Catalytic Selectivity of CYP2D6

Substrates for CYP2D6 include tricyclic antidepressants, p-blockers, class 1 antiarrhythmics. In brief, the structural similarities of many of the substrates and inhibitors in terms of position of hydroxylation, overall structure (aryl-alkylamine) and physicochemistry (ionized nitrogen at physiological pH), have allowed template models such as that illustrated as Figure 7.3 to be constructed.

Fig. 7.3 Template model for CYP2D6 with Y the site of oxidation, a is the distance from Y to a heteroatom which is positively charged (normally 5-7 A).

Fig. 7.3 Template model for CYP2D6 with Y the site of oxidation, a is the distance from Y to a heteroatom which is positively charged (normally 5-7 A).

All the template models produced have the same common features of a basic nitrogen atom at a distance of 5-7 A from the site of metabolism which is in general on or near a planar aromatic system. It is currently believed that aspartic acid residue 301 provides the carboxylate residues which binds the basic nitrogen of the substrates.

With CYP2D6 therefore the catalytic selectivity relies heavily on a substrate-protein interaction. The relative strength of the proposed ion pair association between the basic nitrogen and the active site of aspartic acid means that the affinity for substrates will be high. This is borne out by the enzyme having lower Km and Ki values than other CYPs. Thus CYP2D6 is often a major enzyme in drug oxidation despite its low abundance in human liver. This statement is particularly true for low concentrations or doses of drugs, the low Km values rendering the enzyme easily saturable

(see Section 2.12). An example of this is the antiarrythmic compound propafenone (Figure 7.4) [2] which is converted to 5-hydroxy propafenone by CYP2D6.

The dependence on CYP2D6 metabolism and the relatively high clinical dose (see Figure 7.5) mean that the metabolism is readily saturable over a narrow clinical dose range, so that small increases in dose can lead to disproportionate increases in plasma concentration, and a resultant steep dose-response curve.

Fig. 7.5 Relationship between plasma concentration and dose of propafenone, a CYP2D6 substrate.

Fig. 7.5 Relationship between plasma concentration and dose of propafenone, a CYP2D6 substrate.

1 0 300 450 600 900

1 0 300 450 600 900

CYP2D6 is also problematic in drug therapy since the enzyme is absent in about 7 % of Caucasians due to genetic polymorphism. In these 7 % (poor metabolizers) clearance of CYP2D6 substrates such as propafenone (Figure 7.4) [3] are markedly lower and can lead to side-effects in these subsets of the population. This correlation of enhanced side-effects in poor metabolizers (lacking CYP2D6) compared to extensive metabolizers (active CYP2D6) has been made for propafenone. The example of betaxolol [4] shows how knowledge of the properties that bestow pharmacological activity can be combined with metabolism concepts to produce a molecule with improved performance. Cardioselectivity for p-adrenoceptor agents can be conferred by substitution in the para position of the phenoxy-propanolamine skeleton. The para position or methoxyethyl substituents (e.g. metoprolol) in this position are the major sites of metabolism for these compounds. This reaction is catalysed by CYP2D6, and the efficiency of the enzyme means that metoprolol shows high clearance and resultant low bioavailability and short half-life. Manoury et al. [4] designed the series of compounds leading to betaxolol on the hypothesis that bulky stable substituents in the para position (Figure 7.6) would be resistant to metabolism and also cardioselec-tive.

Fig. 7.6 Structures of metoprolol and betaxolol an analogue designed to be more metabolically stable.

Fig. 7.6 Structures of metoprolol and betaxolol an analogue designed to be more metabolically stable.

Beside the actual steric bulk of the substituent, cyclopropyl is much more stable to hydrogen abstraction than other alkyl functions and represents an ideal terminal group. These changes make betaxolol a compound with much improved pharmacokinetics compared to its lipophilic analogues.

Was this article helpful?

0 0
Defeat Depression

Defeat Depression

Learning About How To Defeat Depression Can Have Amazing Benefits For Your Life And Success! Discover ways to cope with depression and melancholic tendencies! Depression and anxiety particularly have become so prevalent that it’s exceedingly common for individuals to be taking medication for one or even both of these mood disorders.

Get My Free Ebook


Post a comment