Racemic drugs: racemic mixture, racemic compound, or pseudoracemate?
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Pharmaceutical Preparations↗
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Structural differences in D and L-monellin in the crystals of racemic mixture.
The racemic mixture of synthetic d and l-monellin has been crystallized, and its structure has been determined by X-ray crystallography at 1.9 A resolution. The crystal structure consists of two d and two l-monellin molecules in the P1 unit cell with a pseudo-centrosymmetrical arrangement. The final structure reveals small but significant structural differences between d and l-monellin in the same crystal. Possible reasons for these differences and their implications are discussed.
Crystallography, X-Ray↗
[S-(+)-ketamine versus ketamine racemic mixture: hemodynamic studies].
OBJECTIVE: Evaluation of hemodynamic effects of S-(+)-ketamine versus ketamine-racemic mixture during induction of anesthesia, during steady-state of a fentanyl-midazolam-anesthesia and in the period of aortic cross-clamping during extracorporeal circulation. METHODS PATIENTS: 80 patients scheduled for coronary revascularization. STUDY DESIGN: double-blind, randomized. STUDY 1: Induction of anesthesia with ketamine-racemic mixture (3 mg/kg) or S-(+)-ketamine (1.5 mg/kg) plus midazolam 0.15 mg/kg. PARAMETERS: invasive hemodynamic monitoring including right ventricular volumes and pressure. STUDY 2: Bolus of ketamine-racemic mixture (3 mg/kg), S-(+)-ketamine (1.5 mg/kg) or placebo during steady-state anesthesia with fentanyl and midazolam. PARAMETERS: see study 1, additionally left ventricular systolic and end-diastolic pressure and maximum speed of left ventricular pressure increase (dp/dt). STUDY 3: Bolus of ketamine-racemic mixture (3 mg/kg), S-(+)-ketamine (1.5 mg/kg) or placebo in the period of aortic cross clamping during ECC. PARAMETERS: mean systemic pressure, central venous pressure, reservoir volume. RESULTS STUDY 1: Heart rate and systemic blond pressure remained unchanged until intubation, which caused significant increases of these parameters. Stroke volume Index and cardiac index decreased in the S-(+)-group compared with racemic mixture, right- and left ventricular filling parameters remained unchanged throughout the study. STUDY 2: There were no significant hemodynamic changes with time or between the groups. STUDY 3: Significant arterial vasodilation was observed in the racemic mixture group, venous parameters remained unchanged. CONCLUSION: There were no major differences in the hemodynamic profiles of S-(+)-ketamine and the racemic mixture. S(+)-ketamine did not provide hemodynamic advantages. The use of both preparations should be limited to selected clinical situations in patients with reduced coronary reserve.
Aged↗
A comparative study of Ro 03-8799: racemic mixture and enantiomers.
The maximum single dose of the 2-nitroimidazole hypoxic cell radiosensitiser Ro 03-8799 is limited to 1 g/m2 by the occurrence of a well characterised acute syndrome of sweating, nausea and mental changes. In an attempt to increase the tolerable dose, the clinical toxicity of the racemic mixture was compared with that of the R- and S-enantiomers of Ro 03-8799. Twelve patients received escalating alternate doses of racemic mixture and R- or S-enantiomer, the dose levels being 0.25 g/m2, 0.5 g/m2, 0.75 g/m2 and 1.0 g/m2. Careful monitoring of the acute syndrome failed to demonstrate any consistent differences between racemic mixture and either enantiomer. This would suggest that the toxicity is not mediated via any specific central nervous system receptor. It is concluded that separation of Ro 03-8799 into its enantiomers will not enable a clinically useful increase in dosage.
Dose-Response Relationship, Drug↗
Parity violation and chiral symmetry breaking of a racemic mixture.
The chiral symmetry breaking of a racemic mixture by the parity violating weak interaction is considered. Particular attention is given to a mechanism recently proposed by Mason and Tranter whereby the weak neutral current interaction in chiral molecules leads to the differential absorption of unpolarized light by D vs. L enantiomers. After extending the usual theory of optical activity to include weak neutral currents, it is found that for spin-allowed transitions in typical organic molecules the weak photoabsorption asymmetry is much smaller than the value obtained using the reasoning of Mason and Tranter. Upon making a comparison with other mechanisms, it is concluded that differential radiolysis by beta electrons is likely to produce the largest symmetry breaking effect by the weak interaction.
Beta Particles↗
Racemic mixtures: harmless or potentially toxic?
Issues involved in the development and evaluation of racemic drug mixtures are described. Administration of a racemic drug mixture is in reality administration of two drugs with distinct pharmacokinetic and pharmacodynamic properties. Compared with the active enantiomer, the inactive enantiomer in a racemic mixture often has different rates of absorption, metabolism, and excretion, as well as different affinities for tissue receptor and protein receptor binding sites. It may be an agonist or antagonist, produce adverse effects, increase efficacy, or place an undue burden on clearance mechanisms. Thus, the pharmacokinetic and pharmacodynamic properties, pharmacologic activity, and toxicity of each enantiomer in a racemic drug mixture need to be determined. When pharmacokinetics of enantiomers differ, the contribution of each enantiomer to effectiveness and toxicity and whether the mixture may be more beneficial than a single enantiomer will need to be considered before racemic mixtures are marketed.
Animals↗
Comparative stereoselective pharmacokinetic analysis of 10-hydroxycarbazepine after oral administration of its individual enantiomers and the racemic mixture to dogs.
PURPOSE: 10-hydroxycarbazepine (MHD) is the active metabolite of the new antiepileptic drug oxcarbazepine. MHD is a chiral molecule with an asymmetric carbon at position 10. The purpose of this study was to evaluate the stereoselectivity in the pharmacokinetics of the enantiomers of MHD after oral administration of the individual MHD enantiomers and the racemic mixture to dogs. METHODS: A racemic mixture of MHD and the individual MHD enantiomers were administered to six dogs in a crossover design. Plasma and urine concentrations of R(-)- and S(+)-MHD were determined by a stereoselective high-performance liquid chromatography assay. RESULTS: The area under the concentration-time curve of R(-)-MHD was significantly greater than that of S(+)-MHD after the administration of the individual enantiomers but not after the administration of MHD in a racemic form. The formation clearance of the S(+)-MHD glucuronide was approximately three times greater than that of R(-)-MHD glucuronide. No difference was found in the renal clearance and protein binding of R(-)- and S(+)-MHD enantiomers. CONCLUSIONS: The pharmacokinetics of the MHD enantiomers was found to be stereoselective, mainly as a result of the stereoselectivity in the glucuronidation process. The difference in the pharmacokinetic parameters found after administration of individual MHD enantiomers compared with the administration of MHD in a racemic form suggests the possibility of interaction between the two enantiomers. Stereoselective pharmacokinetic and pharmacodynamic studies are needed to evaluate the rationale of developing MHD as a new antiepileptic drug, either in a stereospecific or racemic form.
Administration, Oral↗
Pharmacokinetics of levofloxacin in comparison to the racemic mixture of ofloxacin in man.
After oral administration of a single dose of 200 mg of levofloxacin and 400 mg racemic mixture of ofloxacin to 6 healthy male volunteers in a double-blind, randomised cross-over study, concentrations of the unchanged isomers were determined at various times in serum and urine, over 28 hours and 48 hours, respectively. Each dosing was followed by a wash-out period of one week. Ofloxacin concentrations were determined using an enantioselective and a non-enantioselective high pressure liquid chromatography (HPLC) assay. The two measurements obtained were compared by linear distribution independent regression, and were found to be equivalent. Maximum serum concentration (Cmax) of levofloxacin after the administration of 200 mg of the levo-isomer was 2.42 mg/l (chiral derivatization HPLC, mean values); the corresponding area under the serum concentration-time curve (AUC0-28) was 17.0 mg x h/l. The corresponding Cmax values after the administration of 400 mg (+/-)-isomer (chiral derivatization HPLC and reversed phased HPLC, mean values) were 2.05 mg/l, 1.98 mg/l and 4.41 mg/l for (-)-, (+)- and (+/-) isomer, respectively. The AUCS0-28 were 17.0, 14.6 and 32.7 mg x h/l, respectively. The pharmacokinetics of the (-)- and (+)-isomer were shown to be almost equal. In serum and urine no reracemisation of the (-)-isomer to a racemic mixture was observed. General tolerability was good; no side effects were reported.
Adult↗
Effect of racemic mixture and the (S+)-isomer of ketamine on temporal and spatial summation of pain.
We have compared the analgesic efficacy of the racemic mixture and the stereoisomer (S+) of the NMDA antagonist ketamine. In a double-blind, three-way crossover, placebo-controlled study, we assessed the following: pain evoked by small/large area pressure stimuli, pain detection threshold and pain ratings to small/large area of heat stimuli, pain detection threshold and pain rating to heat stimuli of brief/long duration, summation pain threshold and pain ratings to repeated heat/electrical stimuli, side effects and reaction time. Plasma concentrations of 350 ng ml-1 for ketamine (racemic) and 180 ng ml-1 for ketamine (S+) were tried. We found that ketamine (racemic) prolonged the reaction time more than ketamine (S+). Both drugs affected pain caused by repeated stimuli or stimuli of long duration equally or more than a single stimulus of short duration. They also affected pain evoked from large areas equally or more than pain evoked from small areas. The (S+)-isomer was approximately twice as potent as the racemic mixture of ketamine in inhibiting central summation.
Adult↗
In vitro effect of the racemic mixture and the (-)enantiomer of N-n-propyl-3-(3-hydroxyphenyl)-piperidine (3-PPP) on postsynaptic dopamine receptors and on a presynaptic dopamine autoreceptor.
The racemic mixture and the (-)enantiomer of the putative dopamine autoreceptor agonist 3-PPP were investigated in vitro using dopamine-sensitive adenylate cyclase in homogenates of rat striatum as a model for a postsynaptic D1-receptor type and inhibition of electrically-evoked tritium overflow from rat striatal slices preincubated with [3H]choline and [3H]dopamine as a model for a postsynaptic D2- and a presynaptic dopamine autoreceptor type, respectively. In contrast, to apomorphine, neither the racemic mixture nor the (-)enantiomer exerted any effect, suggesting agonistic properties in all three receptor models. However, both (+/-)3-PPP and (-)3-PPP were weak antagonists at postsynaptic D1- and D2-receptors. The results of the present investigation suggest that the in vivo effects of 3-PPP are either the result of metabolic activation or that this drug activates an other dopamine autoreceptor type, pharmacologically different from that one modulating dopamine release.
Adenylyl Cyclases↗
Effects of R and S enantiomers and a racemic mixture of carprofen on the production and release of proteoglycan and prostaglandin E2 from equine chondrocytes and cartilage explants.
OBJECTIVE: To examine effects of carprofen (enantiomers and a racemic mixture) on the metabolism of equine chondrocytes. SAMPLE POPULATION: Cartilage from clinically normal horses. PROCEDURE: Effects of carprofen on proteoglycan neosynthesis, glycosaminoglycan (GAG) release and prostaglandin (PG) E2 production by unstimulated chondrocyte monolayers and cartilage explants were examined, as were similar variables in monolayers and explants exposed to carprofen and recombinant human interleukin 1beta (IL-1). Carprofen (enantiomers and racemic mixture) was used alone or along with IL-1 on monolayers and explant cultures. Medium was collected 48 to 96 hours later, and cartilage was digested. Proteoglycan synthesis was assessed as the amount of 35S-labeled proteoglycan in medium and digested cartilage. Total GAG content of the medium and digested cartilage was measured, and proteoglycan degradation was calculated. Radioimmunoassay was used to measure PGE2 production. RESULTS: Carprofen significantly decreased PGE2 production by unstimulated chondrocytes and antagonized an IL-1-induced increase in PGE2 production. Carprofen significantly increased proteoglycan synthesis in unstimulated monolayers and explants. Concurrently, there was a decrease in GAG release by explants. Use of IL-1 significantly decreased proteoglycan synthesis, but the highest concentrations of carprofen partially reversed this effect in chondrocyte monolayers. CONCLUSIONS: Carprofen had a potentially beneficial effect on proteoglycan metabolism of equine chondrocytes. This effect was sufficiently strong at the highest concentrations to overcome inhibitory effects of IL-1 on proteoglycan synthesis. Carprofen also inhibited PGE2 production by unstimulated and IL-1-stimulated chondrocytes. Carprofen induced these enantiomer-specific effects. CLINICAL RELEVANCE: Use of carprofen in osteoarthritic horses may induce beneficial changes in articular cartilage matrix.
Animals↗
Parallel kinetic resolution of racemic mixtures: a new strategy for the preparation of enantiopure compounds?
Kinetic resolution of racemic mixtures is a well-established methodology for the preparation of optically active compounds. However, excellent enantioselectivities are required to obtain them in enantiopure form, due to the decrease in ee when conversion values are close to 50%. To overcome this limitation, a parallel (asymmetric) reaction can remove the disfavored enantiomer. In this review, several examples of this strategy showing its wide range of applicability are described, as well as their mathematical treatment and some new applications in combinatorial chemistry.
Journal Article↗
Approximation function for the direct calculation of rate constants and Gibbs activation energies of enantiomerization of racemic mixtures from chromatographic parameters in dynamic chromatography.
An approximation function for enantioselective dynamic chromatography of racemic mixtures of interconverting enantiomers has been derived that allows the direct calculation of enantiomerization rate constants (k1 and k(-1)) and Gibbs activation energies of enantiomerization, deltaG++ , from chromatographic parameters, i.e., retention times of the enantiomers A and B ((t(A)R and t(B)R), peak widths at half height (WA and wB) and the relative plateau height (hplateau), without computer simulation. The reaction rate constants of enantiomerization, k(-1), obtained with this approximation function, have been validated by comparison with a simulated dataset of 15,625 chromatograms. The mean, standard deviation and confidence interval show a high correlation between the approximated and simulated rate constants. The average deviation from the Gibbs activation enthalpy of enantiomerization, deltaG++, has been estimated to be as small as about +/- 0.11 RT.
Chromatography↗
Studies on drug metabolism by use of isotopes. XXIX--Studies of the differences in biological fates of ephedrine isomers by use of a pseudo-racemic mixture.
The differences in metabolic fates of the optical isomers of ephedrine were investigated by use of a pseudo-racemic mixture technique. In rats, the (-)-isomer was more easily p-hydroxylated than the (+)-isomer. A stereoselective reaction in the formation of the glucuronides of ephedrine, norephedrine and p-hydroxyephedrine was observed. The (-)-isomers were more easily subjected to glucuronide formation than the (+)-isomers. In human subjects, N-demethylation proved to be a stereoselective reaction. It is also suspected that oxidative dealkylation of norephedrine is a stereoselective reaction.
Animals↗
Competitive inhibition by the D-isomer in racemic mixtures used as substrate in kinetic studies: a simple method for data treatment.
A set of equations was applied that allows the use of racemic mixtures for the estimation of kinetic parameters in systems where the L-isomer is substrate and the D-isomer a competitive inhibitor, displaying data as double reciprocal plots. A statistical treatment was introduced that renders compatible the output of presently available programs with the specific model requirements, with few additional calculations. An example is shown with beta-trypsin and its inhibition of benzozyl-D-arginine p-nitroanilide (Ki = 1.12 mM, pH 8,0, 37 degrees C).
Benzoylarginine Nitroanilide↗
A trans-tetrahydrobenzoxanthene receptor for the resolution of racemic mixtures of sulfonylamino acids.
An enantioselective cleft-type receptor for sulfonylamino acids has been prepared and its use for the resolution of the amino acid racemic mixture is shown.
Amino Acids↗
Stereospecificity of phenylalanine plasma kinetics and hydroxylation in man following oral application of a stable isotope-labelled pseudo-racemic mixture of L- and D-phenylalanine.
L-[15N]Phenylalanine and D-[2H5]phenylalanine have been administered orally to two healthy adult volunteers as a pseudo-racemic mixture at a dose of 25 mg/kg each. After oral application, the plasma kinetics of phenylalanine and tyrosine have been followed by the combined use of high pressure liquid chromatography and field desorption mass spectrometry. Additional incubation with D-amino acid oxidase was used to determine the enantiomeric composition of the differently labelled species of phenylalanine and tyrosine. D-Phenylalanine plasma levels show a faster rise to higher maximum values compared to L-phenylalanine (D/L ratio at maximum 3.19, 3.26). L-Phenylalanine is efficiently hydroxylated to L-tyrosine. In contrast, conversion of D-phenylalanine to the L-form with subsequent hydroxylation to L-tyrosine was observed. From the plasma kinetics it is estimated that about 1/3 of the applied dose of 25 mg/kg of D-phenylalanine is converted to the L-isomer. Of the administered dose of L-phenylalanine only very small amounts are excreted into urine as such (0.25%, 0.8%), whereas a substantial amount of the D-phenylalanine dose is found in urine (27.4%, 38.0%).
Adult↗
New estimates of asymmetric decomposition of racemic mixtures by natural beta-radiation sources.
The Vester-Ulbricht hypothesis suggests that the chirality of biological molecules originates from the beta-radiolysis of prebiotic racemic mixtures. Despite the inconclusiveness of past investigations, recent calculations have shown that beta particles, because of their helicity, radiolyse L- and D-enantiomers at slightly different rates, the asymmetry, AR, being predicted to be 10(-11) (new experimental tests, give /AR/ < 2 x 10(-9)). Before this, the size of the radiolysis-induced chiral polarization, eta R (eta triple bond (nL - nD)/(nL + nD) where nL and nD are the numbers of L and D molecules present), was estimated for different values of AR; according to Keszthelyi et al., if /AR/ approximately 10(-11), /eta R/ can never exceed the chiral polarization, /eta F/, produced by statistical fluctuations, thus invalidating the V-U hypothesis. Here we re-examine the major assumptions on which these calculations were based and find that several overly restrictive conditions were imposed, which, when relaxed, allow the condition /eta R/ > /eta F/, in accordance with the V-U hypothesis.
Amino Acids↗