6.2. CYP2D6-Related Biochemical and Hemodynamic Phenotypes in Alzheimer’s Disease
It appears that different CYP2D6 variants, expressing EMs, IMs, PMs, and UMs, influence to some extent several biochemical parameters, liver function, and vascular hemodynamic parameters which might affect drug efficacy and safety. Blood glucose levels are found to be elevated in EMs (*1/*1 vs. *4/*10) and in some IMs (*4/*10 vs. *1xN/*4), whereas other IMs (*1/*5 vs. *4/*4) tend to show lower levels of glucose compared with PMs (*4/*4) or UMs (*1xN/*4). The highest levels of total-cholesterol are detected in the EMs with the CYP2D6*1/*10 genotype (vs. *1/*1, *1/*4 and *1xN/*1). The same pattern has been observed with regard to LDL-cholesterol levels, which are significantly higher in the EM-*1/*10. In general, both total cholesterol levels and LDL-cholesterol levels are higher in EMs (with a significant difference between *1/*1 and *1/*10), intermediate levels are seen in IMs, and much lower levels in PMs and UMs; and the opposite occurs with HDL-cholesterol levels, which on average appear much lower in EMs than in IMs, PMs, and UMs, with the highest levels detected in *1/*3 and *1xN/*4. The levels of triglycerides are highly variable among different CYP2D6 polymorphisms, with the highest levels present in IMs (*4/*10 vs. *4/*5 and *1xN/*1) [11,102,104]. These data clearly indicate that lipid metabolism can be influenced by CYP2D6 variants or that specific phenotypes determined by multiple lipid-related genomic clusters are necessary to confer the character of EMs and IMs. Another possibility might be that some lipid metabolism genotypes interact with CYP2D6-related enzyme products leading to the definition of the pheno-genotype of PMs and UMs. No significant changes in blood pressure values have been found among CYP2D6 genotypes; however, important differences became apparent in brain cerebrovascular hemodynamics. In general terms, the best cerebrovascular hemodynamic pattern is observed in EMs and PMs, with higher brain blood flow velocities and lower resistance and pulsatility indices, but differential phenotypic profiles are detectable among CYP2D6 genotypes. For instance, systolic blood flow velocities (Sv) in the left middle cerebral arteries (LMCA) of AD patients are significantly lower in *1/*10 EMs, with high total cholesterol and LDL-cholesterol levels, than in IMs (*4/*10); and diastolic velocities (Dv) also tend to be much lower in *1/*10 and especially in PMs (*4/*4) and UMs (*1xN/*4), whereas the best Dv is measured in *1/*5 IMs. More striking are the results of both the pulsatility index (PI = (Sv-Dv)/Mv) and resistance index (RI = (Sv-Dv)/Sv), which are worse in IMs and PMs than in EMs and UMs. These data taken together seem to indicate that CYP2D6-related AD PMs exhibit a poorer cerebrovascular function which might affect drug penetration into the brain with the consequent therapeutic implications [11,99,100,101,102,103,104].