Plasma concentration enantiomeric ratio

Should an early decision be made to develop the eutomer, then the drug development program would be the same as for conventional NCEs, with the possible exception that assessment of in vitro and/or in vivo chiral inversion may be desirable. However, if development continues with the racemate, time, cost, and staff resource commitments become magnified. For example, a very important variable to consider is spedes differences in enantiomer exposure. Appropriate toxicokinetic studies are advisable in order to assure that, at toxicological doses, the animal species tested have attained suffident plasma concentrations of each enantiomer to support clinical evaluation at therapeutic doses in humans. The enantiomeric ratio (based on maximum drug concentrations fCmax] and/or area under the plasma drug concentration-time curve [ALJC]) should be evaluated, and... 

Because stereoselective processes are species-related, the enantiomeric ratios of plasma concentrations at various times and areas under the plasma concentration-time curves may differ among animal species after the administration of a drug racemate. Chiral inversion, which occurs to a variable extent in different species, can be equivocally established only by administering individual enantiomers to the animal species of interest and measuring, using a sensitive stereospecific analytical method, the enantiomer administered and the optical antipode in biological fluids and tissues. The pharmacokinetic parameters based on plasma concentration-time data for each of the enantiomers can be statistically compared. 

It is usual in humans for the S(+)-enantiomer of 2-arylpropionic acids to predominate in plasma and for the S(- -)- to R(-)-enantiomeric ratio of plasma concentrations to increase with time after administration of the racemate, which is often attributed to metabolic inversion of the chiral center of the R( )-enantiomers to their S(- -)-antipodes. ° In humans, the S(- -)-enantiomer is generally eliminated more slowly than is the R( )-enantiomer. The extent of chiral inversion of fenoprofen, which has been attributed to the differential rate of formation of the CoA-thioester by hepatic microsomes, varies widely among species. It has been estimated to be 90% in dogs, 80% in sheep, 73% in rabbits, 60% in humans, 42% in rats,f and 38% in horses. ... 

Because stereoselective processes are species-related, the enantiomeric ratios of plasma concentrations at various times and areas under the plasma concentration-time curves may differ between animal species following the... 

Rolipram is a racemic selective inhibitor of cAMP phosphodiesterase that has been used in the treatment of endogenous depression. The R(—)-enantiomer possesses the majority of the therapeutic eflect. After separate administration of the enantiomers by the oral and intravenous routes (Tables 1 and 2), no stereoselectivity appeared in plasma concentrations or in calculated pharmacokinetic [146]. However, it is not known whether this is also true after the administration of the racemate, because enantiomer-enantiomer interactions may affect the enantiomeric plasma concentration ratios of a number of chiral drugs. 

Karim, A. Piergies, A. Verapamil stereoisomerism enantiomeric ratios in plasma dependent on peak concentrations, oral input rate, or both. Clin. Pharmacol. Ther. 1995, 58, 174—184. 

Figure 4 Mean SEM plasma concentration-time curves of total verapamil (left panel) and enantiomeric (R/S) ratios (right panel) in 12 healthy young men who each received a 240 mg single dose of racemic verapamil as immediate-release (IR fasting) and sustained-release (SR fed) formulations in a randomized crossover study. Insets show mean SEM for the individual peak concentration (Cniax) (total) and R/S ratios associated with these Cmax (total) values. p<0.05. (From Ref. 26, with permission.)...

Figure 7 Ibuprofen, a prototype category II racemic drug with chiral inversion. Mean (w = 4) plasma concentration-time curves of R-ibuprofen, S-ibuprofen, and enantiomeric S/R ratios after oral administration of racemic ibuprofen given as an immediate-release (upper panel three 200 mg doses 6 hours apart) and controlled-release formulation (lower panel two 300 mg doses 12 hours apart). The arrows on the time axes indicate the time of drug administration. (From Ref. 26, with permission.)... 

The above-described oral-input-related changes in enantiomeric ratios in the plasma for ibuprofen, propranolol, etodolac, and verapamil have been documented only after administration of the IR and CR formulations or after oral input rates that differ substantially. An important issue that needs to be addressed is what if the two formulations compared are CR formulations whose input rate differences are not that substantial Can a relatively small difference between the rate of release/dissolution produce significant changes in the concentrations of the active enantiomer that cannot be detected by measurement of the total drug concentration ... 

For enantiomeric drugs with low organ clearance, differences in renal or hepatic clearance between stereoisomers may reflect their free fraction in the plasma and not real stereoselectivity of the ability of the organ to remove the free enantiomers (intrinsic clearance) from the plasma. Clearance differences between stereoisomers of verapamil and disopyramide may be a function of plasma protein binding differences. In addition, volumes of distribution as well as concentration ratios of stereoisomers in body fluids to total plasma and blood are influenced by plasma protein binding. For example, the larger volume of distribution and greater total body clearance of R-disopyramide compared to the S isomer may be explained by the lower... 

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