETICS OF ACETYLCHOLINESTERASE IN THE RESISIANT AND SUSCEPTIBLE STRAINS OF HOUSEFLY (MUSCA DOMESTICA)

Abstract Acetylcholinesterase (AChE) in the susceptible (S) and the resistant (R) strains of housefly (Musca domestica) was investigated using kinetic analysis. The V_max values of AChE for hydrolyzing acetylthiocholine (ATCh) and butyrylthiocholine (BTCh) were 4578.50 and 1716.08nmol/min/mg* protein in the R strain, and were 1884.75 and 864.72 nmol/min/mg. protein in the Sstrain, respectively. The V_max ratios of R to S enzyme were 2.43 for ATCh and 1.98 for BTCh. The K_m values of AChE for ATCh and BTCh were 0.069 and 0.034 mmol/L in the S strain, and 0.156, 0.059 mmol/L in the R strain, respectively. The K_m ratios of R to S enzyme were 2.26 for ATCh and 1.74 for BTCh. The k_i ratios of S to R enzyme for three insecticides propoxur, methomyl and paraoxon were 46.04, 4.17 and 2. 86, respectively. In addition, k_cat and k_cat/K_m for measuring turnover and catalytic efficiency of AChE were determined using eserine as titrant. The k_cat values of AChE from the R strain for both ATCh and BTCh were higher than those values from the S strain. But the values of k_cat/K_m were in contrary to the k_cat values with R enzyme compared to S enzyme. The AChE catalytic properties and sensitivity to the inhibition by three insecticides in the R and S strains of housefly were discussed based on contribution of V_max, K_m, k_i, k_cat and k_cat/K_m. All these data implied that AChE from the R strain might be qualitatively altered. We also observed an intriguing phenomenon that inhibitors could enhance the activity of AChE from the resistant strain. This “flight reaction” of the powerful enzyme might be correlated with the developing resistance of housefly to organophosphate or carbamate insecticides.     

Stereoselective Degradation of alpha‐Cypermethrin and Its Enantiomers in Rat Liver Microsomes

Alpha‐cypermethrin (α‐CP), [(RS)‐a‐cyano‐3‐phenoxy benzyl (1RS)‐cis‐3‐(2, 2‐dichlorovinyl)‐2, 2‐dimethylcyclopropanecarboxylate], comprises a diastereoisomer pair of cypermethrin, which are (+)‐(1R‐cis‐αS)–CP (insecticidal) and (?)‐(1S‐cis‐αR)–CP (inactive). In this experiment, the stereoselective degradation of α‐CP was investigated in rat liver microsomes by high‐performance liquid chromatography (HPLC) with a cellulose‐tris‐ (3, 5‐dimethylphenylcarbamate)‐based chiral stationary phase. The results revealed that the degradation of (?)‐(1S‐cis‐αR)‐CP was much faster than (+)‐(1R‐cis‐αS)‐CP both in enantiomer monomers and rac‐α‐CP. As for the enzyme kinetic parameters, there were some variances between rac‐α‐CP and the enantiomer monomers. In rac‐α‐CP, the V_max and CL_int of (+)‐(1R‐cis‐αS)–CP (5105.22 ± 326.26 nM/min/mg protein and 189.64 mL/min/mg protein) were about one‐half of those of (?)‐(1S‐cis‐αR)–CP (9308.57 ± 772.24 nM/min/mg protein and 352.19 mL/min/mg protein), while the K_m of the two α‐CP enantiomers were similar. However, in the enantiomer monomers of α‐CP, the V_max and K_m of (+)‐(1R‐cis‐αS) ‐CP were 2‐fold and 5‐fold of (?)‐(1S‐cis‐αR)‐CP, respectively, which showed a significant difference with rac‐α‐CP. The CL_int of (+)‐(1R‐cis‐αS)–CP (140.97 mL/min/mg protein) was still about one‐half of (?)‐(1S‐cis‐αR)–CP (325.72 mL/min/mg protein) in enantiomer monomers. The interaction of enantiomers of α‐CP in rat liver microsomes was researched and the results showed that there were different interactions between the IC₅₀ of (?)‐ to (+)‐(1R‐cis‐αS)‐CP and (+)‐ to (?)‐(1S‐cis‐αR)‐CP(IC_50(?)/(+) / IC_50(+)/(?) = 0.61). Chirality 28:58–64, 2016. © 2015 Wiley Periodicals, Inc.     

Input rate-dependent stereoselective pharmacokinetics: Effect of pulsatile oral input

Computer simulation was used to test the effects of pulsatile oral input on the stereoselectivity in the area under the blood concentration–time curves (AUCs) of the enantiomers of racemic drugs. The effects of input rate determinants, namely, dose, dosage interval, and formulation on the stereoselectivity were investigated under both steady-state and nonsteady-state conditions. Simulations were carried out for drugs undergoing Michaelis–Menten hepatic metabolism with different enantiomeric maximum velocity (V_max) or constant (K_m) values. With pulsatile input, the enantiomeric AUC ratios of both types of drugs were dependent on all the determinants of input rate. However, in most cases, the direction of input rate-dependent changes in the enantiomeric AUC ratios for drugs with different enantiomeric V_max was opposite of that for drugs with different enantiomeric K_m. The direction and magnitude of changes in the enantiomeric AUC ratios were also dependent on the selected dose, dosage interval, and formulation. Further, different conclusions could be reached based on the nonsteady-state and steady-state data. Additional simulations were then performed to test the effects of input rate-dependent stereoselective pharmacokinetics on the bioequivalence of chiral drugs with nonlinear metabolism. These simulations suggested that bioequivalence studies based on the racemic drug measurement may result in erroneous conclusions for the individual enantiomers. The results of this study may be used as a tool for the design of experiments to test the input rate dependence of stereoselective pharmacokinetics and bioequivalence of racemic drugs in animals and humans. © 1994 Wiley-Liss, Inc.     

The effects of (±)-, (+)-, and (−)-atenolol,sotalol, and amosulalol on the rat left atria and portal vein

The effects of (±)-, (+)-, and (?)-atenolol, sotalol, and amosulalol alone on the rat left atria and portal vein and on the respective β₁- and β₂-adrenoceptor-mediated responses to isoprenaline have been determined. (±)-Atenolol at 10^?6 M had no effect whereas high concentrations of (+)- and (?)-sotalol, 10^?5–10^?4 M, and (±)-, (+)-, and (?)-amosulalol depressed the response of the rat left atria to cardiac stimulation which indicates membrane stabilizing activity. None of the drugs tested had any effect alone on the rat portal vein. The order of potency as antagonists was (±)-amosulalol > (±)-atenolol > (±)-sotalol at β₁-adrenoceptors and (±)-amosulalol > (±)-sotalol > (±)-atenolol at β₂-adrenoceptors. (±)-Atenolol and (±)-amosulalol are β₁-selective whereas (±)-sotalol is β₂-selective. For each of the racemic β-blockers, the β₁- and β₂-adrenoceptor blocking activity was predominantly due to the (?)-enantiomer. © 1993 Wiley-Liss, Inc.     

Enantioselective pharmacokinetics of lercanidipine in healthy volunteers

OBJECTIVE: The enantioselective kinetic disposition of lercanidipine, a dihydropyridine type of third-generation calcium antagonist, was investigated in six healthy male volunteers following a single 20 mg racemic oral dose. METHODS: Serial plasma samples were obtained from 0 to 24 h after drug administration. Lercanidipine enantiomers were analysed using a chiral LC-MS-MS method. RESULTS: The following differences (p < 0.05, Wilcoxon test) between (S) and (R) enantiomers were found (median): C(max) 2.071 ng mL(-1) versus 1.681 ng mL(-1); AUC(0-24)12.352 ng h mL(-1) versus 10.063 ng h mL(-1) and Cl/f 732.16 L h(-1) versus 1891.84 L h(-1). The AUC(0-infinity) values for (S)-LER were 1.21-fold higher than those for (R)-LER. CONCLUSION: The pharmacokinetics of LER was enantioselective in healthy volunteers following a single dose of 20 mg of the unlabeled racemic drug.     

Influence of rheumatoid arthritis in the enantioselective disposition of fenoprofen

To investigate the influence of rheumatoid arthritis on the stereoselective disposition of fenoprofen administered as a racemic mixture, eight patients with rheumatoid arthritis receiving calcium rac-fenoprofen (200 mg/8 h) and 7 healthy volunteers given single oral dose (600 mg) were investigated. Serial blood samples and urine were collected from zero to 24 h after fenoprofen (FEN) administration. The following differences were observed between the (+)-(S) and (-)-(R)-FEN in the patients with rheumatoid arthritis (means 95% CI, Wilcoxon test, P < 0.05): C(max) 14.1 (12.5-15.8) versus 3.6 (2.5-4.7) microg/ml; AUC(ss) (0-8) 80.5 (67.3-93.7) versus 12.1 (8.8-15.4) microg.h/ml; Cl(T)/f 1.3 (1.0-1.5) versus 9.1 (6.5-11.8) l/h; and t(1/2) 3.1 (2.3-3.9) versus 1.2 (0.8-1.6) h. The Cl(T)/f of (-)-(R)-FEN was reduced in patients with rheumatoid arthritis when compared to healthy volunteers: 9.1 (6.5-11.8) versus 17.4 (13.9-20.9) l/h; P < 0.05 Mann-Whitney test. The administration of rac-FEN as a single dose to healthy volunteers or multiple doses to patients with rheumatoid arthritis resulted in lower Cl(T)/f for the (+)-(S)-FEN. The lower Cl(T)/f of (-)-(R)-FEN observed for patients with rheumatoid arthritis is consistent with lower clearance by inversion, although other metabolic pathways, drug interactions, and bioavailability of the individual enantiomers may also contribute to the difference.