## 3 Pharmacokinetics of Chiral \(\beta\)-Blockers
### Metabolism
Metabolization by CYP2D6 is stereoselective in favor of the (\(R\))-enantiomer, whereas the metabolization by CYP3A4 is not stereoselective [110; 111]. As shown by [PERSON] [112], rifampicin (an activator of CYP3A4) produces a 30% reduction in biological half-life of bisoprolol while cimetidine effects no significant changes in the pharmacokinetics of bisoprolol. Timolol is for the greater part metabolized, approx. 20% of it, however, is eliminated unaltered. Besides the main metabolites formed by opening of the morpholine ring, oxidation of one of the methyl groups in the aminopropanol moiety takes place as well, yielding hydroxytimolol. Deamination and oxidation leads to derivatives of thiadazolyloxoacetic acid. In vitro studies confirmed that timolol is metabolized mainly by CYP2D6 while CYP2C19 plays only minor role [113; 114; 115]. The main part of metipranolol is metabolized by desacetylation to desacetylmetipranolol during the first pass through the liver. This metabolite can be further oxidized to yield derivatives of butyric acid [116; 117; 118]. Atenolol is metabolized to a glucuronid. The oxidative hydroxylation of the methylene in the carbamoyl-methyl group provides hydroxyatenolol, which possesses approx. one tenth of the activity of atenol [119; 120]. In comparison with the structure of metoprolol, betaxolol contains a cyclopropylalkyl group in position 4 of the phenol moiety, which gives rise to a slowdown of liver metabolism of this drug. Thus, betaxolol exhibits 6 times slower metabolism, twice higher bioavailability, and a prolongated biological half-life (16-22 h), as compared to metoprolol [121]. As reported by [PERSON], betaxolol is metabolized in rats as well as in humans in a way similar to metoprolol, except that the cleavage of the cyclopropylmethyl group is slower. Merely 15% of betaxolol is subject to first pass metabolism [122]. The ester group present in the structure of esmolol undergoes rapid hydrolysis in blood, leading to quick onset of the pharmacological effect as well as its rapid abatement. Its metabolite, 3-[4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl]propionic acid, has 400 times lower activity toward \(\beta_{1}\)-receptors than esmol [123]. Bopindolol acts as a prodrug, initially undergoing hydrolysis in the organism to provide the active form. In comparison with pindolol, which is excreted partly unaltered, partly as glucuronide and sulfate, the pharmacological effect of bopindolol sets on later but lasts longer [123; 124]. Labetolol contains two stereogenic centers and forms four stereoisomers. Its (\(RR\))-isomer exhibits activity towards \(\beta\)-receptors while the (\(SR\))-isomer is an \(\alpha\)-blocker. A minor part of the drug is excreted from organism in unchanged form, even though the main part is metabolized. The main metabolites are glucuronides, particularly alcohol glucuronides. Labetalol was titrated to male and female patients in order to achieve antihypertensive effect. The parameters were adjusted in accord with the dose. The fraction of the administered drug achieved in the biophase was 80% higher in women, even if the antihypertensive effect remained the same. This observation can be explained by differences in the concentrations of the \(\alpha\)-blocking (\(SR\))-isomer and the relatively inactive (\(SS\))- and (\(SR\))-isomers (60%-80% higher in women) [125; 126]. [PERSON] et al. reported stereoselectivity in the pharmacokinetics of labetalol after its oral administration, as a consequence of liver and first-pass metabolism. Lower levels of the (\(RR\))- and (\(SR\))-enantiomers in blood plasma were confirmed by means of HPLC on a Chirobiotic V chiral columns and mobile phase consisting of methanol/acetic acid/diethylamine [127]. Bufuralol, another \(\beta\)-blocker of the aryloxyaminoethanol type, is metabolized on the basis of debrisoquin polymorphism. It reaches higher levels of the (\(S\))-(-)-enantiomer in slow metabolizers.