CES1 SNPs and their impacts on the PK and PD of CES1 substrate medications
| AA/Nucleotide Change (db SNP ID) | Citation | Treatment | Population | Design/Outcome | Result | Conclusion |
|---|---|---|---|---|---|---|
| G143E (rs71647871) | Patrick et al., 2007; Zhu et al., 2008 | Methylphenidate | n = 20 (with one carrier) | Prospective study | The study unexpectedly found one volunteer with elevated PK parameters of methylphenidate; Cmax of l-methylphenidate was 100-fold higher (62 ng/ml) compared with the rest of participants | The later analysis found this volunteer had G143E and D260fs SNPs, which resulted in elevated plasma concentration of methylphenidate |
| Single dose of 0.3 mg/kg | Healthy volunteers | Aim: to examine the interaction between methylphenidate and alcohol | ||||
| Nemoda et al., 2009 | Methylphenidate | n = 122 (with seven carriers) | Retrospective study | G143E carriers needed lower doses of methylphenidate for symptom reduction compared with noncarriers (0.410 vs. 0.572 mg/kg, P = 0.022) | G143E impaired methylphenidate metabolism in vivo | |
| Dose adjusted based on symptom reduction × 1 mo | Hungarian patients with ADHD | Outcome: methylphenidate dose reduction | ||||
| Stage et al., 2017a | Methylphenidate | n = 22 (with six carriers) | Open labeled, prospective, PK study | G143E carriers showed 152.4% higher AUC (53.3 ng × ml−1 × h−1) compared with the noncarrier group (21.4 ng × ml−1 × h−1) (P < 0.0001) | G143E carriers had higher exposure to methylphenidate compared with noncarriers | |
| Single dose 10 mg | Healthy Danish Volunteers | |||||
| Lewis et al., 2013 | Clopidogrel | n = 506 (with seven carriers) | Retrospective subanalysis of two clinical studies: 1) PAPI Study | 1) A 50% higher active metabolite concentration was observed in G143E carriers (n = 7, 30.3 ng/ml) compared with noncarriers (n = 499, 19.0 ng/ml) (P = 0.001) | G143E carriers had higher plasma concentrations of clopidogrel active metabolites and consequently had a higher antiplatelet effect | |
| 1) Patients in PAPI received 300 mg loading dose (LD) with 75 mg maintenance dose (MD) | n = 350 (with six carriers) | 2) Patients who were clopidogrel-treated at Sinai Hospital | ||||
| 2) Patients from Sinai Hospital received either 300 or 600 mg LD (n = 204) with MD, or just received 75 mg MD | Patient going through percutaneous coronary intervention (PCI) | Outcome: 1) PK parameter: Clopidogrel and its active metabolite concentration 2) PD parameter: ADP-stimulated platelet aggregation | 2) The inhibition of ADP-induced platelet aggregation effect was 24% higher in G143E carriers (reduced to 71% from baseline) compared with noncarriers (reduced to 57% from baseline) (P = 0.003) | |||
| Tarkiainen et al., 2015a | Clopidogrel | n = 22 (with 10 carriers) | Prospective, PK/PD study | 1) AUC0–∞ ratios of the clopidogrel carboxylic acid to clopidogrel was 53% less in G143E carriers (P = 0.009) | G143E carriers had higher exposure to clopidogrel active metabolite, and consequently had a higher antiplatelet aggregation effect | |
| Single dose 600 mg | Healthy volunteers | PD outcome: inhibition of P2Y12-mediated platelet aggregation | 2) Average inhibition of P2Y12-mediated platelet aggregation in the carriers was 19 percentage points higher in noncarriers (P = 0.036) | |||
| Tarkiainen et al., 2015b | Enalapril, Quinapril | n = 22 (with 10 carriers) | Prospective PK study | 1) AUC0–∞ of the enalapril active metabolite enalaprilat was 20% lower in the G143E carriers (n = 10) compared with noncarriers (n = 12) (P = 0.049) | G143E carriers had a lower enalaprilat exposure compared with noncarriers | |
| Single dose 10 mg Enalapril or Quinapril | Healthy volunteers | 2) AUCs0-∞ of the quinapril and its active metabolite (i.e., quinaprilat) were not significantly different between the noncarriers and carriers (P = 0.114) | ||||
| Tarkiainen et al., 2012 | Oseltamivir | n = 22 (with nine G143E heterozygotes, 1 G143E homozygote) | Prospective PK Study | 1) The AUC0–∞ ratio of oseltamivir carboxylate (active metabolite) to oseltamivir (parent molecule) was 23% lower in G143E heterozygotes compared with noncarriers (P = 0.006) | G143E carriers had less exposure to oseltamivir active metabolite compared with noncarriers | |
| Single dose 75 mg | Healthy volunteers | 2) The one G143E homozygous individual had an AUC0–∞ of oseltamivir that was approximately 360% greater than the noncarriers | ||||
| Shi et al., 2016c | Dabigatran | n = 102 human liver samples | In vitro study with human liver samples | The activation rates of DABE, M1, and M2 in G143E carriers were 53% (P = 0.018), 43% (P = 0.004), and 37% (P = 0.001) of normal carriers (after normalized by CES1 expression) | G143E carriers had a lower dabigatran activation rate, potentially resulting in a lower dabigatran active metabolite concentration in the carriers | |
| Shi et al., 2016b | Sacubitril | n = 53 (with five carrier) human liver samples | In vitro study with human liver samples | The activation rates of sacubitril were lower in the carriers compared with the noncarriers (4.2 vs. 7.2 nmol/mg protein/min, P = 0.025) | G143E carriers had a lower sacubitril activation rate, potentially resulting in a lower sacubitril active metabolite plasma concentration in the carriers | |
| E220G (rs200707504) | Oh et al., 2017 | Oseltamivir 75 mg single dose | n = 20 (with eight carriers) | Prospective, PK study | AUC0–48 h of oseltamivir was increased by 10% (P = 0.334) and AUC0–48 h of oseltamivir carboxylate was decreased by 5% (P = 0.513) in carriers | E220G appears to have no significant impact on oseltamivir activation in humans |
| S75N (rs2307240) | Xiao et al., 2017 | Clopidogrel | n = 851 (with 372 carriers) | Retrospective PD analysis | CES1 S75N carriers (n = 372) had more cerebrovascular events (P < 0.001), acute myocardial infarction (P < 0.001), and unstable angina (P < 0.001) compared with noncarriers | S75N appears to increase the function of CES1, resulting in the decreased efficacy of clopidogrel |
| 75 mg × 1 y | Outcome: cerebrovascular events, acute myocardial infarction, and unstable angina | |||||
| Johnson et al., 2013 | Methylphenidate | n = 44 (with 2 carriers) | Naturalistic, prospective study | No significant differences in methylphenidate side effect were found between carriers and noncarriers (P = 1) | S75N does not appear to affect the function of CES1 | |
| Weight based dosing × 6 wk | Children with ADHD | Outcome: side effect reported via behavioral questionnaires | ||||
| Wang et al., 2017 | Enalapril | n = 36 (with three carriers) | In vitro study with human liver samples | No statistical difference in enalapril activation rate or CES1 protein expression level between carriers and noncarriers | S75N does not appear to affect the function of CES1 | |
| −816A>C (rs3785161) | Geshi et al., 2005 | Imidapril | n = 105 (with 47 carriers) | Prospective clinical study | Greater systolic blood pressure reduction (24.1 mm Hg) was observed compared with noncarriers (17.6 mm Hg) after 8 wk of imidapril therapy (P = 0.0184) | −816A>C appears to up-regulate the CES1P1 VAR expression |
| 5–10 mg × 8 wk | Patients with hypertension | |||||
| Xie et al., 2014 | Clopidogrel | n = 162 (with 75 carriers) | Retrospective PD analysis | The carriers had decreased VASP-PRI (45.93 vs. 53.18%) (P = 0.014) | −816A>C appears to up-regulate the CES1P1 VAR expression | |
| 300 or 600 mg (LD) or 75 mg (MD) for minimum 5 days | Patient on dual antiplatelet therapy (i.e., aspirin and clopidogrel) with coronary heart diseases | Outcome: VASP-PRI to measure platelet reactivity | ||||
| Zou et al., 2014 | Clopidogrel | n = 249 (with 108 heterozygous carrier, 17 homozygous carrier) | Retrospective PD analysis | A lower ADP-induced maximum platelet aggregation (21.5%, n = 125) was observed compared with noncarriers (31.7%, n = 124) (P = 0.001) | −816A>C appears to down-regulate the CES1P1 VAR expression | |
| 300 mg LD + 75 mg MD × 3 day | Patient going throught PCI | Outcome: maximum platelet aggregation (MPA) | ||||
| Zhu et al., 2016 | Trandolapril | 1) n = 486 (with 109 heterozygous carriers, 10 homozygous carriers) | 1) Retrospective analysis of the INternational VErapamil SR Trandolapril Study | 1) No association between the -816A>C and the blood pressure–lowering effect of trandolapril | −816A>C does not appears to be associated with overall CES1 function | |
| 2–4 mg × 104 wk | 2) n = 100 (in vitro study) (26 heterozygous carriers, three homozygous carriers) | 2) In vitro study with human liver samples | 2) Not associated with CES1 protein expression and trandolapril activation in human liver samples | |||
| Outcome: blood pressure | ||||||
| −75G>T (rs3815583) | Bruxel et al., 2013 | Methylphenidate | n = 205 (with 129 carriers) | Retrospective PD analysis | The carriers had worse appetite reduction compared with noncarriers (41% vs. 77%, P = 0.01) | −75G>T appears to be associated with decreased CES1 function |
| Dose titrated up × 3 mo as tolerable | Outcome: appetite reduction - the side effect of methylphenidate | |||||
| Sai et al., 2010 | Irinotecan | n = 177 | Retrospective PK analysis | The carriers had higher plasma (SN-38 + SN-38G)/irinotecan AUC ratios relative to noncarriers (P = 0.027) | −75G>T appears to be associated with higher CES1 function | |
| 100 mg m−2 weekly or 150 mg m−2 biweekly | 177 Patients who were Japanese with cancer | |||||
| Nelveg-Kristensen et al., 2016 | ACEI | n = 200 Patients with congestive heart failure | Retrospective PD analysis | The -75G>T genotypes did not significantly impact the plasma ATII/ATI ratios in the study subjects or fatal outcomes (i.e., cardiovascular death and all-cause death) | −75G>T was not associated with CES1 function | |
| 1168-33C>A (rs2244613) | Paré et al., 2013 | Dabigatran | n = 2944 (with 587 carriers) | Retrospective Genome-Wide Association Study (GWAS) of Randomized Evaluation of Long-term Anticoagulation Therapy clinical trial | The carriers had lower trough concentrations of the active metabolite (15% decrease per allele; P = 1.2 × 10−8) and a lower risk of any bleeding (odds ratio, 0.67; P = 7 × 10−5) compared with noncarriers | 1168-33C>A appears to be associated with lower CES1 function |
| 110 or 150 mg twice daily | Patients with atrial fibrillation (within 6 mo) and additional risk factors for stroke | Outcome: trough concentrations of dabigatran, bleeding risk | ||||
| Shi et al., 2016b | Dabigatran | n = 102 (with 29 heterozygous carriers and five homozygous carriers) | In vitro study with human liver samples | No association between 1168-33C>A and dabigatran activation | 1168-33C>A appears to be not associated with CES1 function |