Stereoselective Interaction Between Tetrahydropalmatine Enantiomers and CYP Enzymes in Human Liver Microsomes

Tetrahydropalmatine (THP), with one chiral center, is an alkaloid that possesses analgesic and many other pharmacological actives. The aim of the present study is to investigate stereoselective metabolism of THP enantiomers in human liver microsomes (HLM) and elucidate which cytochrome P450 (CYP) isoforms contribute to the stereoselective metabolism in HLM. Additionally, the inhibitions of THP enantiomers on activity of CYP enzymes are also investigated. The results demonstrated that (+)‐THP was preferentially metabolized by HLM. Ketoconazole (inhibitor of CYP3A4/5) inhibited metabolism of (?)‐THP or (+)‐THP at same degree, whereas the inhibition of fluvoxamine (inhibitor of CYP1A2) on metabolism of (+)‐THP was greater than that of (?)‐THP; moreover, the metabolic rate of (+)‐THP was 5.3‐fold of (?)‐THP in recombinant human CYP1A2. Meanwhile, THP enantiomers did not show obvious inhibitory effect on the activity of various CYP isoforms (CYP1A2, 2A6, 2C8, 2C9, 2C19, 2E1, and 3A4/5), whereas (?)‐THP, but not (+)‐THP, significantly inhibited the activity of CYP2D6 with the Ki value of 6.42 ± 0.38 μM. The results suggested that THP enantiomers were predominantly metabolized by CYP3A4/5 and CYP1A2 in HLM, and (+)‐THP was preferentially metabolized by CYP1A2, whereas CYP3A4/5 contributed equally to metabolism of (?)‐THP or (+)‐THP. Besides, the inhibition of CYP2D6 by (?)‐THP may cause drug–drug interaction, which should be considered. Chirality 25:43–47, 2013. © 2012 Wiley Periodicals, Inc.     

Chiral HPLC determination and stereoselective pharmacokinetics of tetrahydroberberine enantiomers in rats

Tetrahydroberberine (THB), a racemic mixture of (+)‐ and (?)‐enantiomer, is a biologically active ingredient isolated from a traditional Chinese herb Rhizoma corydalis (yanhusuo). A chiral high performance liquid chromatography method has been developed for the determination of THB enantiomers in rat plasma. The enantioseparation was carried out on a Chiral®‐AD column using methanol:ethanol (80:20, v/v) as the mobile phase at the flow rate 0.4 ml/min. The ultraviolet detection was set at 230 nm. The calibration curves were linear over the range of 0.01–2.5 μg/ml for (+)‐THB and 0.01‐5.0 μg/ml for (?)‐THB, respectively. The lower limit of quantification was 0.01 μg/ml for both (+)‐THB and (?)‐THB. The stereoselective pharmacokinetics of THB enantiomers in rats was studied after oral and intravenous administration at a dose of 50 and 10 mg/kg racemic THB (rac‐THB). The mean plasma levels of (?)‐THB were higher at almost all time points than those of (+)‐THB. (?)‐THB also exhibited greater C_max, and AUC_0–∞, smaller CL and V_d, than its antipode. The (?)/(+)‐enantiomer ratio of AUC_0–∞ after oral and intravenous administration were 2.17 and 1.43, respectively. These results indicated substantial stereoselectivity in the pharmacokinetics of THB enantiomers in rats. Chirality, 2012. © 2012 Wiley Periodicals, Inc.     

Stereoselective metabolism of benalaxyl in liver microsomes from rat and rabbit

Benalaxyl (BX), methyl‐N‐phenylacetyl‐N‐2,6‐xylyl alaninate, is a potent acylanilide fungicide and consist of a pair of enantiomers. The stereoselective metabolism of BX was investigated in rat and rabbit microsomes in vitro. The degradation kinetics and the enantiomer fraction (EF) were determined using normal high‐performance liquid chromatography with diode array detection and a cellulose‐tris‐(3,5‐dimethylphenylcarbamate)‐based chiral stationary phase (CDMPC‐CSP). The t_1/2 of (?)‐R‐BX and (+)‐S‐BX in rat liver microsomes were 22.35 and 10.66 min of rac‐BX and 5.42 and 4.03 of BX enantiomers. However, the t_1/2 of (?)‐R‐BX and (+)‐S‐BX in rabbit liver microsomes were 11.75 and 15.26 min of rac‐BX and 5.66 and 9.63 of BX enantiomers. The consequence was consistent with the stereoselective toxicokinetics of BX in vitro. There was no chiral inversion from the (?)‐R‐BX to (+)‐S‐BX or inversion from (+)‐S‐BX to (?)‐R‐BX in both rabbit and rat microsomes. These results suggested metabolism of BX enantiomers was stereoselective in rat and rabbit liver microsomes. Chirality, 2011. © 2010 Wiley‐Liss, Inc.     

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.     

Enantioselective Toxic Effects and Degradation of Myclobutanil Enantiomers in Scenedesmus obliquus

Research on the enantioselective environmental behavior of chiral pesticides has been a hot spot of environmental chemistry recently. In this study, the acute toxicity of myclobutanil enantiomers was investigated with the aquatic algae Scendesmus obliquus. After exposure for 96 h, the EC₅₀ values for (?)‐myclobutanil, rac‐myclobutanil and (+)‐myclobutanil were 3.951, 2.760, and 2.128 mg/L, respectively. The photosynthetic pigment (chlorophyll a, chlorophyll b, and carotenoids) and antioxidant enzyme activities catalase (CAT) were determined to evaluate the different toxic effects when S. obliquus were exposed to 1.5, 5 and 15 mg/L of rac‐myclobutanil, (?)‐myclobutanil, and (+)‐myclobutanil for 96 h, respectively. In addition, the degradation of myclobutanil enantiomers in S. obliquus was also studied. Myclobutanil in the medium inoculated with algae degraded faster than in the uninoculated medium. The degradation of (?)‐myclobutanil was faster than that of (+)‐myclobutanil at a concentration of 3 mg/L. On the basis of these data, the acute toxicity and toxic effects of myclobutanil against S. obliquus were concluded to be enantioselective, and such enantiomeric differences should be taken into consideration in pesticide risk assessment. Chirality 25:858–864, 2013. © 2013 Wiley Periodicals, Inc.     

Stereoselective urinary excretion of bupivacaine and its metabolites during epidural infusion

A sensitive and efficient chiral assay for bupivacaine and its three principal metabolites desbutylbupivacaine, 4′‐hydroxybupivacaine, and 3′‐hydroxybupivacaine has been applied to urine from five male patients receiving postoperative epidural infusions of rac‐bupivacaine fentanyl over 60–120 hr. The fraction of the dose of bupivacaine (total dose 840–2093 mg) accounted for in urine was 75 ± 6%. The rate of excretion of bupivacaine enantiomers approximated a steady state after ∼30 hr with values of 1.27 ± 0.26 and 0.76 ± 0.13 mg hr⁻¹ for (R)‐ and (S)‐enantiomers, respectively. The fraction of the dose of bupivacaine enantiomer excreted unchanged in the urine (fe) varied from 14.3% to 39.1% for (+)‐(R)‐bupivacaine and 9.2% to 14.0% for (−)‐(S)‐bupivacaine in the five patients. The rate of excretion of all metabolites also reached a steady state after ∼30 hr and the relative amounts of metabolites excreted into urine (fm) suggest bupivacaine is subject to regioselective and stereoselective clearance, which may vary from patient to patient. Chirality 11:50–55, 1999. © 1999 Wiley‐Liss, Inc.     

Separation and toxicity of salithion enantiomers

Enantioseletive toxicities of chiral pesticides have become an environmental concern recently. In this study, we evaluated the enantiomeric separation of salithion on a suite of commercial chiral columns and assessed the toxicity of enantiomers toward butyrylcholinesterase and Daphnia magna. Satisfactory separations of salithion enantiomers could be achieved on all tested columns, that is, Chiralcel OD, Chiralcel OJ, and Chiralpak AD column. However, the Chiralpak AD column offered the best separation and was chosen to prepare micro‐scale of pure salithion enantiomers for subsequent bioassays. The first and second enantiomers eluted on the Chiralpak AD column were further confirmed to be (?)‐S‐salithion and (+)‐R‐salithion, respectively. The half inhibition concentrations to butyrylcholinesterase of racemate, (+)‐R‐salithion, and (?)‐S‐salithion were 33.09, 2.92, and 15.60 mg/l, respectively, showing (+)‐R‐enantiomer being about 5.0 times more potent than its (?)‐S‐form. However, the median lethal concentrations (96 h) of racemate, (+)‐R‐salithion, and (?)‐S‐salithion toward D. magna were 3.54, 1.10, and 0.36 μg/l, respectively, suggesting that (?)‐S‐salithion was about 3.0 times more toxic than (+)‐R‐form. Racemic salithion was less toxic than either of the enantiomers in both bioassays, suggesting that antagonistic interactions might occur between the enantiomers during the toxication action. This work reveals that the toxicity of salithion toward butyrylcholinesterase and D. magna is enantioselective, and this factor should be taken into consideration in the environmental risk assessment of salithion. Chirality 2009. © 2009 Wiley‐Liss, Inc.     

In vitro inhibition of aromatase by the enantiomers of aminoglutethimide and analogs

The in vitro aromatase activity in microsomal fractions from rat ovary and its inhibition by enantiomers of aminoglutethimide (AG), rogletimide (RG), and cyclohexylaminoglutethimide (ChAG) were studied by analysing the [³H]H₂O released when [1β-³H]androstenedione was converted to estrone. Maximum velocity (V_max) and the Michaelis-Menten constant (K_m) of the microsomal aromatase enzyme were 17.40 ± 0.45 pmol/ml/mg protein/min and 1.02 ± 0.06 μM, respectively. The IC₅₀s for the enantiomers were similar for (+)-R-AG and (?)-R-ChAG (0.86 ± 0.06 and 0.89 ± 0.15 μM, respectively). (+)S-ChA'G was most potent with IC₅₀ of 0.075 ± 0.003 μM. The IC₅₀s for (?)-S-AG, (+)-R-RG, and (?)-S-RG were in the same range (23.15 ± 2.74, 24.58 ± 2.46, and 24.43 ± 2.20 μM, respectively). © 1994 Wiley-Liss, Inc.     

Bidirectional Chiral Inversion of Trantinterol Enantiomers After Separate Doses to Rats

The chiral inversion and pharmacokinetics of two enantiomers of trantinterol, a new β₂ agonist, were studied in rats dosed (+)‐ or (?)‐trantinterol separately. Plasma concentrations of (+)‐ and (?)‐trantinterol were measured by chiral stationary phase liquid chromatography tandem mass spectroscopy (LC‐MS/MS). The apparent inversion ratio was calculated as the ratio of AUC_0‐t of (?)‐trantinterol or (+)‐trantinterol inverted from their antipodes to the sum of the AUC_0‐t of (?)‐ and (+)‐trantinterol. Following single intravenous administration, both given enantiomers declined in similar plasma concentrations, suggesting that the two enantiomers have approximately the same disposition kinetics by the route of intravenous administration. However, after single oral administration, plasma concentrations of uninverted (?)‐trantinterol at many timepoints were significantly higher than those of uninverted (+)‐trantinterol, suggesting that the two enantiomers undergo apparently different absorption or metabolism after oral administration. Significant bidirectional chiral inversion occurred after intravenous and oral administration of (+)‐ or (?)‐trantinterol. After dosing with optically pure enantiomer, the concentration of the administered enantiomer predominated in vivo. The AUC_0‐36 of (+)‐trantinterol after intravenous and oral dosing of (?)‐trantinterol were 16.6 ± 5.2 and 33.3 ± 16%, respectively of those of total [(+) + (?)] trantinterol. The AUC_0‐36 of (?)‐trantinterol after intravenous and oral dosing of (+)‐trantinterol were 19.6 ± 8.8 and 37.9 ± 4.5%, respectively, of those of total [(?) + (+)] trantinterol. After intravenous administration of (+)‐ and (?)‐trantinterol the chiral inversion ratios of the two enantiomers were not significantly different and similar results were found for oral administration. The extent of chiral inversion after intravenous administration was apparently lower, indicating that the bidirectional chiral inversion was not only systemic but also presystemic. Chirality 25:934–938, 2013.© 2013 Wiley Periodicals, Inc.     

Stereoselective protein binding of tetrahydropalmatine enantiomers in human plasma,HSA, and AGP,but not in rat plasma

Tetrahydropalmatine (THP) is one of the active alkaloid ingredients of Rhizoma Corydalis. THP has a chiral center, and the stereoselective pharmacokinetics and tissue distribution have been reported. The aim of the present article is to study the stereoselective protein binding of THP using equilibrium dialysis followed by HPLC‐UV analysis. The results showed that THP stereoselectively binds to human serum albumin (HSA), α₁‐acid glycoprotein (AGP), and proteins in human plasma. The fraction binding of (+)‐THP was significantly higher than that of (?)‐THP, whereas such stereoselectivity was not found in rat plasma. The affinity of HSA and AGP to (+)‐THP, expressed as nK_A, were 9.0 × 10³ M^?1 and 2.34 × 10⁵ M^?1, respectively, which were notablely higher than to (?)‐THP, with the nK_A of 3.4 × 10³ M^?1 and 1.44 × 10⁵ M^?1, respectively. The binding site of HSA for (?)‐THP was Site I, whereas for (+)‐THP was both Site I and Site II. The F1/S variants of AGP were proved to be the key variants (?)‐ and (+)‐THP binding to both. Finally, the AGP binding drugs, such as mifepristone, were demonstrated to reduce the fraction binding of (?)‐ and (+)‐THP with pure AGP (1 mg/ml) but did not affect the fraction binding of both (?)‐ and (+)‐THP with proteins in human plasma. It can be concluded that protein binding of THP is species dependent and stereoselective, both HSA and AGP contribute to the stereoselective binding to THP enatiomers, and AGP binding drugs may not cause the drug–drug interaction on THP in healthy human plasma. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Enantioselective Metabolism and Interference on Tryptophan Metabolism of Myclobutanil in Rat Hepatocytes

Myclobutanil, (RS)‐2‐(4‐chlorophenyl)‐2‐(1H‐1, 2, 4‐triazol‐1‐ylmethyl) hexanenitrile is a widely used triazole fungicide. In this study, enantioselective metabolism and cytotoxicity were investigated in rat hepatocytes by chiral HPLC‐MS/MS and the methyl tetrazolium (MTT) assay, respectively. Furthermore, tryptophan metabolism disturbance in rat hepatocytes after myclobutanil exposure was also evaluated by target metabolomics method. The half‐life (t1/2) of (+)‐myclobutanil was 10.66 h, whereas that for (?)‐myclobutanil was 15.07 h. Such results indicated that the metabolic process of myclobutanil in rat hepatocytes was enantioselective with an enrichment of (?)‐myclobutanil. For the cytotoxicity research, the calculated EC₅₀ (12h) values for rac‐myclobutanil, (+)‐ and (?)‐myclobutanil were 123.65, 150.65 and 152.60 µM, respectively. The results of tryptophan metabolites profiling showed that the levels of kynurenine (KYN) and XA were both up‐regulated compared to the control, suggesting the activation effect of the KYN pathway by myclobutanil and its enantiomers which may provide an important insight into its toxicity mechanism. The data presented here could be useful for the environmental hazard assessment of myclobutanil. Chirality 27:643–649, 2015. © 2015 Wiley Periodicals, Inc.     

Enzymatic and chromatographic chiral discrimination of racemic (thio)glycidyl esters: Part I. A chemoenzymatic approach to both enantiomers of thioglycidyl esters

Both hitherto unknown (+)-(R)- and (?)-(S)-thioglycidyl esters, (R)-( 2 ) and (S)-( 2 ), have been synthesized with different high enantiomeric excesses (ee) by two routes from the corresponding rac-glycidyl esters rac-( 1 ). The first includes a porcine pancreatic lipase (PPL)-mediated kinetic resolution of these esters followed by sulfuration with practically complete inversion to the (+)-(R)-enantiomer (+)-(R)-( 2 ) (36–86% ee). (?)-(S)-Thioglycidyl esters (?)-(S)-( 2 ) are obtained by the reverse reaction sequence (43–80% ee). In the latter case the hydrolysis rate is lower than that of analogous glycidyl esters. Moreover, the dependence of enantiomeric excess on the size of the acyl-group is of the opposite tendency. Therefore, in both cases suitable selection of the acid residue gives rise to maximum enantioselectivity. The irreversible lipase-catalyzed acylation of rac-glycidol and rac-thioglycidol, however, was found to be a less suitable alternative. The enantiomeric excess of recovered homochiral esters was determined by chiral chromatography using modified cellulose stationary phases (OB, OD). © 1993 Wiley-Liss, Inc.     

Enantioselective determination of hydroxychloroquine and its major metabolites in urine and the observation of a reversal in the (+)/(−)-hydroxychloroquine ratio

A sequential achiral-chiral high-performance liquid chromatographic system has been developed for the quantitation in urine of the enantiomers of hydroxychloroquine (HCQ), and of its 3 major metabolites, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bisdesethylchloroquine (BDCQ). HCQ and its metabolites were separated and quantified on a cyano-bonded phase, and the enantiomeric ratios were determined using a Chiral-AGP chiral stationary phase. The assay validation and application of this method to a preliminary study in a human volunteer are presented. In this subject, the initial 0-4 h urine contained the 2 HCQ enantiomers in a ratio of (+)-HCQ:(?)-HCQ of 3:2; by the 2,064 h of the study, this ratio had reversed to (+)-HCQ:(?)-HCQ of 3:7. © 1993 Wiley-Liss, Inc.     

Chiral Resolution and Absolute Configuration of the Enantiomers of the Psychoactive “Designer Drug” 3,4‐Methylenedioxypyrovalerone

Illicit rac‐MDPV (3,4‐methylenedioxypyrovalerone), manufactured in clandestine labs, has become widely abused for its cocaine‐like stimulant properties. It has recently been found as one of the toxic materials in the so‐called “bath salts,” producing, among other effects, psychosis and tachycardia in humans when introduced by any of the several routes of administration (e.g., intravenous, oral, etc.). The considerable toxicity of this “designer drug” probably resides in one of the enantiomers of the racemate. In order to obtain a sufficient amount of the enantiomers of rac‐MDPV to determine their activity, we improved the known synthesis of rac‐MDPV and found chemical resolving agents, (+)‐ and (–)‐2’‐bromotetranilic acid, that gave the MDPV enantiomers in >96% enantiomeric excess as determined by ¹H nuclear magnetic resonance and chiral high‐performance liquid chromatography. The absolute stereochemistry of these enantiomers was determined by single‐crystal X‐ray diffraction studies. Chirality 27:287‐293, 2015. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.     

The biological activities of prothioconazole enantiomers and their toxicity assessment on aquatic organisms

Chiral fungicide prothioconazole has a wide range of antifungal spectrum; however, little research has been conducted to evaluate prothioconazole on an enantiomeric level. Five target pathogens and three common aquatic organisms were tested for the enantioselective bioactivity and toxicity of prothioconazole in this work. The antifungal activity of the enantiomers against wheat phytoalexin, rice blast fungus, exserohilum turcicum, Alternaria triticina, and Fusarium avenaceum was determined, and it was found that (?)‐prothioconazole were 85 to 2768 times more active than (+)‐prothioconazole toward these target organisms. In order to reflect the risk to aquatic ecosystem, the acute toxicity of the enantiomers to Daphnia magna, Chlorella pyrenoidosa, and Lemna minor L. was assessed. It was observed that the toxicity of (?)‐prothioconazole to D. magna was 2.2 times higher than (+)‐prothioconazole, but it was lower to C. pyrenoidosa and L. minor L. The toxicities of (+)‐enantiomer and (?)‐enantiomer to D. magna and C. pyrenoidosa were synergy, indicating that the racemate had higher threat to the organisms. It could be concluded that the effects of prothioconazole on target organisms and the acute toxicity to nontarget species were enantioselective with (?)‐enantiomer possessing higher efficiency and lower toxicity. Such enantiomeric differences should be taken into consideration when assessing the performance of prothioconazole.     

Stereoselective metabolism and toxicity of the herbicide fluroxypyr methylheptyl ester in rat hepatocytes

We investigated the stereoselective degradation kinetics and toxicity of fluroxypyr methylheptyl ester (FPMH) in rat hepatocytes using a chiral high‐performance liquid chromatographic method. The T_1/2 of (−)‐FPMH was about two times longer than that of (+)‐FPMH after the rat hepatocytes were incubated with 10, 20, and 50 μM of rac‐FPMH. There was no chiral conversion or transformation during their incubation with the hepatocytes. Toxicity differences were observed among the two enantiomers of FPMH and fluroxypyr (FP) in their EC₅₀ values in rat hepatocytes. Of all the tested compounds, FP was most toxic to the rat hepatocytes. The (−)‐FPMH enantiomer showed higher toxicity than the (+)‐FPMH, whereas the racemic mixture displayed intermediate toxicity. The data presented here are important for a more thorough understanding of this pesticide and should be useful for its full environmental assessment. Chirality, 2011. © 2011 Wiley‐Liss, Inc.     

Stereoselectivity of the carbonyl reduction of dolasetron in rats,dogs, and humans

The initial step in the metabolism of dolasetron or MDL 73, 147EF [(2α,6α,8α,9aβ)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl 1H-indol-3-carboxylate, monomethanesulfonate] is the reduction of the prochiral carbonyl group to give a chiral secondary alcohol “reduced dolasetron.” An HPLC method, using a chiral column to separate reduced dolasetron enantiomers, has been developed and used to measure enantiomers in urine of rats, dogs, and humans after dolasetron administration. In all cases, the reduction was enantioselective for the (+)-(R)-enantiomer, although the dog showed lower stereoselectivity, especially after iv administration. An approximate enantiomeric ratio (+/?) of 90:10 was found in rat and human urine. The contribution of further metabolism to this enantiomeric ratio was considered small as preliminary studies showed that oxidation of the enantiomeric alcohols by human liver microsomes demonstrated only minor stereoselectivity. Further evidence for the role of stereoselective reduction in man was obtained from in vitro studies, where dolasetron was incubated with human whole blood. The enantiomeric composition of reduced dolasetron formed in human whole blood was the same as that found in human urine after administration of dolasetron. Enantioselectivity was not due to differences in the absorption, distribution, metabolism, or excretion of enantiomers, as iv or oral administration of rac-reduced dolasetron to rats and dogs lead to the recovery, in urine, of essentially the same enantiomeric composition as the dose administered. It is fortuitous that the (+)-(R)-enantiomer is predominantly formed by carbonyl reductase, as it is the more active compound. © 1995 Wiley-Liss, Inc.     

Pharmacokinetics of nateglinide enantiomers and their metabolites in Goto‐Kakizaki rats,a model for type 2 diabetes mellitus

The pharmacokinetics of (?)‐N‐(trans‐4‐isopropylcyclohexanecarbonyl)‐D ‐phenylalanine (nateglinide) and its enantiomer (L‐enantiomer) was studied in Goto‐Kakizaki (GK) rats after intravenous administration of nateglinide or L‐enantiomer at a dose of 40 μmol/kg body weight. Nateglinide, its L‐enantiomer and their metabolites in serum, bile and urine were determined. The total clearance (CL_tot) and the volume of distribution (V_d) was slightly higher for nateglinide than those for L‐enantiomer in control rats, although the differences were not statistically significant. The cumulative excretions of L‐M1 (major metabolite of L‐enantiomer) and L‐M2 (major metabolite of L‐enantiomer) into bile were almost the same as that of M1 (major metabolite of nateglinide)and M2 (major metabolite of nateglinide). In GK rats, CL_tot and V_d were higher for nateglinide than those for L‐enantiomer. The cumulative excretion of L‐M1 and L‐M2 were not different from those of M1 and M2, respectively, into bile or urine. CL_tot and V_d for nateglinide or L‐enantiomer in GK rats were not different from those in control rats. The total excretion of M1, M2, L‐M1, and L‐M2 into bile or urine in GK rats was not substantially different from that of control rats. These results suggest that the L‐enantiomer of nateglinide shows higher CL_tot and V_d compared with nateglinide, especially in the diabetic state. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Toxic doses of rac-, (−)-(S)- and (+)-(R)-propranolol in rats and rabbits

The contribution of the individual enantiomers ([+]-[R]- and [−]-[S]-propranolol) to rac-propranolol intoxication was studied in anaesthetized, spontaneously breathing (SB) rats and artificially ventilated (AV) rats and rabbits. In the SB rat, propranolol (30 mg.kg⁻¹.h⁻¹ i.v.) decreased heart rate and mean arterial blood pressure and caused hypoventilation, serious hypoxaemia, respiratory acidosis, and death by respiratory arrest. Survival time (ST) in the (+)-(R)-propranolol group (ST 91 ± 5 min) was significantly longer than in the rac-propranolol group (ST 68 ± 6 min). In AV rats and rabbits toxic doses of rac-, (−)-(S)- and (+)-(R)-propranolol, 30 mg.kg⁻¹.h⁻¹ and 15 mg.kg⁻¹.h⁻¹ i.v., respectively, induced comparable effects on haemodynamic variables as in the SB rat. Artificial ventilation lengthened ST by a factor of three to four in rats. In the AV rat, ST's were not significantly different between the rac-, (−)-(S)- and (+)-(R)-propranolol groups. In the rabbit, as in the SB rat, ST in the (+)-(R)-propranolol group was significantly longer than ST's in the rac- and (−)-(S)-propranolol groups. The acute respiratory acidosis in SB rats and the prolonged ST in AV rats suggest that respiratory failure is the primary and cardiovascular failure the secondary cause of death in propranolol intoxication. The potentiation of the toxic effect of the enantiomers observed after dosing the racemate instead of the pure enantiomers could not be explained by a stereoselective difference in plasma propanolol concentration. © 1996 Wiley-Liss, Inc.     

Investigations into the chirality of the metabolic sulfoxidation of cimetidine

The individual enantiomers of cimetidine sulfoxide were resolved by preparative chromatography using a Chiralcel OC stationary phase and were characterized by the determination of optical rotation and circular dichroism spectra. Cimetidine sulfoxide was isolated from the urine of two healthy male volunteers following oral administration of cimetidine (400 mg). Urine was collected every 2 h for 12 h postdosing, after which time HPLC analysis indicated negligible recovery of the drug as the sulfoxide. Some 7% of the dose was recovered as cimetidine sulfoxide over this period. The enantiomeric composition of cimetidine sulfoxide was determined by sequential achiral—chiral chromatography using the OC phase. Over the collection period the enantiomeric ratio was found to be constant in all samples at (+/?) of 71 ± 2.5:29 ± 2.5. The enantiomeric composition of cimetidine sulfoxide was also determined in rat urine (24 h) following the administration of cimetidine (30 mg/kg po) to male Wistar rats (n = 7). The enantiomeric ratio in this case was found to be (+/?) 57 ± 2.3:43 ± 2.3. These preliminary data indicate that sulfoxidation of cimetidine is stereoselective with respect to the (+)-enantiomer and that species variation in enantiomeric composition occurs. © 1994 Wiley-Liss, Inc.