CES1 Metabolic Enzyme

Carboxylesterase 1 (CES1) is the most abundant enzyme in the liver (approximately 1% of liver proteins). CES1 accounts for 80 to 95% of hydrolysis in the liver. It is also found in small amounts in the lungs and brain.
In addition to its important role in the breakdown of xenobiotic compounds, CES1 appears to be involved in endogenous metabolic functions, such as:¹

• Cholesterol esters
• triglycerides
• bioactive lipids

Methylphenidate is primarily metabolized by carboxylesterase 1A1 (CES1) in the liver to ritalinic acid (a-phenyl-2-piperidineacetic acid).² The former assumption that MPH is metabolized by hepatic lysozymal enzymes is now outdated.³
CES1 primarily metabolizes L-MPH and, to a lesser extent, d-MPH. As a result, more d-MPH (dexmethylphenidate) remains in the plasma. Most MPH preparations contain a racemic mixture of d- and L-MPH, although only d-MPH is pharmacologically active.⁴ 60 to 80% of the ingested MPH is excreted in the urine as Ritalin acid.⁵

• Aromatic hydroxylation to p-hydroxymethylphenidate (p-hydroxy-MPH)⁴, accounting for between 1.5 and 12 percent of the degradation.
• Microsomal oxidation to 6-oxo-methylphenidate (6-oxo-MPH; inactive metabolite)⁴, accounting for up to 2.5% of MPH.
• The percentage of MPH excreted unchanged is reported to range from less than 1%⁵ to 2% in urine and 3% in feces⁴

CES1 activity is highly variable. The factors contributing to this variability were still largely unknown in 2018.⁶
There are significant individual differences in the response to many drugs metabolized by CES1.¹ The expression and activity of CES1 vary widely among humans. Therefore, there may be substantial individual differences in the pharmacokinetics and pharmacodynamics of drugs metabolized by CES1. The bioavailability of MPH in children ranges from 11% to 53%.⁷

Factors that influence degradation by CES1 can be non-genetic or genetic in nature:⁸

1. Non-genetic factors that influence CES1 metabolism¶

• Stage of development
• Gender
• Drug interactions (see substrates, inhibitors, inducers)

2. Genetic factors that influence CES1 metabolism¶

The level of CES1 expression is related to the degree of methylation of the CpG islands (CGIs) in the CES1 promoter. Melatonin reduces the level of methylation of the CES1 promoter by promoting the expression of sirtuin 1 (SIRT1), which mediates the deacetylation of DNA methyltransferase 1 (DNMT1).⁹

2.1. CES1 gene variants¶

In a gene variant, a single position in the genetic material is altered (as if a single letter had been swapped). Variants of the CES1 gene influence the rate at which MPH is broken down. However, the available studies tend to show reduced breakdown or a loss of function, which conflicts with the faster breakdown observed in practice in some people with ADHD and the barely observed prolonged effect of MPH.

CES1 gene variants with functional effects are rare. The main factors influencing CES1 metabolism appear to depend on other influences.⁶

To date, just under 200 variants have been found in the CES1/CES1P1 gene region.¹

• genetic polymorphisms
  • Single-nucleotide polymorphisms (SNPs)
    • More than 2,500 single-nucleotide polymorphisms (SNPs) have been identified in the CES1 gene (NCBI dbSNP). Some SNPs, such as G143E, D269fs, E220G, and L40T, are deleterious to the gene’s enzymatic activity and could alter CES1-mediated drug metabolism. However, these variants account for only a small portion of CES1 variability, leaving the majority unexplained.¹⁰
    • G143E (rs71647871)
      • Prevalence: 3.7% among Caucasians¹¹, 3% among 200 Danes, allele frequency 1.6%¹², 2.9% among 173 Hungarians.¹³
      • G143E carriers required less MPH;^{6 12} in one study, the amount was 28% less¹⁴, although up to a 2.5-fold increase in d-MPH AUC was observed at the same dose of MPH¹⁵, and one-third of MPH was metabolized¹⁶. Carriers of the G143E (rs71647871) variant showed a 149% higher AUC of d-MPH than non-carriers after a single dose of 10 mg MPH (median 53.3 vs. 21.4 ng/mL per hour; p < 0.0001). An increased AUC was also observed in patients with a homozygous CES1 duplication. The variant thus explained part of the variation in potency but not in duration of action in individual cases. Genotype-based dose prediction is currently not possible.¹²
      • Participants who were heterozygous for the CES1 G143E variant (p.Gly143Glu from rs71647871)
        • metabolize MPH significantly more slowly¹⁷, about half as fast as non-carriers¹⁸
          • Male G143E carriers who consume alcohol are likely to have a higher risk of MPH overexposure
        • p.Gly143Glu (rs71647871) appears to significantly impair the metabolism of:¹
          • Methylphenidate
          • Trandolapril
          • Oseltamivir
      • p.Gly143Glu resulted in a complete loss of the hydrolytic activity of the enzyme carboxylesterase 1 (CES1) with respect to methylphenidate. This resulted not only in high concentrations but also in elevated hemodynamic parameters (blood pressure/pulse).¹⁹²⁰
      • A computer-aided modeling study identified rs71647871 as a highly significant covariate in determining interindividual differences in MPH metabolism. rs71647871 GA resulted in a 2.4-fold increase in plasma d-MPH exposure. rs71647871 may be a risk factor for adverse effects of MPH.¹⁷
    • p.Asp260fs results in a complete loss of the hydrolytic activity of the enzyme carboxylesterase 1 (CES1) toward methylphenidate. MPH levels and hemodynamic measurements (blood pressure/pulse) were elevated.¹⁹
    • rs115629050 TG (p.Ala270Ser)
      • An in silico simulation showed significantly reduced MPH degradation, with approximately 68% higher plasma d-MPH exposure compared to the wild-type genotype. For rs115629050 TG, the scores were equal to or greater than those for rs71647871 GA in 6 out of 9 models.¹⁷
      • rs115629050 reduces CES1²¹
      • In vitro, rs115629050 TG had no effect on drug metabolism with respect to angiotensin²²
    • E220G (c.662A>G, rs200707504) is thought to be associated with reduced CES1 activity²³
    • c.428G>A (p.Gly143Glu, rs121912777) is thought to be associated with reduced CES1 activity²³
    • c.780delT (p.Asp260fs, rs71647872) is thought to be associated with reduced CES1 activity²³
    • c56G>T (rs3826190) is thought to be associated with reduced CES1 activity²³
    • c.808G>T (rs115629050) is thought to be associated with reduced CES1 activity²³
    • rs114119971 may be associated with reduced CES1 activity:²⁴
      • The average MPH dose for the 2 (out of 99) children with ADHD was 0.42 mg/kg/day, compared to 0.88 mg/kg/day for people without ADHD
    • S75N (rs2307240)
      • appears to increase the activity of CES1 in response to clopidogrel²⁵
      • does not appear to affect CES1 activity in relation to methylphenidate in children²⁶
    • rs3815589
      • does not appear to affect CES1 activity in relation to methylphenidate in children²⁷
    • rs2287194
      • does not appear to affect CES1 activity in relation to methylphenidate in children²⁸
    • rs2244613
      • does not appear to affect CES1 activity in relation to methylphenidate in children²⁹
      • which was significantly correlated with sadness as a side effect of immediate release MPH in A/A carriers
      • rs2244613-G was associated with an increased risk of side effects from MPH in patients with comorbid ASA³⁰
    • rs2002577
      • does not appear to affect CES1 activity in relation to methylphenidate in children³¹
      • tended to correlate with sadness as a side effect of immediate release MPH in G/G carriers
    • rs2307244
      • does not appear to affect CES1 activity in relation to methylphenidate in children³²
    • rs12443580
      • does not appear to affect CES1 activity in relation to methylphenidate in children³³
    • The 75 T/G and 75 G/G polymorphisms appear to be associated with a more severe loss of appetite when taking MPH compared to the T/T variant.³⁴
    • Various CES1A2 promoter haplotypes are thought to be associated with increased CES1 expression:¹
      • 47C,
      • 46T
      • 41G
      • 40
      • 37C
      • 34G
      • 32T
• rs2307235-A
  • Increased risk of side effects from MPH in patients with concomitant ASA use³⁰
• rs8192950-T
  • Increased risk of side effects from MPH in patients with concomitant ASA use³⁰
• rs2302722-C
  • reduced risk of side effects from MPH in patients with concomitant ASA use³⁰
  • Number of copies options⁴
    • The various CES1 variants exist in multiple haplotypes and diplotypes. Individuals may carry more than two active copies of CES1 (i.e., two copies of CES1 and one copy of CES1A2 for a total of three copies, or two copies of CES1 and two copies of CES1A2 for a total of four copies).
      • Individuals can carry more than two active copies of CES1

Stevens et al. compiled studies that examined the effects of genetic variants on the efficacy of MPH.⁴

A model calculation based on healthy individuals estimated that, in the presence of multiple relevant CES1 variants, the exposure to active d-methylphenidate can increase two- to sevenfold. By contrast, the influence of body weight is minimal. At 50 kg, the exposure was 29% higher, and at 100 kg, it was 24% lower than at the reference weight of 70 kg; furthermore, weight did not significantly alter the effect of the gene variants. For dosing purposes, this means that genetically determined variability far exceeds weight-related variability. A dosage based solely on weight cannot therefore account for these differences, which explains why two people of the same weight may require very different doses.¹⁷

2.2. CES1 haplotypes, hybrid genes¶

A haplotype is a chain of several gene variants on the same chromosome that are inherited together as a package.

There are two known haplotypes of CES1:¹⁴⁶

• The first haplotype (“wild type”) is a hybrid gene consisting of
  • CES1P1
    • CES1P1 (CES1A3) is an inactive, truncated pseudogene. It is located near CES1 on chromosome 16. CES1P1 appears to have arisen through gene exchange.
  • CES1A1 (prototype of CES1)
• The second haplotype is a hybrid allele consisting of
  • CES1A1
  • CES1A2 (a CES1-like variant)
    • A computer-based modeling study found significantly reduced MPH degradation and approximately 70% higher plasma d-MPH exposure in individuals with two CES1A2 copies compared to the wild-type genotype¹⁷
    • A CES1A2 copy resulted in approximately 22% higher MPH levels¹⁷
    • CES1A2 showed increased degradation of irinotecan³⁵
    • A clinical study of oseltamivir found that the CES1 diplotype had no effect on metabolism³⁶
    • A study of 99 children on MPH found that:²⁴
      • The average MPH dose was 0.79 mg/kg/day.
      • The mean MPH dose by haplotype was
        • CES1A2/CES1A2: 0.92 mg/kg for
        • CES1A2/CES1P1: 0.81 mg/kg
        • CES1P1/CES1P1: 0.78 mg/kg

As a result, some people carry two nearly identical copies of CES1 on the same chromosome.¹
With four copies of CES1, MPH clearance was lowest, and the MPH AUC was approximately 1.5 times higher than in the control group¹⁵
When there were two or three copies of CES1, the rate of MPH degradation was only slightly reduced¹⁵

Hybrid gene variants include:

• CES1P1 with CES1
  • higher transcriptional activity than CES1P1
• CES1A2 (another hybrid gene variant derived from CES1 and CES1P1)
  • has 2% of the transcription efficiency of CES1
• CES1A1b
• CES1A1c (CES1VAR)
  • has no noticeable effect on the metabolism of medications⁶

2.3. The number of CES1 gene copies influences MPH degradation¶

The number of CES1 gene copies also influences the rate of MPH breakdown. Contrary to the expectation that a higher copy number would be associated with increased breakdown, one study found reduced breakdown. Individuals with 4 CES1 copies had d-MPH levels (AUC) that were 45% (P = 0.011) and 61% (P = 0.028), respectively, higher d-MPH levels (AUC) than control subjects or individuals with 3 copies of CES1.²⁰

2.4. POR gene variants do not affect CES1 metabolism¶

Unlike with CYP 450 enzymes, the efficacy of CES1 is not influenced by genetic variants of the POR gene (cytochrome P450 oxidoreductase, NADPH-P450 oxidoreductase, CPR).

3. CES1 substrates / CES1 inhibitors / CES1 inducers¶

This list—like all information on ADxS.org—is not intended for personal therapeutic use. Although we strive to gather all available information, the list is nonetheless incomplete. Errors cannot be ruled out. Please consult your doctor or pharmacist.

The lower the IC50, the higher the therapeutic potency of an active ingredient.
The smaller Ki is, the greater the binding affinity and the smaller the amount of drug needed to inhibit the enzyme’s activity.
If Ki is much greater than the maximum drug concentration to which a patient is exposed during typical administration, it is unlikely that the drug will inhibit the enzyme’s activity.³⁷
The inhibition constant Ki is the inhibitor concentration at which half of the enzymes are inhibited.
Ki reflects binding affinity, while IC50 indicates the functional potency of an inhibitor for a drug. The calculation of Ki takes IC50 into account.
Noncompetitive enzyme inhibition: Ki approximately equal to IC50
Competitive/noncompetitive inhibition: Ki is approximately half the IC50

3.1. CES1 Substrates¶

CES1 plays a crucial role in the breakdown of various active ingredients.⁸

• 11-Deoxyalisol A (terterpenoid)

• 2-Oxo-clopidogrel (anticoagulant)³⁸

• 25-O-ethylalisol A (triterpenoid)

• Alismanol B (terterpenoid)

• Alismanol D (terterpenoid)

• Alismanol F (terterpenoid)

• Amphetamines (CNS active ingredients)²¹

  • METH
  • although primarily via CYP2D6

• Benzapril (ACE inhibitor, angiotensin receptor-neprilysin inhibitor, ARNI)³⁸

• Capecitabine (cancer drug)

• Cholesterol (endogenous compound)

• Ciclesonide (immunosuppressant, adrenal glucocorticoid)³⁸

• Cilazapril (angiotensin receptor-neprilysin inhibitor, ARNI)³⁸

• Clopidogrel (anticoagulant)³⁹

• Dabigatran e xilate (anticoagulant)³⁹

• Delapril (angiotensin receptor-neprilysin inhibitor, ARNI)³⁸* Clofibrate (antihyperlipidemic agent)³⁸

• Dimethyl fumarate (MS medication)

• Enalapril (ACE inhibitor, angiotensin receptor neprilysin inhibitor, ARNI)³⁸

• Fenofibrate (antihyperlipidemic drug)³⁸

• Fatty acid ethyl ester (endogenous compound)

• Fosinopril (angiotensin receptor-neprilysin inhibitor, ARNI)³⁸

• Flumazenil (CNS active ingredient)

• Heroin (CNS active ingredient)

• Imidapril (ACE inhibitor, angiotensin receptor-neprilysin inhibitor, ARNI)³⁹³⁸

• Irinotecan (cancer drug)

• Cocaine(CNS active ingredient)

• Lovastatin (lipid-lowering drug)³⁸

• Meperidine (CNS active ingredient)

• Methylphenidate (CNS active ingredient)

• Moxeipril (angiotensin receptor-neprilysin inhibitor, ARNI)³⁸

• Mycophenolate mofetil (an immunosuppressant)

• Nintedanib (cancer drug)³⁸

• Oseltamivir (antiviral drug)³⁹

• Oxybutynin (anticholinergic; used, among other things, for urinary incontinence; antispasmodic)³⁸

• Para-nitrophenyl valerate (pesticide)

• Perindopril³⁸

• Quinapril (ACE inhibitor, angiotensin receptor neprilysin inhibitor, ARNI)³⁸

• Ramipril (ACE inhibitor, angiotensin receptor neprilysin inhibitor, ARNI)³⁸

• Rufinamide (CNS active ingredient)

• Sacubitril (angiotensin receptor-neprilysin inhibitor, ARNI; antihypertensive agent)³⁸

• Sarin (chemical warfare agent)

• Simvastatin (hyperlipidemia medication)³⁸

• Sofosbuvir (antiviral drug)

• Soman (chemical warfare agent)

• Tabun (chemical warfare agent)

• Telotristat ethyl (tryptophan hydroxylase inhibitor)³⁸

• Telotristat etiprat (cancer drug)

• Temocapril (angiotensin receptor-neprilysin inhibitor, ARNI)³⁸

• Tenofovir alafenamide (antiviral agent)

• Trandolapril (ACE inhibitor, angiotensin receptor-neprilysin inhibitor, ARNI)³⁸

• Trans-permethrin (pesticide)

• Travoprost (prostaglandin analog)³⁸

3.2. CES1 inhibitors¶

These active ingredients inhibit the breakdown of MPH by CES1 and should therefore, if possible, not be combined with MPH. We hypothesize, however, that for ultra-rapid metabolizers, such a combination could be helpful, provided it is accompanied by particularly close medical monitoring.

• 11-Deoxo-glycyrrhetinic acid (IC50: 10.5 µM) (terterpenoid)
• 1,12-Epoxy-5E,8E,14E-eicosatrienoic acid (IC50: 27 µM) (plant fatty acid)
• 15-Deoxy-12,14-prostaglandin J2 (IC50: 12 µM) (plant-derived fatty acid)
• 22(R)-hydroxycholesterol (unsaturated fatty acid, weak)⁴⁰⁴⁰
• 24(S)-Hydroxycholesterol (unsaturated fatty acid, weak)⁴⁰
• 24(S),25-epoxycholesterol (IC50 = 8.1 μM) (unsaturated fatty acid, moderate)⁴⁰
• 25-Hydroxycholesterin (unsaturated fatty acid, weak)⁴⁰
• 27-hydroxycholesterol (27-HC) (IC50 = 33 nM, Kiapp = 10 nM) (unsaturated fatty acid, partially noncompetitive inhibitor)⁴⁰
  • impaired intracellular CES1 activity following treatment of intact THP1 cells
• 3-O-(-Carboxypropionyl)-11-deoxo-glycyrrhetinic acid 30-ethyl ester (IC50: 20.4 µM) (terterpenoid)
• 4,15-Epoxy-5E,8E,11E-eicosatrienoic acid (IC50: 38 µM) (plant-derived fatty acid)
• 7-ketocholesterol (unsaturated fatty acid, weak)⁴⁰
• Alcohol (strong) ⁴¹⁷
  • When taking alcohol and MPH at the same time:⁴¹
    • Does the MPH concentration increase in humans?
    • Alcohol inhibits CES1-mediated MPH degradation by catalyzing the conversion of MPH to ethylphenidate⁷⁴²
      • It appears that more l-ethylphenidate (pharmacologically inactive) is formed than d-ethylphenidate⁴³
      • Ethylphenidate appears to be toxic
      • Ethylphenidate is associated with significantly higher plasma levels of d-MPH and enhanced euphoric effects⁷
      • Ethylphenidate binds to DAT with similar strength, but binds less strongly to NET than MPH⁴³
• Arachidonic acid (potent) (IC50: 2 µM; Ki: 1.7 µM) (plant-derived fatty acid)⁴⁰
  • the most potent fatty acid inhibitor of recombinant CES1
  • acted through a non-competitive mechanism (Kiapp = 1.7 μM)
• Aripiprazole (high potency) (IC50: 5.7 µM)⁴⁴⁷
• ic acid (triterpenoid), (Ki: 0.64 µM) (potent)³⁸
• Bavachinin (Ki: 0.5 µM) (strong) (plant-based, phenol)³⁸
• Bakuchiol (plant-based)³⁸
• Benzoic acid-4-O-D-(6-galloyl)-glucopyranoside (plant-derived, phenol)³⁸
• Brevifolin (herbal)³⁸
• Cannabidiol (cannabinoid), (Ki: 0.974 µM) (potent)³⁸⁴⁵
  • Nevertheless, CBD (cannabidiol) increased the MPH concentration and AUC only slightly⁴⁶
• cannabinol (cannabinoid), (Ki: 0.263 µM) (potent)³⁸
• , celastrol (triterpenoid), (IC₅₀: 4.43 µM) (potent)³⁸
• Cholesterol (unsaturated fatty acid, low)⁴⁰
• Corilagina (plant-based)³⁸
• Coryfolin (strong) (Ki: 1.9 µM) (plant-derived, phenol)³⁸
• Corylin (strong) (Ki: 0.7 µM) (plant-derived, phenol)³⁸
• Corylifol A (plant-based, phenol)³⁸
• Coryfolin (Ki: 9.4 µM) (plant-derived, phenol)³⁸
• Desmethoxyyangonin (Ki = 25.2 μM)⁴⁷
• Dihydrokavain (Ki = 105.3 μM)⁴⁷
• Dihydromethysticin (Ki = 68.2 μM)⁴⁷
• Dihydrotanshinone (strong) (Ki: 0.39 µM) (Tanshinone)
• Ellagic acid 4-O-D-glucopyranoside (plant-derived, phenol)³⁸
• Euphorbic acid (triterpenoid)
• Euphorbin A (triterpenoid)
• Euphorbin B (triterpenoid)
• Euphorbin C (triterpenoid)
• Fatty acids inhibit CES1⁴⁰
  • particularly unsaturated fatty acids
• Fluoxetine (strong) (IC50: 6.1 µM)⁴⁴⁷
• Gallic acid-4-O-D-(6-O-galloyl)-glucopyranoside (plant-derived, phenol)³⁸
• Gallic acid 3-O-D-(6-O-galloyl)-glucopyranoside (plant-derived, phenol, phenol)³⁸
• Gambogic acid³⁸
• Glycyrrhetinic acid (terterpenoid), (IC₅₀: 13 µM) (potent)³⁸
• Isobavachalcone (plant-derived, phenol)³⁸
• Kaempferol (flavonoid), (Ki: 62 µM)³⁸
• Kavain (Ki = 81.6 μM)⁴⁷
• , cryptotanshinone (tanshinone), (Ki: 0.54 µM) (very potent)³⁸
• Kuwanon G (plant-based, phenol)³⁸
• Linoleic acid (strong) (IC50: 9 µM) (plant-derived fatty acid)
• Linolenic acid (IC50: 19 µM) (plant-derived fatty acid)
• , luteolin (flavonoid), (Ki: 5.34 µM) (potent)³⁸
• Methysticin (Ki = 35.2 μM) (kavalactone)⁴⁷
• Miltiron (strong) (Ki: 0.39 µM) (tanshinone)
• Myristic acid (strong) (IC50: 9 µM) (plant-derived fatty acid)
• Myristoleic acid (IC50: 12 µM) (plant-derived fatty acid)
• Naringenin (flavonoid), (IC₅₀: 30 µM)³⁸
• Neobavaisoflavones (strong) (Ki: 5.3 µM) (plant-derived, phenolic)³⁸
• Oleic acid (strong) (IC50: 7 µM) (plant-derived fatty acid)
• Oheno (plant-based, phenol)³⁸
• Oleanolic acid (triterpenoid), (IC₅₀: 0.28 µM) (strong)³⁸
• Oxysterol⁴⁰
  • Cholesterol metabolite; also inhibits CES1
• Pachyminic acid (triterpenoid), (Ki: 21.7 µM)³⁸
• Paeoveitol B (plant-based, phenol)³⁸
• Palmitic acid (IC50: 25 µM) (plant-derived fatty acid)
• Palmitoleic acid (potent) (IC50: 7 µM) (plant-derived fatty acid)
• Perphenazine (potent) (IC50: 13.9 µM)⁴⁴⁷
• Pyron-2-O-D-(6-galloyl)-glucopyranoside (plant-derived, phenol)³⁸
• Pyron-2-O-D-(2,6-digalloyl)-glucopyranoside (plant-derived, phenol)³⁸
• Pryomeconic acid 3-O-D-glucopyranoside 6-(O-4-hydroxybenzoate) (plant-derived, phenol)³⁸
• Quercetin (flavonoid), (Ki: 33.4 µM)³⁸
• Resveratrol³⁸
• Sanggenon C (plant-based, phenol)³⁸
• Sanggenon D (plant-based, phenol)³⁸
• Scopoletin-7-O-D-(6-galloyl)-glucopyranoside (plant-derived)³⁸
• Sulforaphane³⁸
• Tanshinone I (Tanshinone), (Ki: 26.3 µM)³⁸
• Tanshinon IIA (Tanshinon), (Ki: 6.89 µM) (strong)³⁸
• Tanshinone IIA sulfonate (Ki: 100 µM) (tanshinone)
• Δ⁹-tetrahydrocannabinol (cannabinoid), (Ki: 0.541 µM) (very potent)³⁸⁴⁵
• Thioridazine (potent) (IC50: 7.0 µM)⁴⁴⁷
• Ursolic acid (triterpenoid), (Ki: 0.24 µM) (strong)³⁸
• Compound 12 (triterpenoid)
• Compound 13 (triterpenoid)
• Yangonin (Ki = 24.9 μM)⁴⁷

3.3. CES1 Inductors¶

A combination of methylphenidate and inducers results in a significant decrease in blood levels of MPH.

• Carmabazine is thought to be an inducer of CES1.⁴⁴
• Glucose (sugar)⁴⁸
• Phenobarbital (possible)⁴⁴
• Phenytoin (possible)⁴⁴
• Rifampin (possible)⁴⁴
• Sulforaphane compounds (antioxidant)³⁸, sulforaphane (4-methylsulfinylbutyl isothiocyanate; 1-isothiocyanato-4-methylsulfinylbutane) is a dietary and plant-based phytochemical that occurs in plants as a biologically inactive precursor
  • Sulforaphane is a potent CES1 inducer⁴⁹
• -trinitrobenzenesulfonate (strong)
  • Skin sensitizers, such as those used in testing cosmetic products, can increase CES1 levels by up to 20 times.⁵⁰
• Cinnamaldehyde (strong)
  • Skin sensitizers, such as those used in testing cosmetic products, can increase CES1 levels by up to 20 times.⁵⁰

Practical Benefits of CES1 Genetic Testing¶

A study suggests that genotype-based dose prediction is not currently possible.¹²

A Hungarian study of 173 people with ADHD found an association between carriers of the 143Glu variant and a lower required dose (0.410 vs. 0.572 mg/kg; p = 0.022). The response regarding inattention and hyperactivity remained unchanged. ¹³

In 3 people with ADHD, the need for a very high dose could be explained by genetic factors. In three patients who required 180 to 640 mg of immediate release MPH daily—instead of the maximum dose of approximately 100 mg recommended in the Netherlands—plasma MPH levels were significantly below the model values for a comparison population. Absorption time and volume of distribution were normal, whereas elimination clearance was elevated. CES1 genotyping revealed no variant that would explain the faster metabolism. Despite the extremely high doses, no intolerable side effects occurred. Measurements were taken using daily profiles.⁵¹

In one study, higher CES1 plasma concentrations correlated with lower d-methylphenidate plasma levels. The plasma protein level of CES1 accounted for approximately 50% of the variability in d-MPH plasma levels. It is possible that an individualized dosing strategy based on CES1 measurements could significantly simplify the titration of d-MPH.⁵²