Bidirectional chiral inversion of the enantiomers of the nonsteroidal antiinflammatory drug oxindanac in dogs

The nonsteroidal antiinflammatory drug oxindanac exists as two enantiomers, with most of its pharmacological activity residing in the (S)-isomer. The behavior of its enantiomers was investigated in dogs. Bidirectional inversion occurred in heparinised plasma and blood, with a ratio of enantiomers [S:R] of 7.3:1 being achieved at equilibrium after incubation for 24 h at 37°C. There was no detectable inversion of either isomer in plasma incubated at 4°C for up to 8 h or in aqueous solution at 37°C for up to 36 h. Bidirectional inversion also occurred in vivo, with a ratio of plasma AUC (0 ∞)s [S:R] of 8.1:1. The ratio of enantiomers reached equilibrium within 2 hr following (S)- or rac-oxindanac, and within 8 h following (R)-oxindanac. Elimination t^½s of the isomers were the same (R, 12.1 h, S, 13.3 h). There were no differences in the ratio of enantiomers following oral or intravenous application, suggesting that a systemic site for inversion was predominant. Although concentrations of the respective isomers were similar at equilibrium following administration of either (R)-, (S)-, or rac-oxindanac, AUC (0 ∞)s differed due to the delay in reaching equilibrium. The extent of inversion to the (S)-isomer was 100, 73.2, and 60.7% after administration of (S)-, rac-, and (R)-oxindanac, respectively. Although pharmacological activity might be equivalent at equilibrium following administration of either (R)-, (S)-, or rac-oxindanac; efficacy at early time points should be superior in the order (S) > racemate > (R). In conclusion both enantiomers of oxindanac undergo conversion to their respective antipodes in dogs, although the inversion of R to S is more efficient than that of S to R. This bidirectional inversion occurred in vivo, and in vitro in plasma and blood. © 1994 Wiley-Liss, Inc.     

Metabolic chiral inversion of ibuprofen in isolated rat hepatocytes

Ibuprofen was used to demonstrate that isolated rat hepatocytes offer a suitable in vitro model to investigate the metabolic chiral inversion of anti-inflammatory 2-arylpropionic acids (profens). The inversion of the pharmacologically inactive (-)-(R)-ibuprofen to the active (+)-(S)-ibuprofen was shown to obey apparent first-order kinetics during 5 h and to increase linearly with increasing hepatocyte concentration up to 4 x 10(5) cells/ml. No elimination of (R)-ibuprofen by routes other than inversion was seen, whereas the elimination of (S)-ibuprofen appeared to be saturable.     

A mechanistic investigation of the microbial chiral inversion of 2-phenylpropionic acid by Verticillium lecanii

Previous investigations have described the development of nongrowing suspension of Verticillium lecanii as a microbial model of the mammalian chiral inversion of the 2-arylpropionic acids (2-APAs). Mechanistic studies in mammals have shown that inversion involves loss of the α-methine proton but retention of the original atoms at the β-methyl position, and a mechanism has been proposed involving enzymatic epimerisation of acyl-CoA thioester derivatives of the substrate. Inversion of the 2-APAs by V. lecanii exhibits extensive intersubstrate variation in the presence, rate, extent, and direction of inversion, which are different from those observed in mammalian systems, possibly indicating differences in the mechanism of inversion between mammalian and microbial cells. This study involved the investigation of proton/deuterium exchange by ¹H-nuclear magnetic resonance following incubation of deuterated derivatives of 2-phenylpropionic acid (2-PPA), a model compound, in cell suspensions of V. lecanii and incubation of undeuterated 2-PPA in cell suspensions containing D₂O. The results indicated that the inversion of 2-PPA by V. lecanii also involved exchange of the α-methine proton but complete retention on the original atoms at the β-methyl position. No kinetic deuterium isotope effect was observed, indicating that loss of the α-methine proton is not the rate-limiting step of the inversion process. This suggests that the observed differences between microbial and mammalian systems probably involve the stereoselective acyl-CoA thioester formation step and not the subsequent epimerisation of the resultant diastereomers. Chirality 9:254–260, 1997. © 1997 Wiley-Liss, Inc.     

Estimation of the rate and extent of chiral inversion using linear systems analysis

An alternative method based on linear systems analysis is presented for the analysis of concentration-time data for the enantiomers of the 2-arylpropionic acids. This approach uses deconvolution to estimate the rate and extent of chiral inversion with respect to time, assuming linear pharmacokinetics and time invariance, without the need for complicated modelling procedures. Application to data for the chiral inversion of ibuprofen in the rat indicates that this approach provides a valid alternative to previous procedures for the analysis of chiral inversion data. © 1995 Wiley-Liss, Inc.     

Study on the metabolic mechanism of chiral inversion of S-mandelic acid in vitro

Mandelic acid (MA) is generally used as a biological indicator of occupational exposure to styrene, which is classified as a class of hazardous environmental pollutants. It was found to undergo one-directional chiral inversion (S-MA to R-MA) in Wistar and Sprague-Dawley rats in vivo. This study was aimed to explore the metabolic mechanism of chiral inversion of S-MA in vitro. S-MA was converted to R-MA in rat hepatocytes, whereas MA enantiomers remained unchanged in acidic and neutral phosphate buffers, HepG2 cells, and intestinal flora. In addition, the synthesized S-MA-CoA thioester was rapidly racemized and hydrolyzed to R-MA by rat liver homogenate and S9, cytosolic and mitochondrial fractions. The data suggest that chiral inversion of S-MA may involve the hydrolysis of S-MA-CoA, and its metabolic mechanism could be the same as that of 2-arylpropionic acid (2-APA) drugs.     

Stereoselective chiral inversion of pantoprazole enantiomers after separate doses to rats

(±)-Pantoprazole ((±)-PAN), (±)-5-(difluoromethoxy)-2-[[(3.4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole is a chiral sulfoxide that is used clinically as a racemic mixture. The disposition kinetics of (+)-PAN and (−)-PAN given separately has been studied in rats. Serum levels of (+)- and (−)-PAN and its metabolites, pantoprazole sulfone (PAN-SO₂), pantoprazole sulfide (PAN-S), 4′-O-demethyl pantoprazole sulfone (DMPAN-SO₂), and 4′-O-demethyl pantoprazole sulfide (DMPAN-S) were measured by HPLC. Following single intravenous or oral administration, both enantiomers were rapidly absorbed and metabolized, resulting in similar serum concentrations, suggesting that the two enantiomers have approximately the same disposition kinetics. The major metabolite of both (+)- and (−)-PAN was PAN-SO₂, while DMPAN-SO₂ was also detected as a minor metabolite. Serum levels of PAN-S and DMPAN-S could not be quantified after intravenous or oral administration of either enantiomer. Significant chiral inversion occurred after intravenous and oral administration of (+)-PAN. The AUCs of (−)-PAN after intravenous and oral dosing of (+)-PAN were 36.3 and 28.1%, respectively of those of total [(+) + (−)] PAN. In contrast, the serum levels of (+)-PAN were below quantitation limits after intravenous or oral administration of (−)-PAN. Therefore, chiral inversion was observed only after administration of (+)-PAN, supporting the hypothesis that stereoselective inversion from (+)-PAN to (−)-PAN occurs in rats. Chirality 10:747–753, 1998. © 1998 Wiley-Liss, Inc.     

Extent of chiral inversion of the 2-arylpropionic acids by Cordyceps militaris

The fungus Cordyceps militaris has been previously shown to be capable of inverting the chirality of 2-phenylpropionic acid from its (R)-enantiomer to its (S)-antipode. The structure of this compound is similar to the 2-arylpropionic acid non-steroidal anti-inflammatory drugs, which have also been reported to undergo a similar chiral inversion process in mammals and man. We report here an investigation into the substrate specificity of the enzyme system present in C. militaris using pure enantiomers and racemates of ibuprofen and ketoprofen and racemates of indoprofen, suprofen, flurbiprofen, and fenoprofen and the structurally related compounds 2-phenylbutyric acid and 2-phenoxypropionic acid as substrates, using optimised incubation conditions developed for the inversion of 2-phenylpropionic acid. The results demonstrated that C. militaris is capable of inverting the chirality of all the compounds investigated, which suggests that the active sites of the enzymes are very flexible with regard to the molecular dimensions of the substrate molecule and the spatial occupation of the groups surrounding the chiral centre. Metabolism of all the substrates was observed but the rate of metabolism varied extensively depending on the substrate. Achiral HPLC analysis was used to detect any potential metabolites and the results suggested that the site of the metabolism appeared to be at the aliphatic side groups only, with the aromatic ring being left intact in all cases. These results suggest that C. militaris could be a valuable tool in the investigation of the prospective metabolic fates of new 2-arylpropionic acids during their development. Chirality 10:528–534, 1998. © 1998 Wiley-Liss, Inc.     

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.     

Microbial metabolism of 2-arylpropionic acids: Chiral inversion of ibuprofen and 2-phenylpropionic acid

The metabolism of (R,S)-ibuprofen has been investigated in 24 microbial cultures. Of these Cunninghamella elegans, Mucor hiemalis, and Verticillium lecanii catalyzed the oxidation of the drug to 2-[4-(2-hydroxy-2-methylpropyl)phenyl]propionic acid, a known mammalian metabolite. The extent of metabolism was greatest with V. lecanii, with some 47% of the substrate being consumed over a 7-day incubation period. Enantiomeric analysis indicated stereoselective metabolism of (R)-ibuprofen, the enantiomeric composition of the residual substrate being R/S = 0.25. Following a preparative scale incubation of (R,S)-ibuprofen with V. lecanii, in which the reaction was allowed to go to completion, the metabolite was found to be predominantly of the S-configuration (S/R = 2.1), suggesting that chiral inversion of either the drug and/or the metabolite had taken place. Analysis of extracts following incubation of (R,S)-, (R)-, and (S)-2-phenylpropionic acid with V. lecanii, for 21 days, indicated that chiral inversion of the (R)-enantiomer to its optical antipode had taken place. The results of these investigations indicate that microorganisms, in addition to mammals, are able to mediate the chiral inversion of 2-arylpropionic acids. This observation may have implications for the preparation of optically pure 2-arylpropionic acids. © 1993 Wiley-Liss, Inc.     

Stereospecific determination,chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide

The purposes of this work were (1) to develop a high performance liquid chromatographic (HPLC) assay for the enantiomers of thalidomide in blood, (2) to study their inversion and degradation in human blood, and (3) to study the pharmacokinetics of (+)-(R)- and (?)-(S)-thalidomide after oral administration of the separate enantiomers or of the racemate to healthy male volunteers. The enantiomers of thalidomide were determined by direct resolution on a tribenzoyl cellulose column. Mean rate constants of chiral inversion of (+)-(R)-thalidomide and (?)-(S)-thalidomide in blood at 37°C were 0.30 and 0.31 h^?1, respectively. Rate constants of degradation were 0.17 and 0.18 h^?1. There was rapid interconversion in vivo in humans, the (+)-(R)-enantiomer predominating at equilibrium. The pharmacokinetics of (+)-(R)- and (?)-(S)-thalidomide could be characterized by means of two one-compartment models connected by rate constants for chiral inversion. Mean rate constants for in vivo inversion were 0.17 h^?1 (R to S) and 0.12 h^?1 (S to R) and for elimination 0.079 h^?1 (R) and 0.24 h^?1 (S), i.e., a considerably faster rate of elimination of the (?)-(S)-enantiomer. Putative differences in therapeutic or adverse effects between (+)-(R)- and (?)-(S)-thalidomide would to a large extent be abolished by rapid interconversion in vivo. © 1995 Wiley-Liss, Inc.     

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

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

Enantiomers of thalidomide: blood distribution and the influence of serum albumin on chiral inversion and hydrolysis

The aim of this investigation was to elucidate the distribution and reactions of the enantiomers of thalidomide at their main site of biotransformation in vivo, i.e., in human blood. Plasma protein binding, erythrocyte: plasma distribution, and the kinetics of chiral inversion and degradation in buffer, plasma, and solutions of human serum albumin (HSA) were studied by means of a stereospecific HPLC assay. The enantiomers of thalidomide were not extensively bound to blood or plasma components. The geometric mean plasma protein binding was 55% and 66%, respectively, for (+)-(R)- and (−)-(S)-thalidomide. The corresponding geometric mean blood:plasma concentration ratios were 0.86 and 0.95 (at a haematocrit of 0.37) and erythrocyte:plasma distributions were 0.58 and 0.87. The rates of inversion and hydrolysis of the enantiomers increased with pH over the range 7.0–7.5. HSA, and to a lesser extent human plasma, catalysed the chiral inversion, but not the degradation, of (+)-(R)- and (−)-(S)-thalidomide. The addition of capric acid or preincubation of HSA with acetylsalicylic acid or physostigmine impaired the catalysis to varying extents. Correction for distribution in blood enhances previously observed differences between the pharmacokinetics of the enantiomers in vivo. The findings also support the notion that chiral inversion in vivo takes place mainly in the circulation and in albumin-rich extravascular spaces while hydrolysis occurs more uniformly in the body. In addition, the chiral inversion and hydrolysis of thalidomide apparently occur by several different mechanisms. Chirality 10:223–228, 1998. © 1998 Wiley-Liss, 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.     

Immobilized vancomycin as chiral stationary phase in packed capillary liquid chromatography

Fused silica-packed capillary columns containing vancomycin immobilized by reductive amination on an aldehyde-silica were used to separate enantiomers of some non-steroidal anti-inflammatory drugs. Attempts have been made to qualitatively explain the influence of various mobile phase compositions on the enantioselective retention. The effects of mobile phase pH, buffer, and organic modifier concentrations were investigated as well as the influence of salts of hydrophobic ions added to the mobile phase to induce ion pair retention. Chirality 10:273–280, 1998. © 1998 Wiley-Liss, Inc.     

手性源、手性池和手性农药中间体的开发研究

介绍手性源、手性池和手性分子化合物的基本概念;由手性池化合物制备手性衍生物;比较了手性化合物生物加工与化学加工过程的优、缺点,寻求高效、经济和最合理的综合工艺流程。     

Indirect chiral separation and analyses in human biological fluids of the stereoisomers of a thienothiopyran-2-sulfonamide (TRUSOPT), a novel carbonic anhydrase inhibitor with two chiral centers in the molecule.

The indirect chiral separation of the four stereoisomers (1)-(4) of a novel carbonic anhydrase inhibitor with two chiral centers in the molecule is reported. The method is based on chemical derivatization of the secondary amino group of the inhibitor with chiral isocyanate, formation of diastereomeric urea derivatives, each with three chiral centers in the molecule, and their separation under nonchiral HPLC conditions. The attempts to separate racemic mixture (1) + (2) from its diastereomeric counterpart (3) + (4) under nonchiral conditions, and to separate enantiomers (1) and (2) directly on a chiral stationary phase (CSP) are also reported. The indirect method was utilized for the assessment of an in vivo inversion of configuration at either one or both chiral centers of the molecule of (1). Analyses of selected whole blood and urine samples from human subjects after multiple bilateral topical ocular dosing with (1) did not reveal the presence of any of the three possible stereoisomers (2)-(4) of (1) indicating that the inversion of configuration at neither one nor two chiral centers of (1) occurs in vivo.     

Mechanism of chiral asymmetry generation by chiral autocatalysis in the preparation of chiral octahedral cobalt complex

Chiral asymmetry generation, the predominant production of one enantiomer in a non-chiral environment, could occur in the production of the chiral complex cis-[CoBr(NH₃)(en)₂]Br₂ by the reaction of [Co(H₂O)₂{(OH)₂Co(en)₂}₂](SO₄)₂ with ammonium bromide in an aqueous medium. The main kinetic steps in the reaction system have been determined. During the reaction, the product crystallizes at an early stage. When a very small amount of crystalline enantiomer was added to the reaction system at an early stage, the same enantiomer was produced preferentially; in addition, the enantiomeric excess of the product increased with increasing the stirring rate. Thus, it seems that each enantiomer generates chiral crystals that could self-replicate through secondary nucleation when the solution is stirred; these crystals in turn enhance the production of the same enantiomer. With a computer code that simulates such a kinetic mechanism, it is shown that enantiomeric excess observed in the experiments could be reproduced. Chirality 10:343–348, 1998. © 1998 Wiley-Liss, Inc.     

Embryotoxicity of phenytoin in adrenalectomized CD-1 mice.

It has been proposed that the anticonvulsant drug phenytoin (PHT) and glucocorticoids induce orofacial clefting by the same mechanism. Previous work had demonstrated that PHT treatment significantly increased endogenous maternal corticosterone concentrations for approximately 48 hr after dosing in A/J mice. The purpose of the present investigation was to determine whether PHT is embryotoxic in the absence of endogenous maternal glucocorticoids. Maternal adrenal glands were removed on Day 7 of gestation, and the incidence of clefting after PHT treatment was determined. There was a high level of maternal toxicity following adrenalectomy (ADX) and PHT treatment at either 60 or 75 mg/kg. This increased toxicity did not appear to be due to altered maternal drug levels in ADX mice. There was a significant increase in the clefting incidence among offspring of ADX dams treated with PHT at 60 mg/kg. This dose of PHT did not elevate maternal corticosterone levels in ADX dams. These data suggest that PHT is capable of producing clefts in the absence of endogenous maternal corticosterone.     

Pharmacokinetics of the active antifungal enantiomer, SCH 42427 (RR), and evaluation of its chiral inversion in animals following its oral administration and the oral administration of its racemate genaconazole (RR/SS)

Genaconazole (SCH 39304) is a potent triazole antifungal agent that is active both orally and topically. Genaconazole is a racemic mixture which contains 50% of the RR (SCH 42427) and 50% of the SS (SCH 42426) enantiomers. The RR isomer accounts for most of the antifungal activity of genaconazole. Serum concentrations of the RR and SS enantiomers were analyzed by a chiral HPLC method which involved extraction of serum with organic solvent followed by separation on a Cyclobond I column and quantification by UV absorbance at 205 nm. The bioavailability and pharmacokinetic profiles of the two enantiomers after oral administration of the racemate (genaconazole) were very similar in cynomolgus monkeys. In rats following dosing with genaconazole, the RR enantiomer had a lower C(max) and a longer t(1/2) than the SS enantiomer, while the AUC(I) values of the two enantiomers were similar. Based on chiral HPLC analysis, there was no evidence for the inversion of the RR to the SR isomer, or of the SS to the SR isomer, indicating that there was no chiral inversion of the RR or SS enantiomers in either species. Genaconazole at 20 mg/kg and the RR (SCH 42427) enantiomer at 10 mg/kg had very similar serum concentration-time profiles and C(max), AUC(I), and t(1/2) values for the RR enantiomer in both rats and monkeys, indicating that the two treatments were equivalent with respect to the bioavailability of the RR enantiomer.     

Stereoselective metabolic pathways of ketoprofen in the rat: Incorporation into triacylglycerols and enantiomeric inversion

The enantiomeric bioinversion of ketoprofen (KP) enantiomers and their incorporation into triacylglycerols were investigated in the rat (1) in vitro, using liver homogenates, subcellular fractions, and hepatocytes, and (2) in vivo, in different tissue samples after oral administration of the radiolabelled compounds. In liver homogenates or subcellular fractions, the enantiomer (S)-ketoprofen (S-KP) was recovered unchanged, whereas (R)-ketoprofen (R-KP) was partially converted into its Coenzyme A (CoA) thioester and inverted to S-KP. Both processes occurred mainly in the mitochondrial fraction. This supports the mechanism of inversion via stereoselective formation of CoA thioesters of R-KP, already described for other non-steroidal anti-inflammatory drugs. Incorporation into triacylglycerols was detected after incubation with intact hepatocytes in the presence of added glycerol. The process was stereoselective for R-KP vs. S-KP (covalently bound radioactivity 26,742 ± 4,665 dpm/10⁶ cells vs. 6,644 ± 3,179 dpm/10⁶ cells, respectively). However, no incorporation was found in liver samples after oral administration of either R-KP or S-KP. On the contrary, in adipose tissue samples a significant and stereoselective formation of hybrid triacylglycerols was observed: 11,076 ± 2,790 dpm.g⁻¹ for R-KP vs. 660 ± 268 dpm.g⁻¹ for S-KP. The incorporated R/S ratio, higher in adipose tissue (R/S = 17) than in hepatocytes (R/S = 4), indicates that fat may be the main tissue store for the xenobiotic R-KP in rats. © 1996 Wiley-Liss, Inc.