Drug Chirality

Many drugs are asymmetric. At least 25%are marketed as racemic mixtures (17). The Unit ed States Pharmacopeia recognizes this in defining the chemical standards for many drugs (18). Examples include:

Clomiphene Citrate, USP (Fig. 7.8)

Clomiphene citrate contains not less than 98.0% and not more than 102.0% of a mixture of the (E)- and (2)-geometric isomers of C20H28ClNOAC6H8O7, calculated on an anhydrous basis. It contains not less than 30.0% and not more than 50.0% of the 2-isomer.

Doxepin Hydrochloride, USP (Fig. 7.9)

Doxepin hydrochloride, an (.E)- and (Z)-geometric isomer mixture, contains the equivalent of not less than 98.0% and not more than

Clomiphene Citrate Racemic
Figure 7.8. Clomiphene isomers.

102.0% cf doxepin (C19H21NOAHCl), calculated on a dried basis. It contains not less than 13.6% and not more than 18.1% of the (Z)-isomer and not less than 81.4% and not more than 88.2% of the (^-isomer.

Although not specifically defined as a mixture, it is clear from the assay procedure that it is a mixture. The chromatographic procedure requires preparation of a resolution solution consisting of a mixture of equal volumes of the Cefprozil (2)-isomer standard preparation and of the stock solution used to prepare the Cefprozil (2£)-isomer standard preparation. The final line in the assay reads, "Calculate the quantity, in micrograms of cefprozil (C18H19N3O3S) in each mg of the Cefprozil I taken by adding the values, in micrograms per mg, obtained for the cefprozil (2)-isomer and fcr cefprozil CE)-isomer."

Figure 7.9. Doxepin isomers.

Figure 7.1D. Cefprozil isomers.

It now is realized that many times only one isomer contains the pharmacological activity. The routes of a drug's metabolic degradation also may vary with the isomer. In a few cases, the adverse responses may be stereoselective. Here are a few representative examples in which stereoselectivity can be significant (19).

3.1 Propoxyphene

Dextropropoxyphene [Darvon, (32)] is marketed as an analgesic, and levopropoxyphene (Novrad) as an antitussive (33). (Note that the

Figure 7.9. Doxepin isomers.

Darvon Novrad

brand name Novrad is Darvon spelled backward and, therefore, the mirror image of Darvon.)

3.2 Verapamil

This calcium channel antagonist illustrates why it is difficult to conclude that one isomer

is superior to the other. S-Verapamil (34) is the more active pharmacological stereoisomer than the less active R-verapamil (35), although the former is more rapidly metabolized by the first-pass effect. (First-pass refers to orally administered drugs that are extensively metabolized as they pass through the

7-HydiDxy-S-Warfarin Figure 7.11. CY0450 2C9 metabolism of S-warfarin.
Warfarin Warfarin

Figure 7.12. CYP450 3A4 metabolism of R-warfarin.

R-Warfarin 10-Hydroxy-R-Warfarin

Figure 7.12. CYP450 3A4 metabolism of R-warfarin.

liver. It is not as significant when the drug is administered parenterally because the drug is dispersed before reaching the liver.) Therefore, intravenous administration of the race-mic mixture of verapamil produces a longer duration of action than when administered orally because the more potent S-isomer will be metabolized more slowly.

3.3 Warfarin

The S-isomer of warfarin is more active and is metabolized by the CYP450 2C9 (CYP2C9) isozyme (Fig. 7.11), whereas the R-isomer is metabolized at a different position by CYP450 3A4 (CYP3A4) (Fig. 7.12) (20-22). The fact that two different CYP450 isozymes are required for warfarin metabolism and polymorphism is seen with CYP2C9 increases the chances of drug-drug interactions with this potent anticoagulant. Indeed, the package insert lists 22 different pharmacological classes of drugs that can alter warfarin's pharmacological response, as measured by prothrombin timelinternational normalized ratio (PT/INR). Specific examples are found in Table 7.6.

3.4 Other Examples

There are many synthetic products where the drug is marketed as a specific stereoisomer. Early SAR studies on the phenethyl amines showed that the substituent stereochemistry on both the a-carbon (amine carbon) and j3-carbon (benzylic carbon) is crucial. Dextrorotatory substituents on the /3-carbon increase central activity relative to that of the enantiomeric levorotatory analog. In contrast, levorotatory substituents on the /3-carbon increase peripheral activity relative to that of the dextrorotatory analog. As already mentioned, the dextrorotatory opiates have antitussive activity and low abuse potential whereas the levorotatory opiates are analgesics with such high abuse potential that most are classified as Schedule II drugs by the Drug Enforcement Agency. Sometimes the generic name indicates the specific isomer: dextroamphetamine (Fig. 7.13), dexamethasone (36), dextromethorphan (6), levamisole (37), levobupivacaine (38), levothyroxine (Fig. 7.13), and levodopa (Fig. 7.13).

Table 7.6 Potential Inhibitors and Inducers of Warfarin Metabolism3

Warfarin Isomer

CYP3A4 Inducers

CYP3A4 Inhibitors

R-warfarin Carbamazepine, phenobarbital, dexamethasone, nevirapine, phenytoin, rifabutin, rifampin


Amiodarone, diltiazem, erythromycin, azole antifungals, norfloxacin, zafirlukast, zileuton


S-warfarin Carbamazepine, phenobarbital, phenytoin, primadone, rifampin cimetidine, azole fluoxetine, isoniazid, sertraline, zafirlukast

"Pharmacists Letter, Document 150401 (2001).

"Pharmacists Letter, Document 150401 (2001).

s ch

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