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Abstract: Background: Enalapril is an angiotensin-converting enzyme (ACE) inhibitor approved for the treatment of mild to severe hypertension and congestive heart failure. There is evidence that enalapril may be an organic anion-transporting polypeptide 1B1 (OATP1B1) substrate, suggesting that genetic polymorphisms of the OATP1B1 gene may play a role in causing the interindividual pharmacokinetic differences of this drug. Objective: The purpose of this study was to investigate the functional significance of the OATP1B1 genetic polymorphism on the pharmacokinetics of enalapril and its active metabolite enalaprilat in healthy Chinese adult male participants. Methods: This was a single-center, open-label, single- and multiple-dose study conducted in healthy Chinese male participants. Each participant received a single oral dose of 10 mg enalapril under fasting conditions, followed by enalapril 10 mg/d for 7 days. In the single-dose phase, sequential blood samples were collected from 0 to 24 hours after drug administration. In the multiple-dose phase, samples were obtained before drug administration on days 4, 5, 6, and 7; on day 7, samples were collected from 0 to 72 hours after drug administration. An HPLC-MS/MS method was used to determine plasma concentrations of enalapril and enalaprilat. A polymerase chain reaction technique was used for genotyping of 2 single nucleotide polymorphisms (SNPs) of the OATP1B1 gene: T521C and A388G. The pharmacokinetic parameters of enalapril and enalaprilat were then compared according to genotype groups, using 1-way ANOVA, except for Tmax in which the Mann-Whitney test or Kruskal-Wallis test was used. Results: The study included 32 healthy Han Chinese male participants (age range, 18–28 years; weight range, 50.0–80.0 kg; height range,159–182.0 cm). Twenty-six were OATP1B1*15 noncarriers (homozygous for 521TT), the others were *15 carriers with at least one 521 T>C mutant allele. After single and multiple oral doses of 10 mg enalapril, plasma concentrations of enalapril in *15 noncarriers were lower than that in *15 carriers, with significant difference in area under the curve at steady state (AUCss) between *15 noncarriers and *15 carriers (P = 0.048) in the multiple-dose phase. There were no significant differences in enalapril''s AUC0–24, Cmax, or the ratio of the AUC0–24h in the single-dose study to the AUCss (Rac) between the *15 carriers and noncarriers. In contrast to enalapril, the mean AUC0–24h and Cmax of enalaprilat in *15 noncarriers was significantly higher than those in *15 carriers (P = 0.040 and P = 0.027, respectively) in the single-dose phase. There were no significant differences in enalaprilat''s AUCss or Cmaxss between the 2 groups in the multiple-dose phase. For the 3 groups classified according to the effect of A388G variant in all subjects homozygous for 521T (TT), *1a/*1a, *1a/*1b, and *1b/*1b, no significant difference was found in AUC0–24h, Cmax, and Tmax of enalapril and enalaprilat. Conclusions: In this small population of healthy Chinese men, the OATP1B1*15 allele and T521C variant appeared to be an important determinant of the pharmacokinetics of enalapril. There were significant differences between the *15 carriers and noncarriers in enalapril''s AUCss and enalaprilat''s AUC0–24h, Cmax, and Rac. However, there were no significant differences in enalapril''s AUC0–24, Cmax, or enalaprilat''s AUCss, Cmaxss between the *15 carriers and noncarriers. [Copyright &y& Elsevier]

Abstract: Objective: We compared the efficacy of folic acid (FA) plus enalapril with enalapril alone on the reduction of blood pressure (BP) and fasting plasma glucose (FPG) in adult Chinese hypertensive patients. Methods: Four hundred eighty subjects with mild to moderate BP were randomly assigned to one of three treatment groups: 1) 10 mg of enalapril (control group), 2) 10 mg of enalapril plus 0.4 mg of FA (low-FA group), or 3) 10 mg of enalapril plus 0.8 mg of FA (high-FA group) daily for 8 wk. Generalized linear mixed models were used to compare the reduction in BP and FPG level from baseline to week 8 of the treatment and the difference among the three treatment groups, adjusting for pertinent covariates. Results: Four hundred forty-three subjects (57.3% women, 27–75 y of age) successfully completed the trial. After the 8-wk treatment, compared with baseline, all treatment groups showed significant reduction of BP but not of FPG. There was no significant difference in BP or FPG reduction among the three treatment groups. In subgroup analysis, we found that in subjects with hyperglycemia (FPG ≥6.1 mmol/L) at baseline, FPG reduction was significantly greater in the high-FA group (−0.80 ± 1.20 mmol/L) than in the low-FA group (−0.39 ± 1.44 mmol/L) and the control group (−0.23 ± 1.30 mmol/L). Regression analysis further confirmed that FPG reduction in the high-FA group was −0.68 ± 0.28 mmol/L greater than in the control group (P = 0.015), even after adjustment for important covariates. A dose–response trend was evident (P for trend = 0.025) and the test for an interaction between treatment group and baseline FPG was significant (P < 0.001). Conclusion: In this sample of adult Chinese hypertensive patients, FA combined with enalapril showed a greater beneficial effect on reduction of FPG in a dose-related fashion than did enalapril alone among subjects with hyperglycemia. [Copyright &y& Elsevier]

The article reports on the China Stroke Primary Trial which shows the effectiveness of folic acid, along with enalapril, to prevent first stroke in individuals with hypertension.

Question In Chinese adults with hypertension, does enalapril plus folic acid reduce incident stroke more than enalapril alone? Methods Design Randomized controlled trial (China Stroke Primary Prevention Trial [CSPPT]). ClinicalTrials.gov NCT00794885. Trial was stopped early for efficacy. Allocation Concealed.* Blinding Blinded* (patients, investigators, outcome and data assessors, monitoring committee). Follow-up period Median 4.5 years. Setting 32 communities in Jiangsu and Anhui provinces, China. Patients 20 702 patients 45 to 75 years of age (mean age 60 y, 59% women) who had hypertension (seated resting systolic blood pressure [BP] ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg at screening and recruitment visits or were receiving antihypertensive medication) and good adherence to oral enalapril, 10 mg/d, during a 3-week run-in phase. Exclusion criteria included previous stroke, myocardial infarction (MI), heart failure, coronary revascularization, or congenital heart disease. Intervention Combination pill of oral enalapril, 10 mg/d, plus folic acid, 0.8 mg (n = 10 348), or oral enalapril, 10 mg/d, alone (n = 10 354). Concomitant use of other antihypertensive drugs (except B vitamins) was permitted. Outcomes Primary outcome was first stroke (fatal or nonfatal, ischemic or hemorrhagic). Secondary outcomes included a composite of cardiovascular (CV) events (stroke, CV death, or MI), components of the composite outcome, and all-cause death. Patient follow-up 99.7% (intention-to-treat analysis). Main results The main results are in the Table. Conclusion In Chinese adults with hypertension, enalapril plus folic acid reduced incident stroke more than enalapril alone. [ABSTRACT FROM AUTHOR]