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.     

Enantioselective 2-hydroxylation of RS-8359, a selective and reversible MAO-A inhibitor, by cytochrome P450 in mouse and rat liver microsomes

RS-8359, (+/-)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]-pyrimidine is a racemic compound with a selective and reversible monoamine oxidase A (MAO-A) inhibition activity. The substrate and product enantioselectivity with respect to 2-hydroxylation of RS-8359 enantiomers was studied using mouse and rat liver microsomes. In mice, the (S)-enantiomer was transformed to the cis-diol metabolite, whereas the (R)-enantiomer to the trans-diol metabolite. The Vmax/Km value for the formation of the cis-diol metabolite from the (S)-enantiomer was sevenfold greater than that for the formation of the trans-diol metabolite from the (R)-enantiomer. The greater Vmax/Km value for the (S)-enantiomer was due to the tenfold smaller Km value compared to that for the (R)-enantiomer. The results were in fair agreement with the previously reported low plasma concentrations of the (S)-enantiomer and the high recovery of the cis-diol metabolite derived from the (S)-enantiomer in urine after oral administration of RS-8359 to mice. Similarly to mice, in rats the (R)-enantiomer was transformed to the trans-diol metabolite, whereas the (S)-enantiomer yielded the cis-diol and trans-diol metabolites. The Vmax/Km value for the (R)-enantiomer was larger than that for the (S)-enantiomer in rats, indicating that the low plasma concentration of the (S)-enantiomer in rats might be caused by a metabolic reaction other than P450-dependent hydroxylation. CYP3A was shown to be responsible for the trans-diol formation from the (R)-enantiomer.     

Enantiomeric analysis of terfenadine in rat plasma by HPLC.

Enantiomeric pairs of the antihistaminic drug terfenadine and its carboxylic acid derivative were directly separated by HPLC using an ovomucoid protein column. Absolute configurations of terfenadine enantiomers were assigned by comparing their circular dichroism spectra with those of 1-phenyl-1-butanol enantiomers of known absolute stereochemistry. Terfenadine and its major carboxylic acid metabolite extracted from blood plasma following an oral administration of a racemic terfenadine to rats were found to be enriched in the (S)- and (R)-enantiomers, respectively. The results indicated that the (R)-enantiomer of an orally administered racemic terfenadine was preferentially oxidized in rats to form a carboxylic acid metabolite enriched in the (R)-enantiomer.     

Stereoselective pharmacokinetics of RS-8359, a selective and reversible MAO-A inhibitor, by species-dependent drug-metabolizing enzymes

RS-8359, (+/-)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]pyrimidine selectively and reversibly inhibits monoamine oxidase A (MAO-A). After oral administration of rac-RS-8359 to rats, mice, dogs, monkeys, and humans, plasma concentrations of the (R)-enantiomer were greatly higher than were those of the (S)-enantiomer in all species studied. The AUC((R)) to AUC((S)) ratios were 2.6 in rats, 3.8 in mice, 31 in dogs, and 238 in monkeys, and the (S)-enantiomer was almost negligible in human plasma. After intravenous administration of RS-8359 enantiomers to rats, the pharmacokinetic parameters showed that the (S)-enantiomer had a 2.7-fold greater total clearance (CL(t)) and a 70% shorter half-life (t(1/2)) than those for the (R)-enantiomer but had no difference in distribution volume (V(d)). No significant difference in the intestinal absorption rate was observed. The principal metabolites were the 2-keto form, possibly produced by aldehyde oxidase, the cis-diol form, and the 2-keto-cis-diol form produced by cytochrome P450 in rats, the cis-diol form in mice, RS-8359 glucuronide in dogs, and the 2-keto form in monkeys and humans. Thus, the rapid disappearance of the (S)-enantiomer from the plasma was thought to be due to the rapid metabolism of the (S)-enantiomer by different drug-metabolizing enzymes, depending on species.     

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.     

Toxicokinetics of a single intravenous dose of rac-propranolol versus optically pure propranolol in the rat

Conscious male Wistar SPF Riv:TOX rats were dosed intravenously with 2.5, 5, or 10 mg/kg rac-propranolol·HCl, or with 5 mg/kg of either (-)-(S)- or (+)-(R)-propranolol·HCl. Disposition of (-)-(S)- and (+)-(R)-propranolol after dosing of rac-propranolol was linear in the dose range examined. Total plasma clearance was not changed in animals dosed with the individual enantiomers compared to the animals that were dosed with rac-propranolol. However, for (-)-(S)-propranolol both volume of distribution and elimination half-life decreased, whereas for (+)-(R)-propranolol increases were observed for these characteristics, in animals dosed with the individual enantiomers. Our observations suggest that the (+)-(R)-enantiomer competes with (-)-(S)-propranolol for plasma protein binding sites, resulting in lower plasma protein binding of the (-)-(S)-enantiomer when the racemate is administered. From recent toxicological experiments, it was concluded that rac-propranolol is more toxic than the individual enantiomers in the rat, when dosed iv at the same total mass. It is concluded that the observed potentiation of toxic effects of propranolol enantiomers when administered as a racemate can at least partly be explained by a pharmacokinetic interaction. © 1995 Wiley-Liss, Inc.     

Influence of endotoxin on the stereoselective pharmacokinetics of oxprenolol,propranolol, and verapamil in the rat

The influence of endotoxin-induced inflammation on the enantioselective pharmacokinetics of propranolol, oxprenolol, and verapamil, which bind to α₁-acid glycoprotein, was studied in the rat. The racemic mixtures were given orally. In the control animals, for propranolol and oxprenolol, the plasma concentrations of the (R)-enantiomer were higher than those of the (S)-enantiomer, while for verapamil the reverse was true. Protein binding and intrinsic clearance are the main factors responsible for this enantioselectivity. After endotoxin treatment, for the three drugs tested the plasma concentrations and the plasma binding of both enantiomers were significantly increased. This effect was more pronounced for (R)-propranolol, (R)-oxprenolol, and (S)-verapamil than for their respective antipodes. The enantioselective effect of endotoxin on the plasma concentrations of the drugs studied seems mainly due to the enantioselective increase in binding to α₁-acid glycoprotein. © 1994 Wiley-Liss, Inc.     

Enantioselective inhibition of TNF-α release by thalidomide and thalidomide-analogues

The question whether the immunomodulating activity of rac-thalidomide resides in either the (−)-(S)- or the (+)-(R)-enantiomer was addressed by synthesis and separation of pure enantiomers of thalidomide-analogues which carry a methyl-group at the asymmetric carbon atom and are thus prevented from racemization. The effect of the pure enantiomers of the thalidomide-analogues and also of the enantiomers of thalidomide on relapse of TNF-α was tested in vitro by using stimulated peripheral mononuclear blood cells. Both enantiomers of thalidomide inhibited the release of TNF-α equally well at low concentrations (5 and 12.5 μg/ml) but at higher concentrations (25 and 50 μg/ml) there was a weak but statistically significant selectivity towards the (−)-(S)-enantiomer. In the case of the configuration-stable thalidomide-analogues there was a very pronounced and statistically significant enantioselectivity towards the (S)-form even at lower concentrations (≥5 μg/ml). The (S)-enantiomers of the thalidomide-analogues differed in their inhibitory potency from (−)-(S)-thalidomide suggesting that the introduction of the methyl-group increases the TNF-α-inhibitory activity while the reduction of one of the carbonyl-functions in the glutarimide-moiety to a methylene-group decreases activity. The effect of these small molecular alterations on activity and the enantioselectivity towards the (S)-enantiomers may indicate that thalidomide and its analogues directly interact with one or several cellular target-proteins. © 1996 Wiley-Liss, Inc.     

The influence of aging on the stereoselective pharmacokinetics of propranolol in the rat.

The influence of aging on the pharmacokinetics and the tissue distribution of (R)- and of (S)-propranolol was studied in 3-, 12-, and 24-month-old rats. After both iv and oral administration of rac-propranolol, the plasma concentrations were higher for the (R)- than for the (S)-enantiomer. For the tissue concentrations, the reverse was true. The free fraction of (S)-propranolol in plasma was about 4 times larger than that of (R)-propranolol, and this is the main factor responsible for the differences in kinetics between the two enantiomers. There was a suggestion for a difference in tissue binding between the two enantiomers. With aging, the plasma and tissue concentrations of both enantiomers increase, probably due to a decrease in blood clearance. Tissue binding did not change much with aging. Notwithstanding the marked differences between the kinetics of the propranolol enantiomers, the changes which occur with aging affect both enantiomers to the same degree.     

Stereoselective disposition of tiaprofenic acid enantiomers in rats

The pharmacokinetics and metabolic chiral inversion of the S(+)‐ and R(−)‐enantiomers of tiaprofenic acid (S‐TIA, R‐TIA) were assessed in vivo in rats, and in addition the biochemistry of inversion was investigated in vitro in rat liver homogenates. Drug enantiomer concentrations in plasma were investigated following administration of S‐TIA and R‐TIA (i.p. 3 and 9 mg/kg) over 24 hr. Plasma concentrations of TIA enantiomers were determined by stereospecific HPLC analysis. After administration of R‐TIA it was found that 1) there was a time delay of peak S‐TIA plasma concentrations, 2) S‐TIA concentrations exceeded R‐TIA concentrations from ∼2 hr after dosing, 3) C_max and AUC_(0‐∞) for S‐TIA were greater than for R‐TIA following administration of S‐TIA, and 4) inversion was bidirectional but favored inversion of R‐TIA to S‐TIA. Bidirectional inversion was also observed when TIA enantiomers were incubated with liver homogenates up to 24 hr. However, the rate of inversion favored transformation of the R‐enantiomer to the S‐enantiomer. In conclusion, stereoselective pharmacokinetics of R‐ and S‐TIA were observed in rats and bidirectional inversion in rat liver homogenates has been demonstrated for the first time. Chiral inversion of TIA may involve metabolic routes different from those associated with inversion of other 2‐arylpropionic acids such as ibuprofen. Chirality 11:103–108, 1999. © 1999 Wiley‐Liss, Inc.     

Click synthesis and biologic evaluation of (R)- and (S)-2-amino-3-[1-(2-[18F]fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid for brain tumor imaging with positron emission tomography

The (R)- and (S)-enantiomers of 2-amino-3-[1-(2-[18F]fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid (4) were synthesized and evaluated in the rat 9L gliosarcoma brain tumor model using cell uptake assays, biodistribution studies, and micro-positron emission tomography (microPET). The (R)- and (S)-enantiomers of [18F]4 were radiolabeled separately using the click reaction in 57% and 51% decay-corrected yields, respectively. (S)-[18F]4 was a substrate for cationic amino acid transport and, to a lesser extent, system L transport in vitro. In vivo biodistribution studies demonstrated that (S)-[18F]4 provided higher tumor uptake and higher tumor to brain ratios (15:1 at the 30- and 60-minute time points) compared to the (R)-enantiomer (7:1 at the 30- and 60-minute time points). MicroPET studies with (S)-[18F]4 confirmed that this tracer provides good target to background ratios for both subcutaneous and intracranial 9L gliosarcoma tumors. Based on these results, the 1H-[1,2,3]triazole-substituted amino acid (S)-[18F]4 has promising PET properties for brain tumors and represents a novel class of radiolabeled amino acids for tumor imaging.     

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.     

Influence of N‐hexane inhalation on the enantioselective pharmacokinetics and metabolism of verapamil in rats

Verapamil (VER) is commercialized as a racemic mixture of the (+)‐(R)‐VER and (?)‐(S)‐VER enantiomers. VER is biotransformed into norverapamil (NOR) and other metabolites through CYP‐dependent pathways. N‐hexane is a solvent that can alter the metabolism of CYP‐dependent drugs. The present study investigated the influence of n‐hexane (nose‐only inhalation exposure chamber at concentrations of 88, 176, and 352 mg/m³) on the kinetic disposition of the (+)‐(R)‐VER, (?)‐(S)‐VER, (R)‐NOR and (S)‐NOR in rats treated with a single dose of racemic VER (10 mg/kg). VER and NOR enantiomers in rat plasma was analyzed by LC‐MS/MS (m/z = 441.3 > 165.5 for the NOR and m/z 455.3 > 165.5 for the VER enantiomers) using a Chiralpak® AD column. Pharmacokinetic analysis was performed using a monocompartmental model. The pharmacokinetics of VER was enantioselective in control rats, with higher plasma proportions of the (?)‐(S)‐VER eutomer (AUC^0?∞ = 250.8 vs. 120.4 ng/ml/h; P ≤ 0.05, Wilcoxon test). The (S)‐NOR metabolite was also found to accumulate in plasma of control animals, with an S/R AUC^0?∞ ratio of 1.5. The pharmacokinetic parameters AUC^0?∞, Cl/F, Vd/F, and t_1/2 obtained for VER and NOR enantiomers were not altered by nose‐only exposure to n‐hexane at concentrations of 88, 176, or 352 mg/m³ (P > 0.05, Kruskal‐Wallis test). However, the verapamil kinetic disposition was not enantioselective for the animals exposed to n‐hexane at concentrations equal to or higher than the TLV‐TWA. This finding is relevant considering that the (?)‐(S)‐VER eutomer is 10–20 times more potent than R‐(+)‐VER in terms of its chronotropic effect on atrioventricular conduction in rats and humans. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

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.     

Iron chelation promoted by desazadesferrithiocin analogs: An enantioselective barrier

For patients who require lifelong blood transfusions, there is no efficient means, unless chelation therapy is employed, for elimination of excess iron. Alternatives to desferrioxamine, the currently accepted treatment for transfusional iron overload, are being investigated. The current article focuses on an enantiomeric pair of analogs of desferrithiocin, (+)-(S)- and (-)-(R)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid (4'-hydroxydesazadesferrithiocin). The crystal structure corroborated the absolute configuration of the two compounds, (+) and (-) for the (S)- and (R)-enantiomers, respectively. Job's plots established the tridentate nature of both analogs and circular dichroism spectra confirmed the ligands' antipodal relationship. (+)-(S)-4'-Hydroxydesazadesferrithiocin is a more efficient deferration agent than is the (-)-(R)-enantiomer in a Cebus apella model of iron overload. Pharmacokinetic analyses and IC(50) measurements in L1210 murine leukemia cells were undertaken in an effort to account for the contrast in efficacy between the two enantiomers. Some differences exist in the plasma pharmacokinetic parameters between the two analogs. However, a more plausible explanation may be the apparent differences in transport across the cell membrane; the IC(50) value in L1210 cells of the (+)-(S)-enantiomer was at least 5-fold lower than that of the (-)-(R)-compound.     

The effects of desipramine and iprindole on levels of enantiomers of fluoxetine in rat brain and urine

The antidepressant fluoxetine (FLU) and its N-demethylated metabolite, norfluoxetine (NFLU), each contains a chiral center. The combination of FLU and desipramine (DMI), another antidepressant, has been reported to be useful in treatment of depression, to dramatically increase plasma levels of DMI and also to produce more rapid β-adrenergic receptor down-regulation in brain than caused by DMI alone. We have now begun studies on the effects of this drug combination on the levels of FLU and NFLU enantiomers in the rat. In addition, the combination of FLU and iprindole (IPR) was also investigated. Male Sprague–Dawley rats were treated intraperitoneally with either normal saline vehicle, DMI (5 mg/kg/day), (R,S)-FLU (10 mg/kg/day) or DMI (5 mg/kg/day) + (R,S)-FLU (10 mg/kg/day) for 4 days. Following the last treatment, 24 h urine samples were collected. Rats were sacrificed and brains were removed. For the IPR study, rats were pretreated with either saline or IPR-HCl (11.2 mg/kg) and then treated 1 h later with (R,S)-FLU. After 5 h, the rats were sacrificed and brains were removed. Brain and urine samples were analyzed by gas chromatography with electron-capture detection for free (R)- and (S)-FLU and (R)- and (S)-NFLU after extraction and reaction with (?)-(S)-N-(trifluoroacetyl)prolyl chloride. The results from the brains of the rats treated with DMI/FLU indicate that levels of the enantiomers of both FLU and NFLU were significantly increased over those seen in the animals receiving (R,S)-FLU alone. In the IPR/FLU treated rats, an increase in the brain levels of both (R)- and (S)-FLU was noted when compared with rats receiving (R,S)-FLU alone; however, there appeared to be no increase in the brain levels of NFLU enantiomers. © 1994 Wiley-Liss, Inc.     

Enantioselective plasma protein binding of bimoclomol

The binding of bimoclomol enantiomers to human plasma, its components, as well as to plasma from monkey, dog, rat, and mouse was investigated by ultrafiltration and equilibrium dialysis. The considerably stronger binding of the (-)-(S)-enantiomer found in human plasma is due to the alpha(1)-acid glycoprotein (AAG) component. The binding parameters for AAG (n(R)K(R) = 1.3 x 10(4) M(-1) and n(S)K(S) = 1.0 x 10(5) M(-1)) revealed high enantioselectivity, while the binding to human serum albumin was found to be weak (nK = 5 x 10(3) M(-1)) and not stereoselective. (-)-(S)-Bimoclomol was extensively displaced in the presence of specific marker ligands for the "FIS" subfraction of human AAG. Comparative binding studies indicated considerable differences between plasma of the five species investigated.     

Pharmacokinetics of fexofenadine enantiomers in healthy subjects

Fexofenadine, a substrate of P-glycoprotein and an organic anion transporter polypeptide, is commonly used to assess P-glycoprotein activity in vivo. The purpose of this study was to elucidate the pharmacokinetics of each fexofenadine enantiomer. After a single oral dose of racemic fexofenadine (60 mg), the plasma and urine concentrations of fexofenadine enantiomers were measured over the course of 24 h in six healthy subjects. The mean plasma concentration of R(+)-fexofenadine was higher than that of S(-)-fexofenadine. The area under the plasma concentration-time curve (AUC(0-infinity)) and the maximum plasma concentration (C(max)) of R(+)-fexofenadine were significantly greater than those of the S(-)-enantiomer (P = 0.0018 and 0.0028, respectively). The R/S ratios of AUC and C(max) of fexofenadine were 1.75 and 1.63, respectively. The oral clearance and renal clearance of S(-)-fexofenadine were significantly greater than that of R(+)-fexofenadine (P = 0.0074 and 0.0036). On the other hand, the stereoselective metabolism of fexofenadine using recombinant CYP3A4 was investigated; however, fexofenadine enantiomers were not metabolized by CYP3A4. Fexofenadine is transported by both P-glycoprotein and OATP and is not metabolized by intestinal CYP3A. Our findings suggest that the affinity of P-glycoprotein for S(-)-fexofenadine is greater than its affinity for the R(+)-enantiomer. Thus, P-glycoprotein is likely to have chiral discriminatory abilities.     

Stereoselective disposition and chiral inversion of KE-298, a new antirheumatic drug,in rats

The present study was an attempt to elucidate the relationship between stereoselective pharmacokinetics and protein binding of KE-298 and its active metabolites, deacetyl-KE-298 (M-1) and S-methyl-KE-298 (M-2). Metabolic chiral inversion was also investigated. The levels of unchanged KE-298 in plasma after oral administration of (+)-(S)-KE-298 to rats were lower than those of (−)-(R)-KE-298, whereas the levels of M-1 and M-2 after administration of (+)-(S)-KE-298 were higher than after (−)-(R)-KE-298. In vitro, rat plasma protein binding of (+)-(S)-KE-298 was lower than that of (−)-(R)-KE-298. In contrast, the binding of (+)-(S)-M-1 and (+)-(S)-M-2 was higher than that of (−)-(R)-M-1 and (−)-(R)-M-2. Displacement studies revealed that the (+)-(S) and (−)-(R)-enantiomers of KE-298 and their metabolites bound to the warfarin binding site on rat serum albumin. These results suggest that the stereoselective plasma levels in KE-298 and its metabolites were closely related to enantiomeric differences in protein binding, attributed to quantitative differences in binding to albumin rather than to the different binding sites. Unidirectional chiral inversion was detected after oral administration of either (−)-(R)-KE-298 or (−)-(R)-M-2 to rats both yielding (+)-(S)-M-2. Chirality 9:22–28, 1997 © 1997 Wiley-Liss, Inc.     

Lack of stereoselectivity of the peroxisome proliferation induced by 2-phenylpropionic acid: Evidence against a role for lipid disturbance in peroxisome proliferation

The significance of disturbances of lipid metabolism caused by xenobiotic acyl-CoAs as possible causes of peroxisomal proliferation has been studied with the enantiomers of 2-phenylpropionic acid (2-PPA), the (R)-enantiomer of which is converted to the acyl-CoA in rats while its (S)-antipode is not. rac-2-PPA (250 mg/kg/day ip × 3) was shown to be an hepatic peroxisomal proliferator in male Sprague–Dawley rats on the basis of increases in microsomal cytochrome P-450 content and lauric acid hydroxylation and hepatic CN^?-insensitive palmitoyl-CoA oxidation, a peroxisomal marker activity, while electron microscopy revealed a rise in the peroxisome/mitochondria ratio in hepatocytes. Further studies established the dose–response relationships for these biochemical changes. The (R)- and (S)-enantiomers were administered at a dose of 50 mg/kg/day ip × 3 and both were peroxisome proliferators of very similar potency. The effects of 100 mg/kg/day ip × 3 of the racemate, a dose giving ca. 75% of maximal response, were essentially additive of those of 50 mg/kg/day ip × 3 of its two component isomers. The stereoselectivity of acyl-CoA formation from the enantiomers of 2-PPA was confirmed by their differential inhibition of microsomal palmitoyl-CoA synthesis. Taken together, these data indicate that it is very unlikely that the acyl-CoA of 2-PPA plays any role in the peroxisomal proliferation which this compound causes in the rat. © 1994 Wiley-Liss, Inc.