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

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.

Simultaneous quantitative and qualitative analysis of aliskiren, enalapril and its active metabolite enalaprilat in undiluted human urine utilizing LC-ESI-MS/MS.

The benefit-risk ratio of combined blocking by the direct renin inhibitor aliskiren and an angiotensin-converting enzyme inhibitor (e.g. enalapril) on the renin-angiotensin-aldosterone system is discussed. No method was available for simultaneous determination of both drugs in urine. A novel sensitive method for simultaneous quantification in undiluted human urine was developed which enables systematic pharmacokinetic investigations, especially in poorly investigated populations like children. Matrix effects were clearly reduced by applying solid-phase extraction followed by a chromatographic separation on Xselect(TM) C18 CSH columns. Mobile phase consisted of methanol and water, both acidified with formic acid. Under gradient conditions and a flow rate of 0.4 mL/min the column effluent was monitored by tandem mass spectrometry with electrospray ionization. Calibration curves were constructed in the range of 9.4-9600 ng/mL regarding aliskiren, 11.6-12000 ng/mL for enalapril and 8.8-9000 ng/mL for enalaprilat. All curves were analyzed utilizing 1/x(2) -weighted quadratic squared regression. Intra-run and inter-run precision were 3.2-5.8% and 6.1-10.3% for aliskiren, 2.4-6.1% and 3.9-7.9% for enalapril as well as 3.1-9.4% and 4.7-12.7% regarding enalaprilat. Selectivity, accuracy and stability results comply with current international bioanalysis guidelines. The fully validated method was successfully applied to a pharmacokinetic investigation in healthy volunteers.

The pharmacokinetics of enalapril in children and infants with hypertension.

Forty children with hypertension between the age of 2 months and 15 years received 0.07 to 0.14 mg/kg of enalapril as a single daily dose. Enalapril was administered orally as a novel extemporaneous suspension in children younger than 6 years of age and as tablets in older children. First-dose and steady-state pharmacokinetics were estimated in children ages 1 to 24 months, 25 months to < 6 years, 6 to < 12 years, and 12 to < 16 years. Maximum serum concentrations for enalapril occurred approximately 1 hour after administration. Serum concentrations of enalaprilat, the active metabolite of enalapril, peaked between 4 and 6 hours after the first dose and 3 and 4 hours after multiple doses. The area under the concentration versus time curve (AUC), adjusted for body surface area, did not differ between age groups. Based on comparison of first-dose and steady-state AUCs, the accumulation of enalaprilat in children ranged from 1.13- to 1.45-fold. For children ages 2 to 15 years, mean urinary recovery of total enalaprilat ranged from 58.3% in children ages 6 to < 12 years to 71.4% in children ages 12 to < 16 years. Urinary recovery for children ages 2 to < 6 years was 66.8%. The mean percentage conversion of enalapril to enalaprilat ranged from 64.7% for children ages 1 to 24 months to 74.6% for children ages 6 to < 12 years. The median effective half-life for accumulation ranged from 14.6 hours in children ages 12 to < 16 years to 16.3 hours in children ages 6 to < 12 years. There were two serious adverse events, neither of which was attributed to enalapril or resulted in discontinuation of the study drug. The extemporaneous suspension used in this study was tolerated well. The pharmacokinetics of enalapril and enalaprilat in hypertensive children ages 2 months to 15 years with normal renal function appears to be similar to that previously observed in healthy adults.

Inhibition of esterolysis of enalapril by paraoxon increases the urinary clearance in isolated perfused rat kidney.

The effect of competing elimination pathways on the metabolic and excretory clearance estimates was examined with tracer concentrations of [(3)H]enalapril, which was both metabolized and excreted by the rat kidney. Perturbation was achieved with use of the carboxylesterase inhibitor paraoxon, which inhibited [(3)H]enalapril metabolism to [(3)H]enalaprilat in rat renal S9 fraction. At 0.1, 0.5, 1, and 10 microM paraoxon, esterolysis of enalapril was inhibited by 76 +/- 7, 93 +/- 5, 96 +/- 5, and 93 +/- 6%, respectively. The lowest concentration (0.1 microM) of paraoxon was chosen for single-pass isolated perfused kidney (IPK) studies because viability was least compromised, and the sodium and glucose reabsorptive functions of the IPK remained constant. After an equilibration period (15-20 min at constant pressure, 90-100 mm Hg), perfusion of the rat kidney with [(3)H]enalapril was carried out under constant flow (8 ml/min) for 30 min in the absence and presence of paraoxon (0.1 microM). The metabolic (from 1.83 +/- 0.52 to 1.48 +/- 0.47 ml/min/g) and total renal (from 1.87 +/- 0.46 to 1. 57 +/- 0.41 ml/min/g) clearances of [(3)H]enalapril in the IPKs were decreased significantly (p <.05) in the presence of paraoxon when compared with controls. Concomitantly, the urinary clearance (from 0. 04 +/- 0.07 to 0.09 +/- 0.09 ml/min/g) and the fractional excretion (from 0.23 +/- 0.18 to 0.52 +/- 0.25) of [(3)H]enalapril doubled (p <.05). The study illustrates that a reduction in cellular metabolism of the kidney brings forth a rise in the estimate of clearance of its complimentary pathway, estimate of the excretory (urinary) clearance.

Determination of enalapril and its active metabolite enalaprilat in plasma and urine by gas chromatography/mass spectrometry.

The method for the simultaneous determination of angiotensin-converting enzyme (ACE) inhibitor enalapril and its active metabolite enalaprilat in plasma and urine was developed by gas chromatography/mass spectrometry. Enalapril and enalaprilat in plasma and urine were extracted and cleaned up by using Sep-Pak C18 and silica cartridges. Derivatization was carried out using diazomethane and trifluoroacetic anhydride. Detection by selected ion monitoring was selected to m/z 288 (enalaprilat) and 302 (enalapril). The detection limit of enalapril and enalaprilat was 200 pg/mL in plasma and 2 ng/mL in urine. This method was applied to the pharmacokinetic analysis of enalapril and enalaprilat in body fluids.