Ch H


ar cooh

aio cooh


4.4.4 Excretion

Renal excretion is the net result of glomerular filtration, active secretion and passive and active reabsorption (see Chapter 1). Since glomerular filtration is a passive process differences between enantiomers would not be expected, stereoselective renal clearance may be observed as a result of active secretion, however active reabsorption and renal metabolism may also be significant. Apparent stereoselectivity in renal clearance may also arise as a consequence of stereoselectivity in protein binding rather than active transport. Active renal tubular secretion is thought to be responsible for the differential clearance of the enantiomers of a number of basic drugs with stereoselectivities in the range of 1.0 to 1.8 (Table 4.3). The renal clearance of quinidine has been reported to be four times greater than that of its diastereoisomer quinine.

The renal clearance of diastereoisomeric glucuronide conjugates of both ketoprofen and propranolol have also been reported to show stereoselectivity. In both cases renal clearance is selective for the S-enantiomer conjugate of the drug with selectivities of 3.2 and 1.3 fold for propranolol and ketoprofen respectively.

Relatively little is known regarding the stereoselectivity of the active processes involved in the biliary secretion of drugs. Differences in the biliary recovery of enantiomers has been reported, e.g. acenocoumarol in the rat, however it is not clear if this is due to stereoselectivity in biliary clearance or as a result of other stereoselective processes.

Table 4.3 Stereoselectivity in renal clearance of basic drugs in man.



Disopyramide Chloroquine Pindolol Metoprolol

4.4.5 Pharmacokinetic Parameters

As a result of the above processes compounds administered as racemates rarely exist as 1:1 mixtures of enantiomers in biofluids and tissues, and do not reach their sites of action in equal concentration. The pharmacokinetic profiles of the enantiomers of a racemic drug may differ markedly and hence an estimation of pharmacokinetic parameters, or an examination of drug concentration-effect relationships based on "total" drug, i.e. the sum of the two enantiomer concentrations, present in biological samples may at best yield data of limited value and is potentially highly misleading.

The magnitude of the differences between enantiomers in their pharmacokinetic parameters tend to be relatively modest, frequently 1 to 3 fold, compared to those observed in their pharmacodynamic properties. The differences may however be attenuated depending upon the organisational level that the particular parameter characterises, i.e. the whole body (e.g. systemic clearance, volume of distribution, elimination half-life), whole organ (e.g. hepatic clearance, renal clearance) and macromolecular (e.g. intrinsic metabolite formation clearance, fraction unbound). Thus differences in parameters which reflect the whole body level of organisation may be modest, being composed of potentially multiple organ selectives which intern reflect the selectivity of multiple macromolecular interactions. Differences between enantiomers are potentially greatest in these latter parameters which are associated with a direct interaction with a chiral macromolecule. The stereoselectivity of such multiple processes may vary between enzymes, proteins and organs and it is therefore possible that a comparison of parameters that reflect the whole body level of organisation may mask stereoselectivity at an organ or macromolecular level. For example the ratio (R/S) of the plasma half-lifes, systemic clearance and volume of distribution of the enantiomers of propranolol (Section 4.6.2) are 1.01, 1.17 and 1.18 respectively. However, the plasma protein binding of propranolol shows a preference for the S-enantiomer (Table 4.2) whereas the metabolic clearance via 4-hydroxylation is greater for the R-enantiomer (Table 4.4).

For drugs which are subject to extensive stereoselective first-pass, or presystemic metabolism, the differential bioavailability of the individual enantiomers may give rise to apparent anomalies in drug-concentration effect relationships with route of administration if the enantiomeric composition of material in plasma is not taken into account. Thus, based on measurements of "total" plasma concentrations verapamil appears to be more effective when given intravenously than orally, whereas propranolol shows the opposite effect. In both cases the likely explanation for the observed effects is stereoselective presystemic metabolism which in the case of verapamil is selective for the more active S-enantiomer and for propranolol the less active R-enantiomer (Sections 4.6.1 and 4.6.2).

Care is also required in therapeutic drug monitoring of chiral drugs administered as racemic mixtures. The determination of the plasma concentrations of the individual enantiomers of chiral drugs would be advantageous to define the "real" therapeutic range of such compounds. The therapeutic range of "total" tocainide covers a three fold concentration range whereas the enantiomeric composition of the drug in plasma varies up to two fold.

Stereochemical considerations may also be of significance for understanding drug interactions both between chiral drugs and a second agent (Section 4.6.3) and also to rationalize differences in the disposition of chiral drugs when given as racemic mixtures or single isomers (Section 4.6.1).


As pointed out previously the most important differences between enantiomers occur at the level of receptor interactions, and eudismic ratios are frequently of the order of 100 to 1000 fold. However, it is frequently the case that the "inactive" or less active isomer may contribute to the observed activity of a racemic mixture and a number of possible situations may arise as indicated below.

4.5.1 The pharmacological activity resides in one enantiomer the other being biologically inert

There are relatively few examples of drugs which possess one or two chiral centres as part of their structure in which the pharmacological activity is restricted to a single enantiomer the other being totally devoid of activity. In the case of a-methyldopa the antihypertensive activity resides exclusively in the 5-enantiomer and this agent is marketed as a single isomer. There are a number of examples, e.g. the P-blockers, where the activity is of the order of one to two orders of magnitude greater but in other actions of these agents stereoselectivity is not observed (Section 4.6.2). For compounds with more than two chiral centres it is frequently found that the configurations of all such centres are fixed requirements or activity/specificity in action is lost, e.g. steroids, ACE inhibitors, e.g. enalapril which has the 555-configuration, the 55R isomer being 10-4 fold less active.

4.5.2 Both enantiomers have similar activities

Both enantiomers of the antihistamine promethazine (4.88) have similar pharmacological and toxicological properties, and the introduction of the chiral centre in the dimethylaminoethyl side chain results in a 100% increase in antihistaminic potency compared to the non-chiral analogue. In contrast the enantiomers of the 1-aza substituted derivative, isothipendyl (4.89), have similar activities in vitro but in vivo the (-)-enantiomer is ca half as potent as the (+)-isomer and both are less potent than the racemate. The reason for this observation is by no means clear but may be due to differences in drug disposition, e.g. inhibition of metabolism of the (+)-enantiomer by its antipode.

Similarly, the enantiomers of flecainide (4.90) are equipotent with respect to antiarrhythmic activity, effect on cardiac sodium channels and show no significant

differences with respect to their pharmacokinetic properties. In the case of flecainide little information is available with respect to the toxicity of the individual isomers but the use of a single isomer would appear not to offer a therapeutic advantage.

4.5.3 Both enantiomers are marketed with different indications

The example of dextropropoxyphene (4.55) and levopropoxyphene (4.56) being marketed as analgesic and antitussive agents has been cited previously. Similar differences in activity are found with related opiate derivatives, e.g. dextromethorphan, (+)-3-methoxy-N-methylmorphinan, is a useful antitussive agent which is virtually free from analgesic, sedative or other morphine like effects. Whereas the enantiomer, levomethorphan is a potent opioid with antitussive activity and is addictive.

4.5.4 The enantiomers have opposite effects

Picenadol (4.91) is a phenylpiperidine analgesic that has both opioid agonist and antagonist activity. The analgesic activity resides entirely in the (+)-3S,4R-enantiomer and the (-)-3R,4S-enantiomer is an antagonist. The racemate exhibits the properties of a partial agonist due to the more potent activity of the (+)-isomer at the p opioid receptor and the weak antagonist action of (-)-picenadol at the same receptor.

The pharmacological activities of the enantiomers of several derivatives of aporphine have been examined and in each case the S-enantiomers appear to be antagonists of their

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