What is CES1A1?
The CES1A1 gene encodes carboxylesterase 1, an enzyme involved in the metabolism of several therapeutic medications and some illicit drugs.2 One of the more studied polymorphisms of the CES1A1 gene is a G>A substitution at codon 143. This substitution results in a glycine to glutamate amino acid change (Gly143Glu).2 The CES1A1 Gly143Glu polymorphism is associated with reduced enzyme activity.^2-17 Therefore, since CES1A1 is the primary enzyme responsible for the metabolism of methylphenidate (MPH)1, individuals with the Gly143Glu variant may experience reduced metabolism of this medication.

What do the studies say about the effect of CES1A1 variation on the metabolism of MPH?
This section reviews the studies investigating the effect of the CES1A1 Gly143Glu polymorphism on the metabolism of MPH. This analysis helps determine whether variation in CES1A1 may have a clinically significant impact on MPH metabolism.

Table 1 describes seven studies evaluating the effect of the Gly143Glu variant on MPH metabolism, all of which found the variant to decrease metabolism. This variant was originally discovered in a patient who displayed significant elevations in Cmax (i.e., peak serum concentration) of MPH. The patient was subsequently found to be heterozygous (i.e., having one normal and one variant version of the gene) for the Gly143Glu polymorphism (Gly/Glu).² This finding prompted further investigation of the effect of this polymorphism on MPH metabolism. One in vivo study (n=122) found that Gly/Glu heterozygotes who responded to MPH (n=5) required significantly lower doses of MPH for ADHD symptom reduction.³ Additionally, three other in vivo studies have concluded that the Gly143Glu polymorphism decreases metabolism of MPH.^4-6 One study found that in patients that were heterozygous for the allele, plasma levels of MPH were significantly higher compared to individuals without the variant.⁴ The other two in vivo studies completed further pharmacokinetic and covariate analyses on similar populations, and both found that the Gly143Glu allele reduced metabolism of MPH.^5,6 Two in vitro experiments also found that the Gly143Glu polymorphism impaired CES1A1 catalytic activity, resulting in a substantial decrease in the metabolism of MPH.^2,7

Table 1: Studies Evaluating the Effect of the Gly143Glu Variation on MPH Metabolism

What do the studies say about the effect of CES1A1 variation on the metabolism of other CES1A1 substrates?
This section reviews the studies investigating the effect of the CES1A1 Gly143Glu polymorphism on the metabolism of other medications that are substrates of CES1A1. Since the metabolism of CES1A1 substrates may be affected by the Gly143Glu polymorphism, studies involving this polymorphism and other substrates (besides MPH) can be used to help understand the general effect of the Gly143Glu polymorphism.

Since there is evidence that CES1A1 is substrate specific,⁸ it is important to investigate the data for individual medications. Table 2 describes eleven studies, six in vitro and five in vivo, that have investigated the effect of the Gly143Glu variant on the metabolism of other CES1A1 substrates. All in vitro studies concluded that Gly143Glu led to decreased metabolism of the respective prodrugs, which may indicate lower levels of the biologically active compound. One in vitro study found that the Gly143Glu variant resulted in decreased metabolism of the prodrug trandolapril.⁹ Similarly, other in vitro studies showed that the Gly143Glu variation led to decreased activation of the prodrugs oseltamivir, sacubitril, enalapril, and dabigatran.^10,11,12,13 CES1A1 also plays a role in metabolizing clopidogrel, as well as its active metabolite, into inactive metabolites. One in vitro study found that the Gly143Glu variation resulted in increased levels of clopidogrel and its active metabolite.⁷

Preliminary evidence for oseltamivir was confirmed by an in vivo study (n=22) which showed that those with the heterozygous genotype (Gly/Glu) had an 18% increase in the mean AUC of oseltamivir compared to non-carriers. The metabolism of oseltamivir was even more impaired in the one subject with the Glu/Glu genotype, whose mean AUC value was approximately 290% and 360% greater than those with the Gly/Glu or Gly/Gly genotypes, respectively.¹⁴ Furthermore, in vivo data supports the previous findings regarding clopidogrel; two studies (n=528) found that individuals with the Gly/Glu genotype had significantly higher levels of clopidogrel active metabolite.^15,16 Subsequent in vivo studies with enalapril provided mixed results. One study (n=22) found that the Gly143Glu allele resulted in significantly reduced activation of enalapril,¹⁷ while another (n=44) found no significant differences between carriers and noncarriers.⁸ Quinapril has also been studied in vivo (n=22), and the Gly143Glu allele had no observable effect on hydrolytic activation.¹⁷

Table 2: Studies Evaluating the Effect of the Gly143Glu Variation on Metabolism of Other CES1A1 Substrates

Methodology: The search was conducted within the PubMed database. Results were limited to studies written in English, performed in vitro or on human subjects, and focused on the CES1A1 Gly143Glu polymorphism and medication metabolism. After irrelevant studies were eliminated, a total of 10 in vivo studies and 8 in vitro studies entered the metabolism review.

References

1. Sun, Z. et al. Methylphenidate is stereoselectively hydrolyzed by human carboxylesterase CES1A1. J. Pharmacol. Exp. Ther. 310, 469–476 (2004).
2. Zhu, H. J. et al. Two CES1 Gene Mutations Lead to Dysfunctional Carboxylesterase 1 Activity in Man: Clinical Significance and Molecular Basis. Am. J. Hum. Genet. 82, 1241–1248 (2008).
3. Nemoda, Z., Angyal, N., Tarnok, Z., Gadoros, J. & Sasvari-Szekely, M. Carboxylesterase 1 gene polymorphism and methylphenidate response in ADHD. Neuropharmacology 57, 731–733 (2009).
4. Stage, C. et al. The impact of CES1 genotypes on the pharmacokinetics of methylphenidate in healthy Danish Subjects. Br J Clin Pharmacol. 83, 1506-1514 (2017).
5. Stage, C. et al. The impact of human CES1 genetic variation on enzyme activity assessed by ritalinic acid/methylphenidate ratios. Basic Clin Pharmacol Toxicol. 125, 54-61 (2019).
6. Lyauk Y. K. et al. Population Pharmacokinetics of Methylphenidate in Healthy Adults Emphasizing Novel and Known Effects of Several Carboxylesterase 1 (CES1) Variants. Clin Transl Sci. 9, 337-345 (2016).
7. Zhu, H. J. et al. Carboxylesterase 1 as a Determinant of Clopidogrel Metabolism and Activation. J. Pharmacol. Exp. Ther. 344, 665–672 (2013).
8. Stage, C. et al. The Pharmacokinetics of Enalapril in Relation to CES1 Genotype in Healthy Danish Volunteers. Basic Clin Pharmacol Toxicol. 121, 487-492 (2017).
9. Zhu, H. J., Appel, D. I., Johnson, J. A., Chavin, K. D. & Markowitz, J. S. Role of carboxylesterase 1 and impact of natural genetic variants on the hydrolysis of trandolapril. Biochem. Pharmacol. 77, 1266–1272 (2009).
10. Zhu, H. J. & Markowitz, J. S. Activation of the antiviral prodrug oseltamivir is impaired by two newly identified carboxylesterase 1 variants. Drug Metab. Dispos. 37, 264–267 (2009).
11. Shi, J. et al. Sacubitril is Selectively Activated by Carboxylesterase 1 (CES1) in the Liver and the Activation Is Affected by CES1 Genetic Variation. Drug Metab Dispos. 44, 554-559 (2016).
12. Wang, X. et al. Ces1 genetic variation affects the activation of angiotensin-converting enzyme inhibitors. Pharmacogenomics J. 16, 220-230 (2016).
13. Shi, J. et al. Dabigatran etexilate activation is affected by the CES1 genetic polymorphism G143E (rs71647871) and gender. Biochem Pharmacol. 119, 76‐84 (2016).
14. Tarkiainen, E. K. et al. Carboxylesterase 1 polymorphism impairs oseltamivir bioactivation in humans. Clin. Pharmacol. Ther. 92, 68–71 (2012).
15. Lewis, J. P. et al. The functional G143E variant of carboxylesterase 1 is associated with increased clopidogrel active metabolite levels and greater clopidogrel response. Pharmacogenet. Genomics 23, 1–8 (2013).
16. Tarkiainen, E. K. et al. Carboxylesterase 1 c.428G>A single nucleotide variation increases the antiplatelet effects of clopidogrel by reducing its hydrolysis in humans. Clin. Pharmacol. Ther. 97, 650–658 (2015).
17. Tarkiainen, E. K. et al. Effect of carboxylesterase 1 c.428G>A single nucleotide variation on the pharmacokinetics of quinapril and enalapril. Br J Clin Pharmacol. 80, 1131-1138 (2015).