Administration Of Individual Enantiomers Research Articles

Comparative stereoselective pharmacokinetic analysis of 10-hydroxycarbazepine after oral administration of its individual enantiomers and the racemic mixture to dogs.

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. 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. 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. 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.

Stereoselective pharmacokinetics of ibuprofen in rats: effect of enantiomer-enantiomer interaction in plasma protein binding.

Stereoselective pharmacokinetics of ibuprofen (IB) enantiomers were studied in rats. Unidirectional conversion from R-ibuprofen (R-IB) to S-ibuprofen (S-IB) was observed following intravenous administration. S-IB concentrations in plasma following racemate administration were simulated according to a conventional compartmental model using the parameters obtained after the administration of individual enantiomers, and resulted in overestimation of S-IB concentrations. Binding of IB enantiomers measured in rat plasma was stereoselective, the binding of R-IB being more favorable than that of S-IB. Moreover, there are interactions between IB enantiomers in binding, which may cause the increase of distribution volumes of IB enantiomers in the presence of their antipodes. Hence simulated S-IB concentrations according to a conventional compartment model were significantly greater than those observed. Indeed, when the enantiomer-enantiomer interactions were taken into account, simulation of S-IB concentrations in plasma following racemate administration was in good agreement with observed values. Therefore, interactions between stereoisomers as well as dispositional stereoselectivity have to be considered when pharmacokinetics of stereoisomers after administration of the racemate are compared to those after administration of individual isomers.

Chiral aspects of the metabolism of ethosuximide

Ethosuximide is a chiral drug substance primarily indicated for the treatment of absence seizures. This drug is used clinically as the racemate. The urinary metabolites of ethosuximide (following i.p. administration of the racemate or individual enantiomers to rats) have been studied using chiral gas chromatography (GC) and gas chromatography-mass spectroscopy (GCMS). The metabolites identified were unchanged ethosuximide enantiomers, all four stereoisomers of 2-(1-hydroxyethyl)-2-methylsuccinimide, and a single stereoisomer of 2-ethyl-3-hydroxy-2-methylsuccinimide [derived from (R)-ethosuximide]. Preliminary quantitative studies indicate a degree of stereoselectivity in the fate of ethosuximide since the ratio of (R)- to (S)-ethosuximide in the urine was found to be 0.77:1 (0-24 h sample), 0.64:1 (24-48 h sample), and 0.83:1 (48-72 h sample). This would suggest that the (R)-isomer is preferentially metabolised. Results obtained following the administration of individual enantiomers of ethosuximide indicate that the 2-(1-hydroxyethyl)-2-methylsuccinimide diastereoisomers derived from (R)-ethosuximide are produced in approximately equal proportions [ratio 1.05:1 (0-24 h sample), 1.10:1 (24-48 h sample)], whilst those from (S)-ethosuximide are produced in unequal proportions [ratio 1.65:1 (0-24 h sample), 1.74:1 (24-48 h sample)].

Comparative Pharmacokinetics of Unbound Disopyramide Enantiomers following Oral Administration of Racemic Disopyramide in Humans

To the Editor: A previous study has reported a higher total clearance (CLt) and renal CL (CLr), a longer half-life (t1/2), and a larger apparent volume of distribution (Vd) for R(−)-disopyramide (D) compared with S( +)-D following the administration of racemic D, whereas no differences in these pharmacokinetic parameters were observed between the enantiomers following separate administration. As a possible explanation for these distinct pharmacokinetic properties following racemic D dosing, in vivo plasma protein binding interaction between the two enantiomers has been suggested. However, the protein binding data of D enantiomers have been obtained only after in vitro spiking or after administration of individual enantiomers. To date, no data on the plasma protein binding of D enantiomers following administration of racemic D are available to our knowledge, except our preliminary study which obtained data from only one subject. However, the binding parameters using plasma samples taken serially after administration of racemic D might be different from those obtained after an in vitro study because of possible in vivo binding interactions not only between the two enantiomers of D, but also between enantiomers of D and its main metabolite in humans [mono-N-dealkyl D (MND)], in addition to interindividual variability of plasma D binding. In our recent study, an almost threefold increase in the unbound fraction (fu) at 1.0 μg/mL of S( + )-D was predicted in the presence of 0.5 μg/mL of unbound (+ )-MND, compared with the fu for S( + )-D alone in an in vitro study. Therefore, we decided to administer racemic D and examine whether such in vivo plasma protein binding interactions between D enantiomers and/or between enantiomers of D and MND indeed exist, and whether they result in the difference in pharmacokinetics between D enantiomers when D is given as a racemic mixture. The purpose of the present study was to compare the total and unbound pharmacokinetic parameters of D enantiomers after racemic D dosing and to clarify the factor(s) affecting the distinctive pharmacokinetics observed between the two enantiomers.