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British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 2015 Jun 11;80(5):1131–1138. doi: 10.1111/bcp.12667

Effect of carboxylesterase 1 c.428G > A single nucleotide variation on the pharmacokinetics of quinapril and enalapril

E Katriina Tarkiainen 1, Aleksi Tornio 1, Mikko T Holmberg 1, Terhi Launiainen 1, Pertti J Neuvonen 1, Janne T Backman 1, Mikko Niemi 1
PMCID: PMC4631185  PMID: 25919042

Abstract

Aim

The aim of the present study was to investigate the effects of the carboxylesterase 1 (CES1) c.428G > A (p.G143E, rs71647871) single nucleotide variation (SNV) on the pharmacokinetics of quinapril and enalapril in a prospective genotype panel study in healthy volunteers.

Methods

In a fixed-order crossover study, 10 healthy volunteers with the CES1 c.428G/A genotype and 12 with the c.428G/G genotype ingested a single 10 mg dose of quinapril and enalapril with a washout period of at least 1 week. Plasma concentrations of quinapril and quinaprilat were measured for up to 24 h and those of enalapril and enalaprilat for up to 48 h. Their excretion into the urine was measured from 0 h to 12 h.

Results

The area under the plasma concentration–time curve from 0 h to infinity (AUC0–∞) of active enalaprilat was 20% lower in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (95% confidence interval of geometric mean ratio 0.64, 1.00; P = 0.049). The amount of enalaprilat excreted into the urine was 35% smaller in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (P = 0.044). The CES1 genotype had no significant effect on the enalaprilat to enalapril AUC0–∞ ratio or on any other pharmacokinetic or pharmacodynamic parameters of enalapril or enalaprilat. The CES1 genotype had no significant effect on the pharmacokinetic or pharmacodynamic parameters of quinapril.

Conclusions

The CES1 c.428G > A SNV decreased enalaprilat concentrations, probably by reducing the hydrolysis of enalapril, but had no observable effect on the pharmacokinetics of quinapril.

Keywords: carboxylesterase, CES1, enalapril, p.G143E, quinapril, rs71647871

What is Already Known about this Subject

  • Quinapril and enalapril are prodrugs that are hydrolysed in the liver to active metabolites by carboxylesterase 1 (CES1).

  • The CES1 c.428G > A SNV markedly decreases CES1 activity.

  • There appear to be no previous studies of the effect of CES1 c.428G > A SNV on the pharmacokinetics of ACE inhibitors in humans.

What this Study Adds

  • The CES1 c.428G > A SNV significantly reduced the hydrolytic activation of enalapril, but had no observable effect on quinapril.

  • These data suggest that CES1 genetic variants can affect the pharmacokinetics of angiotensin-converting enzyme (ACE) inhibitors in humans, and that ACE inhibitors differ in their susceptibility to the effects of CES1 genetic variants.

Introduction

The angiotensin converting enzyme (ACE) inhibitors quinapril and enalapril are widely used in the treatment of hypertension and congestive heart failure. Both are ethyl ester prodrugs that are rapidly hydrolysed in the liver to the active metabolites quinaprilat and enalaprilat, respectively 1,2. Parent quinapril and enalapril are relatively weak inhibitors of ACE. However, the active metabolites quinaprilat and enalaprilat are potent inhibitors of ACE, thereby preventing the conversion of angiotensin I to the vasoactive peptide angiotensin II; these effects are mediated by binding to both tissue and plasma ACE 3,4.

Following oral administration, quinapril and enalapril are hydrolysed to the active diacid metabolites quinaprilat (about 40% of an oral dose) and enalaprilat (about 60% of an oral dose) 2,4–8. This bioactivation is catalysed mainly by carboxylesterase 1 (CES1) 9,10, an αβ-hydrolase fold enzyme expressed in various tissues, such as the liver, lungs and adipose tissue, but not in plasma 11–14. A single nucleotide variation (SNV) in the CES1 gene (NM_001025194.1:c.428G > A, p.G143E, rs71647871) has been associated with reduced activity of CES1 in vitro and reduced biotransformation of CES1 substrate drugs, such as methylphenidate, oseltamivir and clopidogrel, in vivo in humans 15–18. In previous in vitro studies, CES1 SNVs have also affected the metabolism of ACE inhibitors, such as trandolapril and imidapril 19,20. However, the effects of CES1 variants on the pharmacokinetics of ACE inhibitors in humans are unknown. The aim of the present study was to investigate the effects of CES1 c.428G > A SNV on the pharmacokinetics of quinapril and enalapril in a prospective genotype panel study in healthy volunteers.

Methods

Subjects

Following a written informed consent, a 12 ml blood sample was drawn into an ethylenediaminetetraacetic acid (EDTA)-containing tube for genotyping from 1109 young healthy Finnish volunteers. Genomic DNA was extracted using standard methods (QIAamp DNA Blood Mini Kit, Qiagen, Hilden, Germany, or Maxwell® 16 LEV Blood DNA Kit, Promega, Madison, WI, USA). The subjects were genotyped for the CES1 c.428G > A SNV by allelic discrimination using the TaqMan® 5′-nuclease assay on an Applied Biosystems 7300 Real-Time polymerase chain reaction (PCR) system (Applied Biosystems, Foster City, CA, USA) or a Life Technologies QuantStudio™ 12 K Flex Real-Time PCR system (Life Technologies, Carlsbad, CA, USA). The CES1 genotyping results have been published previously for 860 of the participants 15. The study was approved by the Coordinating ethics committee of the Hospital District of Helsinki and Uusimaa (record number 48/E0/07).

Of the 1109 genotyped individuals, five women and seven men with the CES1 c.428G/G genotype [mean ± standard deviation: age 24 ± 5 years, height 174 ± 7 cm, weight 75 ± 12 kg and body mass index (BMI) 25 ± 4 kg m–2] and four women and six men with the CES1 c.428G/A genotype (age 26 ± 4 years, height 177 ± 14 cm, weight 70 ± 14 kg and BMI 21 ± 3 kg m–2) participated in a pharmacokinetic study after giving written informed consent. The volunteers were ascertained to be healthy by medical history, physical examination and routine laboratory tests before entering the study. None of the participants used any continuous medication, including oral contraceptives, and none was a tobacco smoker. The pharmacokinetic study was approved by the Coordinating ethics committee of the Hospital District of Helsinki and Uusimaa (record number 228/13/03/00/2012) and the Finnish Medicines Agency Fimea.

Pharmacokinetic study design

In a fixed-order crossover study with two phases, following an overnight fast, the participants ingested a single 10 mg dose of quinapril (Pfizer, Freiburg, Germany) and, after a washout period of at least 1 week, a single 10 mg dose of enalapril (Merck Sharp & Dohme B.V., Haarlem, Netherlands) with 150 ml water at 8 AM. A standardized warm meal was served 4 h and a standardized light meal 7 h and 10 h after quinapril and enalapril ingestion. Systolic and diastolic blood pressures and heart rates were measured twice (mean value was used in the calculations) from the forearm using an automatic oscillometric blood pressure monitor (Omron M6W, Omron Healthcare Co., Ltd., Kyoto, Japan), with the subjects in a sitting position, prior to and at 4 h and 12 h after quinapril and enalapril ingestion. Timed EDTA blood samples (8 ml each) were drawn prior to and up to 24 h after quinapril ingestion, and prior to and up to 48 h after enalapril ingestion for the determination of quinapril, quinaprilat, enalapril and enalaprilat concentrations. The sample tubes were placed on ice immediately thereafter. Plasma was separated within 30 min. Urine was collected up to 12 h after quinapril and enalapril ingestion. Plasma and urine aliquots were stored at –70 °C until analysis. Use of other drugs was prohibited for 1 week before and 3 days after quinapril and enalapril administration. Use of alcohol was prohibited on the day before and the days of quinapril and enalapril administration and on the following blood-sampling days.

Determination of drug concentrations

Plasma samples (100 µl) were prepared for analysis by protein precipitation by acetonitrile containing the internal standards quinapril-d5 (Toronto Research Chemicals, North York, ONT, Canada), enalapril-d5 (Santa Cruz Biotechnology, Inc., St Cruz, CA, USA) and enalaprilat-d5 (Toronto Research Chemicals). Quinapril-d5 served as an internal standard for both quinapril and quinaprilat. The supernatant was evaporated to dryness and the residue was reconstituted with 50 µl of either 35% acetonitrile : 0.1% formic acid in water (quinapril and quinaprilat) or 70% methanol : 0.2% formic acid in water (enalapril and enalaprilat). Urine samples (25–50 µl) were diluted with the acetonitrile-internal standard solution (450 µl) and centrifuged prior to analysis.

The drug concentrations were determined by using an Agilent 1100 series liquid chromatography system (Agilent Technologies, Waldbronn, Germany) coupled to an API 2000 tandem mass spectrometer (AB Sciex, Toronto, ONT, Canada). Quinapril and quinaprilat were separated by an ACE C18-PFP column (3 µm particle size, inner diameter 2.1 × 100 mm; Advanced Chromatography Technologies, Aberdeen, UK) after an ACE3 C18-PFP guard column (2.1 × 10 mm; Advanced Chromatography Technologies), using a linear gradient. The mobile phase A consisted of 0.1% formic acid in acetonitrile and that of B 0.1% formic acid in water. The gradient ran 0.5 min at 35% B, 1.5 min to 70% B, 0.1 min back to 35% B and was held for 9.9 min at 35% B, resulting in a total run time of 12 min. The chromatographic separation of enalapril and enalaprilat was performed with a Waters Sunfire C18 column (3.5 µm, 2.1 × 100 mm; Waters, Milford, MA, USA) equipped with a Waters XBridge guard C18 column (2.1 × 10 mm; Waters), using isocratic separation with 70% methanol and 0.2% formic acid in water and a run time of 5.0 min. For both methods, the mobile phase flow was set at 200 µl min–1 and the injection volume was 10 µl. The mass spectrometry detection was performed using electro-spray ionization in positive mode and monitoring multiple reactions of the [M + H] + precursor ions to the product ions, one mass-to-charge ratio (m/z) transition for each analyte and internal standard: quinapril 439.2–234.1 m/z, quinapril-d5 444.2–239.1 m/z, quinaprilat 411.1–206.2 m/z, enalapril 377.1–234.2 m/z, enalapril-d5 382.1–239.2 m/z, enalaprilat 349.1–206.0 m/z and enalaprilat-d5 354.1–211.0 m/z.

In plasma, the lower limit of quantification was 0.5 ng ml–1 for quinapril and enalapril, and 1.0 ng ml–1 for quinaprilat and enalaprilat. The linear range reached up to 1000 ng ml–1 for quinapril and quinaprilat and up to 300 ng ml–1 for enalapril and enalaprilat. The day-to-day coefficients of variation were below 7% at relevant concentrations for all analytes (n = 7–8). In urine, the lower limit of quantification was 10 ng ml–1 for all analytes. The linear range reached up to 5000 ng ml–1 for quinapril and quinaprilat and up to 3000 ng ml–1 for enalapril and enalaprilat. The intra-day coefficients of variation were below 3.5% at relevant concentrations for all analytes (n = 6).

Pharmacokinetics and pharmacodynamics

The pharmacokinetics of quinapril, quinaprilat, enalapril and enalaprilat were characterized by the peak plasma concentration (Cmax), time to Cmax (tmax), elimination half-life (t½), area under the plasma concentration–time curve from 0 h to infinity (AUC0–∞), amount excreted into urine from 0 h to 12 h (Ae) and renal clearance (Clrenal). The pharmacokinetic parameters were calculated using standard noncompartmental methods using Phoenix WinNonlin, version 6.3 (Certara, St Louis, MO, USA). The pharmacodynamics of quinapril and enalapril were characterized by average systolic and diastolic blood pressures and average heart rates, calculated by dividing the area under the effect–time curve from 0 h to 12 h by 12 h.

Statistical analysis

The results are expressed as geometric means with geometric coefficients of variation (CV) and geometric mean ratios with 95% confidence intervals (CIs) (pharmacokinetic parameters except tmax), arithmetic means with standard deviation (pharmacodynamic parameters) or median with range (tmax) in the text and tables, and as geometric means with 95% CIs in the figures. The data were analysed using the statistical program IBM SPSS 19.0 for Windows (Chicago, IL, USA). The AUC0–∞, Cmax and Ae values were adjusted for 70 kg body weight. The pharmacokinetic parameters (except tmax) were logarithmically transformed before analysis. Differences in the pharmacokinetic (except tmax) and pharmacodynamic parameters between the genotypes were investigated using analysis of variance. The tmax values were compared using the Mann–Whitney U test. Differences were considered statistically significant when P was below 0.05. The number of subjects was estimated to be sufficient to detect a 30% smaller quinaprilat to quinapril or enalaprilat to enalapril AUC0–∞ ratio in subjects with the CES1 c.428G/A genotype than in subjects with the c.428G/G genotype, with a statistical power of at least 80% at an alpha level of 5%.

Results

Effect of CES1 c.428G > A SNV on quinapril

Quinapril Cmax, AUC0–∞, Ae and Clrenal varied 3.4-fold, 3.5-fold, 4.4-fold and 6.0-fold among all subjects, and those of quinaprilat varied 2.5-fold, 3.5-fold, 6.0-fold and 3.2-fold, respectively. The CES1 c.428G > A genotype had no significant effect on the pharmacokinetic or pharmacodynamic parameters of quinapril (Table1, Table2, Figure1). The geometric mean quinaprilat to quinapril AUC0–∞ ratio (CV) was 7.9 (0.38) in subjects with the CES1 c.428G/G genotype and 6.8 (0.47) in those with the c.428G/A genotype. Gender had no significant effect on the pharmacokinetic parameters of quinapril (data not shown).

Table 1.

Pharmacokinetic parameters of a single 10 mg oral dose of quinapril and enalapril in 10 healthy volunteers with the CES1 c.428G/A genotype and 12 with the c.428G/G genotype

Parameter CES1 c.428G/G genotype CES1 c.428G/A genotype c.428G/A to c.428G/G
Geometric mean CV Geometric mean CV Ratio 95% CI P value
Quinapril
 Cmax (ng ml–1) 110 0.28 108 0.33 0.98 0.76, 1.28 0.887
 tmax (h) 0.5 (0.5–1.5) 0.5 (0.5–1.0) 0.582
 t½ (h) 1.1 0.21 1.1 0.22 1.05 0.86, 1.26 0.628
 AUC0–∞ (ng h ml–1) 172 0.24 167 0.35 0.97 0.75, 1.26 0.828
 Ae (mg) 0.41 0.27 0.42 0.49 1.03 0.74, 1.43 0.856
 Clrenal (l h–1) 2.4 0.31 2.5 0.54 1.06 0.74, 1.52 0.756
Quinaprilat
 Cmax (ng ml–1) 359 0.35 303 0.37 0.84 0.62, 1.15 0.270
 tmax (h) 1.5 (1.0–2.0) 1.5 (1.0–2.0) 0.872
 t½ (h) 4.5 0.14 4.9 0.12 1.09 0.97, 1.22 0.140
 AUC0–∞ (ng h ml–1) 1,360 0.24 1,140 0.26 0.84 0.67, 1.05 0.114
 Ae (mg) 3.4 0.52 3.3 0.33 0.98 0.67, 1.43 0.914
 Clrenal (l h–1) 2.6 0.34 3.1 0.15 1.17 0.92, 1.49 0.180
Quinaprilat to quinapril AUC0–∞ ratio 7.9 0.38 6.8 0.47 0.86 0.60, 1.24 0.405
Enalapril
 Cmax (ng ml–1) 87 0.31 74 0.20 0.85 0.68, 1.08 0.178
 tmax (h) 1.0 (0.5–1.5) 1.0 (0.5–1.5) 0.872
 t½ (h) 0.9 0.24 1.0 0.28 1.07 0.85, 1.35 0.539
 AUC0–∞ (ng h ml–1) 145 0.30 131 0.17 0.90 0.72, 1.12 0.334
 Ae (mg) 2.6 0.34 2.1 0.38 0.79 0.58, 1.08 0.136
 Clrenal (l h–1) 18 0.23 16 0.36 0.88 0.68, 1.14 0.321
Enalaprilat
 Cmax (ng ml–1) 47 0.40 34 0.43 0.73 0.51, 1.05 0.085
 tmax (h) 3.5 (2.0–5.0) 3.0 (2.0–5.0) 0.456
 t½ (h) 8.7 0.34 8.9 0.18 1.03 0.80, 1.31 0.825
 AUC0–∞ (ng h ml–1) 386 0.25 308 0.26 0.80 0.64, 1.00 0.049
 Ae (mg) 3.1 0.36 2.0 0.63 0.65 0.43, 0.99 0.044
 Clrenal (l h–1) 11 0.23 9.3 0.32 0.86 0.68, 1.09 0.205
Enalaprilat to enalapril AUC0–∞ ratio 2.7 0.41 2.4 0.38 0.89 0.63, 1.25 0.474
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The AUC0–∞, Cmax and Ae values were adjusted for 70 kg body weight. Tmax data are given as median (range). Abbreviations are as follows: Ae, amount excreted into urine within 12 h; AUC0–∞, area under the plasma concentration–time curve from 0 h to infinity; CI, confidence interval; Clrenal, renal clearance; Cmax, peak plasma concentration; CV, coefficient of variation; tmax, time to Cmax; t½, elimination half-life.

Table 2.

Pharmacodynamic parameters of a single 10 mg oral dose of quinapril and enalapril in 10 healthy volunteers with the CES1 c.428G/A genotype and 12 with the c.428G/G genotype

CES1 c.428G/G genotype CES1 c.428G/A genotype CES1 c.428G/A genotype – c.428G/G genotype
Parameter Mean SD Mean SD Difference 95% CI P value
Quinapril
SBP at baseline (mmHg) 121 13 124 15 2.5 –10, 15 0.684
DBP at baseline (mmHg) 75 6 78 12 2.7 –6, 11 0.496
Heart rate at baseline (min–1) 72 12 66 15 –5.8 –18, 6 0.336
Average SBP (0–12 h) (mmHg) 121 15 119 14 –1.5 –15, 12 0.822
Average DBP (0–12 h) (mmHg) 71 6 71 10 0.3 –7, 8 0.944
Average heart rate (0–12 h) (min–1) 63 11 64 13 1.4 –10, 12 0.798
Enalapril
SBP at baseline (mmHg) 120 11 124 10 4.6 –5, 14 0.310
DBP at baseline (mmHg) 73 5 78 11 4.9 –3, 12 0.196
Heart rate at baseline (min–1) 67 10 61 9 –5.9 –15, 3 0.170
Average SBP (0–12 h) (mmHg) 118 14 119 12 0.7 –11, 12 0.901
Average DBP (0–12 h) (mmHg) 68 7 70 9 2.0 –5, 9 0.578
Average heart rate (0–12 h) (min–1) 62 10 61 10 –1.7 –10, 7 0.699
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Abbreviations are as follows: CI, confidence interval; DBP, diastolic blood pressure; SBP, systolic blood pressure; SD, standard deviation.

Figure 1.

Figure 1

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Geometric mean (95% CI) weight-adjusted plasma concentrations of quinapril and quinaprilat after a single 10 mg oral dose of quinapril in 22 healthy Caucasian subjects with different CES1 genotypes. Open circles indicate subjects with the c.428G/G genotype (n = 12) and solid circles those with the c.428G/A genotype (n = 10). The insets depict the same data on a semi-logarithmic scale. Some error bars were omitted for clarity. CES1, carboxylesterase 1; CI, confidence interval

Effect of CES1 c.428G > A SNV on enalapril

Enalapril Cmax, AUC0–∞, Ae and Clrenal varied 2.7-fold, 2.8-fold, 4.6-fold and 2.5-fold among all subjects, and those of enalaprilat varied 5.1-fold, 2.7-fold, 5.2-fold and 2.6-fold, respectively. The AUC0–∞ of enalaprilat was 20% lower in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (P = 0.049) (Table1, Figure2). Accordingly, enalaprilat Ae was 35% lower in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (P = 0.044). The geometric mean enalaprilat to enalapril AUC0–∞ ratio (CV) was 2.7 (0.41) in subjects with the CES1 c.428G/G genotype and 2.4 (0.38) in those with the c. 428G/A genotype, but the difference was not statistically significant. Furthermore, the CES1 genotype had no significant effect on any other pharmacokinetic or pharmacodynamic parameter of enalapril (Table1, Table2). Gender had no significant effect on the pharmacokinetic parameters of enalapril (data not shown).

Figure 2.

Figure 2

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Geometric mean (95% CI) weight-adjusted plasma concentrations of enalapril and enalaprilat after a single 10 mg oral dose of enalapril in 22 healthy Caucasian subjects with different CES1 genotypes. Open circles indicate subjects with the c.428G/G genotype (n = 12) and solid circles those with the c.428G/A genotype (n = 10). The insets depict the same data on a semi-logarithmic scale. Some error bars were omitted for clarity. CES1, carboxylesterase 1; CI, confidence interval

Discussion

In the present study, the CES1 c.428G > A SNV significantly affected the pharmacokinetics of enalapril but had no significant effect on those of quinapril. The AUC0–∞ of active enalaprilat was 20% lower in individuals with the CES1 c.428G/A genotype than in individuals with the c.428G/G genotype. To our knowledge, this is the first study demonstrating that CES1 genetic variants can affect the pharmacokinetics of an ACE inhibitor in vivo in humans and that ACE inhibitors may differ in their susceptibility to the effects of CES1 variants.

CES1 activity shows marked inter-individual variability, partly explained by genetic variants 21. In vitro studies with expressed recombinant CES1 variant proteins have demonstrated that the CES1 c.428G > A SNV decreases the catalytic function of CES1 by about 70–100%, resulting in a markedly decreased hydrolytic activity towards the biotransformation of methylphenidate, trandolapril, oseltamivir and clopidogrel, as well as the CES1 model substrate p-nitrophenyl acetate (PNPA) 18,20–22. In previous pharmacokinetic studies in humans, the effects of CES1 c.428G > A SNV on the pharmacokinetics of other widely used CES1 substrate drugs have been of the same magnitude or larger than in the present study on enalapril. The CES1-mediated inactivation of methylphenidate was markedly impaired in one individual who was compound heterozygous for the CES1 c.428G > A SNV and a predicted null allele, c.760delT (rs71647872) 20. The Cmax of methylphenidate was sevenfold higher in this subject than in the other 19 study participants 23. The CES1 c.428A allele also impairs the bioactivation of oseltamivir, with the oseltamivir carboxylate to oseltamivir AUC0–∞ ratio being 23% smaller in nine individuals with the c.428G/A genotype and 84% smaller in one individual with the c.428A/A genotype than in 12 individuals with the c.428G/G genotype 15. Furthermore, exposure to parent clopidogrel was about twofold higher in subjects with the c.428G/A genotype than in those with the c.428G/G genotype, leading to considerably increased concentrations of the active metabolite and antiplatelet effects 24.

Apart from genetic variability, CES1 activity can be affected by other factors, such as drug interactions. Several drugs are known substrates or inhibitors of CES1, such as simvastatin, verapamil and carvedilol 9,25,26. Interestingly, in a recent study, trandolapril and enalapril inhibited the CES1-catalysed hydrolysis of clopidogrel, increasing the formation of the active cis 5-thiol metabolite in vitro 27. Use of ACE inhibitors was also associated with an increased risk of clinically significant bleeding in patients co-treated with ACE inhibitors and clopidogrel, suggesting a possible CES1-mediated drug–drug interaction 27.

The human carboxylesterase gene family consists of five protein-coding genes (CES1, CES2, CES3, CES4A and CES5A) and three pseudogenes. Most of the previous research has focused on CES1 and CES2, and the function of other carboxylesterases has not been fully established. CES1 has been estimated to contribute to 80–95% of total hydrolytic activity in the human liver 20 and catalyses the hydrolysis of numerous ester- and amide-containing endogenous compounds, toxins and drugs to their respective free acids 21. The remaining hydrolytic activity in the liver has been attributed to other esterases, including CES2, which shows its highest expression in the intestine 11,18,28. Of note, carboxylesterases have overlapping substrate specificities 10. In addition to CES1, quinapril is also hydrolysed by CES2 10, and, therefore, the significance of CES1 in the bioactivation of quinapril is likely to be smaller than in that of enalapril. This might explain the lack of effect of CES1 c.428G > A SNV on quinaprilat pharmacokinetics. Furthermore, the higher fraction of oral enalapril (60%) bioactivated compared with that of quinapril (40%) can contribute to the different effect of this genetic variant on their pharmacokinetics. In any case, the findings that the CES1 c.428G > A SNV had no observable effect on the pharmacokinetics of quinapril and only a modest effect on the pharmacokinetics of enalapril suggest that quinapril and enalapril are not sensitive probe drugs for CES1 activity in vivo in humans.

In addition to CES genes, other genetic variants might also affect the pharmacokinetics or pharmacodynamics of quinapril and enalapril. For example, polymorphisms in the SLCO1B1 gene, encoding the hepatic influx transporter organic anion-transporting polypeptide 1B1 (OATP1B1), may influence the pharmacokinetics of ACE inhibitors 29–31. Furthermore, several studies have investigated the effects of genetic variants on the pharmacodynamics of ACE inhibitors 32–35. For example, variants in ACE, angiotensinogen, angiotensin receptor 1 and α-adducin 1 have in some studies been associated with the response to ACE inhibitors 36. However, different studies have yielded conflicting results and further studies are required to clarify the role of genetic variability in the pharmacokinetics and pharmacodynamics of ACE inhibitors.

In the present study, P-values were not adjusted for multiple comparisons as all statistical comparisons were defined a priori. Because a substantial number of statistical tests were used, the risk of a false-positive finding should be kept in mind. In any case, considering that the effect of the CES1 c.428G/A genotype on the pharmacokinetics of enalapril was relatively small, the CES1 c.428G/A genotype is unlikely to have a clinically meaningful impact on the efficacy of enalapril. The CES1 c.428G > A SNV is relatively rare, with 4–8% of Caucasian and African-American populations being heterozygous and 0.04–0.16% homozygous for the SNV 15,20. Therefore, after screening more than 1100 individuals, we could only recruit heterozygous individuals into the present study. In a previous study, the CES1-mediated bioactivation of oseltamivir was impaired in one individual with the CES1 c.428A/A genotype to a much greater extent (the oseltamivir AUC elevated almost to fourfold) than in individuals with the c.428G/A genotype 15. Therefore, it is possible that the hydrolysis of enalapril is reduced to a clinically relevant extent in CES1 c.428A/A homozygotes, potentially leading to a reduced antihypertensive efficacy in such patients.

In conclusion, the CES1 c.428G > A SNV significantly reduces the hydrolysis of enalapril to active enalaprilat in humans but has no observable effect on quinapril hydrolysis. This suggests that ACE inhibitors differ in their susceptibility to the effects of the CES1 c.428G > A SNV. Further studies are required to elucidate the effects of CES1 genetic variants on the pharmacokinetics of other ACE inhibitors.

Competing Interests

All authors have completed the Unified competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from: any organisation for the submitted work; no financial relationship with any organisations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.

This study was supported by grants from the Helsinki University Central Hospital Research Fund and the Sigrid Jusélius Foundation (Helsinki, Finland). The authors also thank Ms Eija Mäkinen-Pulli, Ms Lisbet Partanen and Mr Jouko Laitila for skilful technical assistance.

Contributors

EKT, AT, MTH, TL, PJN, JTB and MN designed and performed the research, analysed the data and wrote the manuscript.

References

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