## 3 Pharmacokinetics of Chiral \(\beta\)-Blockers
### Metabolism  
Different enantiomers undergo different transformations in the course of metabolic processes. This can result in the accumulation of the inactive enantiomer, rapid elimination of the active enantiomer, or vice versa. The respective enantiomers of the same \(\beta\)-blockers also activate or inhibit stereoselectively enzymes of the cytochrome P-450 complex. At present, we recognize several isoforms of this cytochrome (e.g., CYP2D6, CYP3A4), which are susceptible to activation or inhibition. \(\beta\)-blockers are degraded by these isozymes and their metabolism can be affected by other substances [91; 92]. Propranolol and other lipophilic \(\beta\)-blockers are metabolized in the liver. Hydrophilic \(\beta\)-blockers (atenolol and sotalol) are excreted via kidneys, in unchanged form or as active metabolites. This is beneficial especially in patients with impaired liver function. \(\beta\)-blockers with equilibrium clearance (e.g., bisoprolol and pindolol) have a low first-pass metabolism, high bioavailability following oral uptake, and are excreted evenly by kidney as well as by liver [93]. Propranolol is metabolized via three main pathways: glucuronidation, hydroxylation of the aromatic ring, and oxidation of the side chain. Upon investigation, eleven metabolites could be identified; approximately 1% was eliminated unchanged. Structures of selected metabolites are given in Figure 12. Hydroxylation of the naphthalene ring in (\(R\))-(\(+\))-propranolol proceeds stereospecifically in positions 4 and 5. The hydroxy derivative of (\(S\))-(-)-propranolol preferentially forms conjugates with glucuronic acid while its optical antipode yields sulfates. Oxidative degradation of the side-chain leads to carboxylic acids (from 1-naphthyl polycarbonate acid to naphthyloxyacetic acid)--a characteristic degradation pathway found in many other aryloxyaminopropanols [94; 95]. Metabolism of propranolol is influenced by genetic polymorphism of the isozymes of cytochrome P-450, especially CYP1A (mphenytoin hydroxylation) and CYP2D6 (debrisoquine hydroxylation). In vitro and in vivo studies revealed that \(N\)-desalkylation of propranolol is catabolyzed by cytochrome subgroup CYP1A and hydroxylation of the naphthalene ring by cytochrome CYP2D6 subgroup. Both metabolic pathways for propranolol are insufficient in slow metabolizers of debrisoquine and mephenytoin (affecting 0.4% of the population). At low concentrations of the substrate the (\(R\))-(\(+\))-enantiomer is metabolized preferentially. The (\(S\))-(-)-isomer of propranolol is metabolized first at higher concentrations. This is due to saturation of first-pass metabolism, especially for (\(R\))-(\(+\))-propranolol. Further investigations are needed to clarify the consequences of this fact for the clinic [95]. As suggested by several studies, some drugs suppress the metabolism of propranolol, in particular of its (\(R\))-(\(+\))-enantiomer. Calcium channel blockers (nicardipine, verapamil, diltiazem) suppress the first-pass metabolism of both enantiomers of propranolol, with a preference for the (\(R\))-(\(+\))-isomer. In a similar way, cimetidine (an antagonist of H2-receptors) reduces clearance of (\(R\))-(\(+\))-propranolol [96]. Quinidine, a selective inhibitor of CYP2D6, diminishes hydroxylation of the aromatic part of propranolol, especially of its (\(R\))-(\(+\))-isomer [97; 98]. Clearance of propranolol was found to be 63% higher in men than in women. The reason for this is the rapid metabolizing of the side-chain and glucuronidation during the first pass through the liver in men [99]. Metoprolol is also metabolized in the liver by cytochrome CYP2D6, involving oxidation and \(\alpha\)-hydroxylation of benzyl (10%). This pathway is stereospecific for (\(S\))-(-)-metoprolol. \(O\)-demethylation and oxidation to carboxylic acids represent the main metabolic routes, particularly for (\(R\))-(+)-metoprolol (65%), and are inhibited by verapamil. The third metabolic pathway involves \(N\)-desalkylation (<10%) [100].