Pharmacological Importance of Chiral Separations - Chiral Separations by Capillary Electrophoresis - page 8

1.4.1 A BSORPTION
Absorption is the process of the movement of the drug from the place of adminis-
tration into the bloodstream. This process requires the transport of drug molecules
through cell membranes. Three possible mechanisms are described: passive dif-
fusion through the membrane, facilitated diffusion via channels or carriers, and
active transport via carriers and pump systems. The absorption of most drugs is
a passive process; however, drugs can also be absorbed via active processes like
receptor-mediated transport. Active absorption may favor one enantiomer or the
two enantiomers may differ in absorption characteristics. l-Dopa, for example, is
actively absorbed from the gastrointestinal tract. d-Dopa, on the other hand, enters
the bloodstream via passive diffusion [20].
The absorption rate is also an important parameter. An example is ibuprofen that
is already described earlier. The chiral inversion of inactive R -ibuprofen to the active
S -enantiomer in the gastrointestinal tract depends on the absorption rate: the longer
the drug stays in the gastrointestinal tract (i.e., low absorption rate), the greater will
be the extent of inversion [35].

1.4.2 D ISTRIBUTION
Once the drug is available in the bloodstream, it will distribute throughout the
different compartments of the body. Two physicochemical properties are essentially
responsible for the distribution of drugs: plasma- and tissue protein binding and
the partition coefi cient. Partitioning into various sites is a physical property and is
therefore not considered as enantioselective. However, binding to proteins, which
consists of chiral building blocks, can show stereoselectivity.
Stereoselective binding of chiral drugs to serum albumin and α 1 -acid glyco-

protein has already been shown. For example, the afi nity for the binding of the
essential amino acid S -tryptophan to the benzodiazepine and indole site of human
serum albumin is about 100 times greater than that of R -tryptophan. An interesting
example is the antihypertensive drug propranolol. S -propranolol binds to

α 1 -acid
glycoprotein to a slightly greater extent than R -propranolol [19,27,35]. However, the
stereoselective binding to human serum albumin is opposite of that observed for
α 1 -acid glycoprotein [20]. The overall stereoselectivity in the binding of propranolol
to human serum resembles that seen for

α 1 -acid glycoprotein, meaning that the
free fraction of the R -enantiomer is higher than that of the pharmacological active
S -enantiomer [27].
Stereoselective distribution may also occur as a result of drug-lipid interactions.
Hanada et al. [36] have observed stereoselective binding of verapamil and disopyra-
mide to phosphatidylserine, a tissue-binding site for basic drugs, with R -verapamil
and R -disopyramide being preferentially bound [20,21,36].
Stereoselective interactions with tissue uptake transporter systems and storage
mechanisms have also been reported [20]. van Bree et al. [37] have studied the trans-
port of baclofen and its enantiomers across the blood-brain barrier in rats. They
showed that the blood-brain barrier clearance of R -baclofen was approximately four
times higher than that of the S -enantiomer. On the basis of their obtained results,