Chiral pharmacokinetic(absorption and distribution)

By :Maryam kazemiPh.D student of pharmaceutics

• A carbon atom to which four different groups is attached is asymmetric or chiral.

The two resulting isomers, termed optical isomers or enantiomers, are mirror images of each other and have identical physical characteristics.

• Molecules having more than one asymmetric center but which are not mirror images of each other are termed

diastereoisomers and are physically different.

• Solutions of enantiomers rotate polarized light. An enantiomer which rotates light to the right is dextrorotatory, abbreviated as d or (+).

• The other enantiomer will rotate the light to the left by the same absolute magnitude and is laevorotatory, abbreviation I or (-).

• A racemate is an equal mixture of the enantiomers and does not rotate polarized light.

• Chirality and drug development

In pharmaceutical industries:

56% of the drugs currently in use are chiral molecules and 88% of the last ones are marketed as racemates, consisting of an equi molar mixture of two enantiomers.

Although the enantiomers of chiral drugs have the same chemical connectivity of atoms.

they exhibit marked differences in their pharmacology, toxicology, pharmacokinetics, metabolism etc. 

when chiral drugs are synthesized, as much effort goes towards the rigorous separation of the two enantiomers.

This ensures that only the biologically active enantiomer is present in the final drug preparation.

The enantiomers of a chiral drug differ in their interactions with enzymes, proteins, receptors and other chiral molecules too including chiral catalysts.

These differences in interactions, in turn, lead to differences in the biological activities of the two enantiomers, such as

their pharmacology, pharmacokinetics, metabolism, toxicity, immune response etc.

*Surprisingly, biological systems can recognize the two enantiomers as two very different substances. *

Pharmacokinetics stereoselectivty

Absorption • Passive intestinal absorption • Carrier transporter stereoselectivity Distribution • Protein binding• Tissue distribution Metabolism • first pass metabolism • Phase I and phase II metabolism Elimination

Pharmacokinetics and Chirality

Absorption:• The penetration of drugs across biological membranes can be regarded as being largely a passive, and consequently nonchiral .

Absorption and stereoselectivity • Passive intestinal absorption For the majority of racemic drugs, absorption appears to be by passive diffusion , provided no stereoselectivity.

• Carrier mediated transporter :Stereoselective intestinal transporter is the main cause for marked differences in the oral absorption of enantiomers.L-methotrexate have 40 fold higher Cmax and AUC than D-methotrxate.

there was a 15% difference in the bioavailability of the enantiomers of atenolol, Although it was postulated that this was a result of an enantioselective active absorption.

Pharmacokinetic differences resulting out of : stereoisomerism can be in absorption like L‑Methotrexate is better absorbed than D‑Methotrexate. Esomeprazole is more bioavailable than racemic omeprazole.

Active transport, which involves recognition of the enantiomers by the carrier protein, may be expected to demonstrate enantioselectivity

L dopa, methotrexate and folinic acid. It may be expected, however, that unless there is some natural restrict ion to passive absorption, such enantioselectivity would affect only the rate, and not the extent, of absorption.

although levodopa(L-dopa) is absorbed much more rapidly than D-dopa, they are both absorbed to the same extent.

distribution Stereoselectivity in drug distribution may occur as a result of binding to either plasma or tissue proteins and transport via specific tissue uptake and storage mechanisms

The majority of drugs bind in a reversible manner to plasma proteins, notably to human serum albumin (HSA) and/or a1-acid glycoprotein (AGP).

Acidic drugs bind preferentially to HSAbasic drugs predominantely bind to AGP.

• Protein binding Stereoselective plasma protein binding could influence distribution and elimination because the major determinant of drug distribution and elimination is protein binding.

The enantiomers may display different magnitudes of stereoselectivity between the various proteins found in plasma the R-propranolol binding to albumin is greater than S-propranolol .the opposite is observed for 1 -acid glycoprotein.

S‑Warfarin is more extensively bound to albumin than R‑Warfarin, hence it has lower volume of distribution. Levocetrizine has smaller volume of distribution than its dextroisomer .d‑Propranolol is more extensively bound to proteins

than l‑Propranolol.

• Highly albumin bound• Less potent• Highly metabolised• Low plasma concentration

• highly bound to AAG available as unbound

• 40-100 time more potent

• Less metabolized • High plasma

concentration

Protein binding• Particularly large differences in protein binding affinities have been observed between benzodiazepine enantiomers; up to 35-fold for oxazepam hemisuccinate.

• Differences are generally much smaller, but for highly bound drugs these differences may account for significant differences in total renal clearance and total body clearance.

• For disopyramide, enantioselective and concentration dependent protein binding account for the stereoselective differences in renal clearance of the enantiomers following administration of the racemic drug.

distribution• Also of interest is the enantioselective protein binding interaction reported between warfarin and lorazepam acetate.

• R,S-warfarin allosterically increased the binding of S-lorazepam acetate but there was no effect on them R-enantiomer.

• Similarly, S-lorazepam acetate increased the binding of R,S-warfarin

o many antiarrhythmic drugs are marketed as racemates such as disopyramide, encainide, flecainide, mexiletine, propafenone, tocainide, etc.

o The absorption of chiral antiarrhythmics appears to be nonstereoselective. However, their distribution, metabolism and renal excretion usually favour one enantiomer versus the other. In terms of distribution,o plasma protein binding is stereoselective for most of these drugs, resulting in up to two-fold differences between the enantiomers in their unbound fractions in plasma and volume of distribution.

• It is noteworthy that stereoselectivity in binding may vary for different proteins, e.g., the protein binding of propranolol to AGP is stereoselective for the S-enantiomer, whereas binding to HSA favors (R)-propranolol.

• In whole plasma the binding to AGP is dominant so that the free fraction of the R-enantiomer is greater than that of (S)-propranolol.

• Enantioselective tissue uptake, which is in part a consequence of enantioselective plasma protein binding, has been reported.

• For example, the transport of ibuprofen into both synovial and blister fluids is preferential for the S-enantiomer owing to the higher free fraction of this enantiomer in plasma.

• In addition, the affinity of stereoisomers for binding sites in specific tissues may also differ and contribute to stereoselective tissue binding, e.g., (S)-leucovorin accumulates in tumor cells in vitro to a greater degree than the R-enantiomer.

• The uptake of ibuprofen into lipids is stereoselective in favor of the R-enantiomer.

Quantitative difference

References:1-Reddy, Indra K., and Reza Mehvar, eds. Chirality in drug design and development. CRC Press, 2004.2-McConathy, Jonathan, and Michael J. Owens. "Stereochemistry in drug action." Primary care companion to the Journal of clinical psychiatry 5.2 (2003): 70.3-Lin, Guo‑Qiang, Jian‑Ge Zhang, and Jie‑Fei Cheng. "Overview of chirality and chiral drugs." Chiral Drugs: Chemistry and Biological Action (2011): 14-18.4-Nguyen, Lien Ai, Hua He, and Chuong Pham-Huy. "Chiral drugs: an overview." Int J Biomed Sci 2.2 (2006): 85-100.5-Lee, Edmund JD, and Ken M. Williams. "Chirality clinical phar-macokinetic and pharmacodynamic considerations." Clinical phar-macokinetics 18.5 (1990): 339-345.