## 3 Pharmacokinetics of Chiral \(\beta\)-Blockers
### Metabolism
\(\alpha\)-Hydroxymetoprolol possesses only one tenth of the activity of metoprolol. However, the hydroxylation of benzyl leads to formation of a new stereogenic center. Studies in vitro and in vivo revealed preferred formation of the (1'\(R\))-configuration [101]. Due to genetic polymorphism, the concentration of racemic propranolol after the administration was 6 times higher in slow metabolizers of debrisoquine as compared to normal metabolizers. Moreover, drugs inhibiting cytochrome CYP2D6, such as chloroquine and halofantine ( antimalarialials), propafenone (an antidysrhythmic), as well as inhibitors of selective reuptake of serotonin, decrease the clearance of metoprolol. Investigations in healthy persons showed that co-administration of metoprolol and paroxetin leads to marked increase in bioavailability, plasma levels, and biological half-life of metoprolol. At the same time, higher concentration of (\(R\))-metoprolol was observed. Cimetidine markedly improves the bioavailability of metoprolol, approx. one third of this increase being attributable to the (\(S\))-enantiomer and the remainder to the (\(R\))-isomer. Thus, it should not  
Figure 12: Chemical structures of selected metabolites of propranolol. come as a surprise that it is difficult to observe this interaction in the clinic. The antituberculotic rifampicin (an activator of microsomal enzymes), on the other hand, lowers the bioavailability of metoprolol [102; 103; 104]. [PERSON] et al. [105] reported a method for determination of metoprolol and \(\alpha\)-hydroxymetoprolol in human serum. The method is aimed at the evaluation of the enzyme phenotype of CYP2D6 with metoprolol as substrate. A survey of different methods for determination of metoprolol along with its metabolite \(\alpha\)-hydroxymetoprolol is presented in the report. The respective stereoisomers of metoprolol were determined in plasma by stereoselective HPLC combined with tandem mass spectrometry. Chiral column Chirobiotic T with methanol/acetic acid/ammonia 100/0.15/0.15 \(v/v/v\) as the mobile phase was employed. Ion trap in combination with ESI ion source in positive ion mode was used for MS detection. The structures of selected metabolites of metoprolol are depicted in Figure 13.  
Carvedilol is metabolized mainly by CYP2D6, a small part also by cytochrome CYP3A4. Thus, its biological half-life will be prolonged in patients with impaired liver function. (\(S\))-caryedilol is metabolized by CYP2D6 and its (\(R\))-antipode by CYP2D9 [106]. In slow metabolizers of carvedilol only the metabolism of the (\(R\))-(\(+\))-isomer is inhibited, leading to marked increase in \(\alpha_{1}\)-adenolytic activity, while the \(\beta\)-adenolytic activity remains unaffected. The particular metabolism of carvedilol could contribute to its long-term \(\beta\)-blocking activity [106]. It was reported [77] that in patients with chronic heart failure the plasma levels of carvedilol and its enantiomers were elevated in equilibrium state. [PERSON] et al. [107] described the stereoselective glucuronidation of carvedilol by UDP-glucuronosyltransferase in liver and in intestinal microsomes using racemic carvedilol and its enantiomers, respectively. As with other \(\beta\)-blockers, chiral HPLC was employed in the studies of pharmacokinetics of carvedilol. [PERSON] [108] reports an increase in bioavailability and biological half-life of (\(R\))-(\(+\))-caryedilol upon combination with fluoxetine (an antidepressant). With the exception of metoprolol, carvedilol, and propranolol, the influence of stereochemical configuration on the pharmacokinetics of \(\beta\)-blockers is only moderate. With acebutolol, higher plasma  
Figure 13: Chemical structures of some metabolites of metoprolol. levels were attained with its (\(S\))-(-)-enantiomer, probably as a result of first-pass metabolism of (\(R\))-(+)-enantiomer [109]. Bisoprolol reaches bioavailability of around 90%, due to its relatively minor first-pass effect. It is metabolized by cytochromes.