Ceiburaiine468 bupivacaine

Differences in absorption may also be observed if the individual enantiomers differ in their effects on local blood flow. For example (-)-bupivacaine (4.68) has a longer duration of action than (+)-bupivacaine following intradermal injection. This difference in activity is due to the vasoconstrictor effects of the (-)-enantiomer reducing blood flow and hence systemic absorption. In vitro both enantiomers have similar potencies.

4.4.2 Distribution

Protein binding

The majority of drugs undergo reversible binding to plasma proteins. In the case of chiral drugs the products of such binding are diastereoisomeric complexes and individual enantiomers would be expected to show differences in binding affinity. Such differences in binding affinity result in differences between enantiomers in the free, or unbound, fraction which is able to distribute into tissue (Table 4.1). The two most important plasma proteins with respect to drug binding are human serum albumin (HSA) and a1-acid glycoprotein (AGP). In general acidic drugs bind predominantly to HSA, whereas basic drugs bind predominantly to AGP.

Differences between enantiomers in plasma protein binding are relatively small (Table 4.1) and in some cases less than 1%. However, such low stereoselectivity in binding may result in much larger differences in the enantiomeric composition of the unbound fraction particularly for highly protein bound drugs, e.g. in the case of indacrinone the free fractions are 0.9% and 0.3% for the (-)-R and (+)-S-enantiomers respectively, i.e. a three fold difference in the free fraction. An extreme example of stereoselectivity in binding is the amino acid tryptophan, the L-enantiomer binding to HSA with an affinity approximately 100 times greater than that of the D-isomer. In terms of drugs, (^-oxazepam hemisuccinate (4.69) binds to HSA with an affinity 40 times that of the R-enantiomer. However, using bovine serum albumin as a protein source the difference in affinity is only three fold. Such species variation in enantioselectivity in plasma protein binding has also been reported for phenprocoumon and disopyramide.

Enantioselectivity in binding may also vary between HSA and AGP. For example in the case of propranolol the binding to AGP is stereoselective for the S-enantiomer, whereas binding to HSA is selective for (R)-propranolol. In whole plasma the binding to AGP predominates and the fraction unbound of the R-enantiomer is greater than that of (S)-propranolol (Table 4.2).

Enantioselectivity in binding may also vary between HSA and AGP. For example in the case of propranolol the binding to AGP is stereoselective for the S-enantiomer, whereas binding to HSA is selective for (R)-propranolol. In whole plasma the binding to AGP predominates and the fraction unbound of the R-enantiomer is greater than that of (S)-propranolol (Table 4.2).

- oxazepam bemisuccmate

Table 4.1 Stereoselectivity in plasma protein binding.

% Unbound

Ratio

Acidic drugs

Acenocoumarol

(S) 2.0

R) 1.8

1.1

Ibuprofen

(S) 0.64

R) 0.42

1.5

Indacrinone

(S) 0.3

R) 0.9

0.33

Moxalactam

(S) 32

(R) 47

0.68

Phenprocoumon

(S) 0.72

(R) 1.07

0.67

Warfarin

(S) 0.9

(R) 1.2

0.75

Mephobarbitone

(S) 53

R) 66

0.80

Pentobarbitone

(S) 26.5

(R) 36.6

0.72

Flurbiprofen

(S) 0.048

(R) 0.082

0.59

Basic drugs

Chloroquine

(S) 33.4

R) 51.5

0.64

Disopyramide

(S) 22.2

R) 34

0.64

Fenfluramine

(S) 2.8

R) 2.9

0.96

Methadone

(-) 12.4

(+) 9.2

1.3

Mexiletine

(S) 28.3

R) 19.8

1.4

Tocainide

(-) 86-91

(+) 83-89

1.0

Verapamil

(S) 11

R) 6.4

1.7

Table 4.2 Stereoselectivity of the plasma protein binding of propranolol enantiomers.

Protein source

Enantiomer free fraction

Ratio R/S

R

s

Whole plasma

G.2G3

G.176

1.15

HSA

G.6G7

G.647

G.94

AGP

G.162

G.127

1.28

Stereoselectivity in plasma protein binding may also influence drug clearance for compounds with a low extraction ratio as total clearance is proportional to fraction unbound. In addition stereoselective displacement of drug enantiomers from plasma protein binding sites may give rise to complexities in drug interactions (see Section 4.6.3). Interactions between enantiomers for plasma protein binding sites may also result in pharmacokinetic complications. For example the protein binding of disopyramide is stereoselective and concentration dependent and the pharmacokinetic parameters of the individual enantiomers differ depending if the drug is administered as the racemate or single isomer.

Tissue distribution

The extent of tissue distribution of a drug depends on both its lipid solubility and relative tissue-plasma protein binding; for example the apparent stereoselective distribution of (S^-ibuprofen into synovial fluid may be explained by differences in protein binding. Relatively few examples of stereoselectivity in tissue binding are known, however this may occur by selectivity in tissue uptake and storage mechanisms. For example there is evidence that the active S-enantiomers of the P-blocking drugs propranolol and atenolol undergo selective storage and secretion by adrenergic nerve terminals in cardiac and other tissue. The selective incorporation of the A-enantiomers of some of the 2-arylpropionic acid non-steroidal antiinflammatory agents into lipid has also been observed. The selective distribution of these agents is associated with their metabolism and the formation of "hybrid" triglycerides, the mechanism of which will be discussed below (Section 4.7.5). This selective deposition results in the accumulation of these agents into lipid the toxicological significance of which is unknown.

4.4.3 Metabolism

In contrast to other processes involved in drug absorption and disposition, drug metabolism frequently shows marked stereoselectivity. The stereoselective step in metabolism may involve a number of different stages in the enzymic reaction sequence. Thus, the binding of the substrate to the enzyme may be stereoselective and associated with the chirality of the binding site. Selectivity may also be associated with catalysis due to the differential reactivity and orientation of potential target groups with respect to the catalytic site.

An examination of the stereochemistry of drug metabolism is of importance as the individual enantiomers of a racemic drug may be metabolised by different routes to yield different products and they are frequently metabolised at different rates. In addition species differences may occur in the metabolism of individual enantiomers and as data derived from animal studies is used to assess potential toxic hazard to man the information may have little relevance.

The stereoselectivity of the reactions of drug metabolism may be examined on the basis of:

1. substrate stereoselectivity, i.e. the selective metabolism of one enantiomer over that of the other;

2. product stereoselectivity, i.e. the selective formation of one particular stereoisomer rather than other possible stereoisomers;

3. substrate-product stereoselectivity, i.e. the selective metabolism of one of a pair of enantiomers to produce one of a number of possible diastereoisomeric products.

In terms of the stereochemical outcome of metabolic transformations reactions may be divided into five groups as indicated below.

1. Prochiral to chiral transformations

In the case of reactions of this type the molecule acquires chirality by metabolism which may take place at a prochiral centre or at a site remote from it. The antiepileptic drug phenytoin (4.70) has a prochiral centre at carbon-5 of the hydantoin ring system and the two phenyl rings are enantiotopic being pro-S and pro-^ as indicated (4.70). The major route of metabolism of phenytoin in both animals and man involves aromatic oxidation which in man shows product stereoselectivity for formation of (S)-4-hydroxyphenytoin (4.71). In contrast, in the dog oxidation takes place in the pro-^ ring to yield (ft)-3-hydroxyphenytoin the reaction showing species selectivity in both stereochemistry and regiochemistry (position).

It has been pointed out above that sulphoxides may be chiral and therefore the metabolic oxidation of sulphides to sulphoxides will produce chiral metabolites. Cimetidine (4.72) undergoes oxidation at sulphur to yield an optically active sulphoxide (4.73) as a major urinary metabolite. The reaction is product stereoselective for the formation of the (+)-enantiomer, the enantiomeric composition of the material in urine being (+/-) 3:1.

Such metabolic transformations may also differ in their stereochemistry depending upon the enzyme system effecting the reaction. For example the model substrate 4-tolylethylsulphide (4.74) undergoes oxidation to yield a sulphoxide (4.75) but the reaction produces predominantly the ^-enantiomer (>95%) when mediated by the flavin-containing monooxygenase (FMO) and predominantly the S-enantiomer when mediated by the cytochrome P450 system.

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