Does Chinese Ethnicity Affect the Pharmacokinetics and Pharmacodynamics of Angiotensin-Converting Enzyme Inhibitors?

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Journal of Human Hypertension (2000) 14, 163–170  2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh REVIEW ARTICLE Does Chinese ethnicity affect the pharmacokinetics and pharmacodynamics of angiotensin-converting enzyme inhibitors?

PYA Ding1, O Yoa-Pu Hu2, PE Pool3 and W-c Liao4 1Department of Internal Medicine, Veterans General Hospital–Taipei, Taipei, Taiwan, Republic of China; 2Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China; 3Reno Cardiology Research Laboratory, Reno, NV 89509, USA; 4The Bristol- Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08563-4000, USA

Information from clinical and pharmacokinetic studies ACEIs showed good blood pressure lowering efficacy in of angiotensin-converting enzyme inhibitors (ACEIs) Chinese (benazepril, enalapril, fosinopril and spirapril), has come from subjects who are mostly male and Cau- with perhaps less blood pressure lowering with cilaza- casian, but the use of ACEIs extends to populations pril or a relatively shorter-term effect with cilazapril or worldwide. Significant differences between Chinese in perindopril compared to Caucasions. Chinese experi- general and male Caucasians have been demonstrated ence more cough from ACEIs (captopril and enalapril) in the pharmacokinetics/dynamics of other drug classes than Caucasians. Data suggest that fosinopril may not that could have implications for the use of ACEIs in the induce cough in as many subjects as other ACEIs, and Chinese population. These include: significant this seems to be true of Chinese as well. The mech- Chinese/Caucasian genetic variation in the renin-angio- anism, currently unknown, could involve fosinopril’s tensin system based on an insertion/deletion (O/D) poly- dual elimination pathway (hepatic and renal). Pharmaco- morphism of the ACE gene; the genetic determination kinetic data also support the use of fosinopril in conges- of plasma ACE activity in the Chinese population; and tive heart failure where elimination pathways may be genetic factors involving the disease substrate which impaired. In conclusion, ethnic differences between Chi- may also influence the response to treatment. Oral and nese and Caucasians with respect to ACE and AGT gene IV pharmacokinetic data from various studies of Chi- polymorphism, which might be expected to differentially nese and Caucasian subjects are available for cilazapril, affect the action of ACEIs in these two ethnic groups, fosinopril, and perindopril, and pharmacodynamic data do not, in fact, have such an effect. Rather, differences are available for eight different ACEIs. Based on these among the ACEIs appear to be more important. Journal data, there are few differences among the pharmacoki- of Human Hypertension (2000) 14, 163–170. netics of ACEIs between Chinese and Caucasians. Most

Keywords: angiotensin-converting enzyme inhibitors; pharmacokinetics; pharmacodynamics; Chinese; ethnicity; genetic variations; fosinopril; cilazapril; perindopril; spirapril; captopril; lisinopril; enalapril; benazepril

Introduction ing. The vast majority of information from clinical studies of ACEIs has come from subjects who are Benefits from the use of angiotensin-converting male and Caucasian, but the use of ACEIs extends enzyme inhibitors (ACEIs) have far exceeded the to populations worldwide. Only a modest number expectations of their early developers, and their of studies have been carried out in the Chinese numbers and indications have proliferated. The population, the world’s largest single ethnic group, compounds differ in whether they: are or are not and significant differences between Chinese in gen- prodrugs; contain a sulfhydryl, carboxyl, or phos- eral and male Caucasians have already been demon- phinyl group as the zinc ligand with ACE; are strated in the pharmacokinetics/dynamics of other metabolised by kidney (most of them), partially by 1 liver or not at all; are excreted by kidney or, in one drug classes. These differences could have impli- case, by kidney and liver; and are short- or long-act- cations for the use of ACEIs in the Chinese population where they are already involved in large trials along with nifedipine (Syst-China hypertension study in elderly Chinese2) and in post-myocardial Correspondence: Philip YA Ding, Head, Division of Cardiology, infarction (MI) patients using captopril (Chinese Veterans General Hospital–Taipei, 201, Section 2, Shih-Pai Road, 3 Taipei, Taiwan 112, Republic of China Cardiac Study (CCS-1) .) Received 1 June 1998; revised 15 October 1998; accepted 21 March 1999 Pharmacokinetics and use of ACE inhibitors in Chinese PYA Ding et al 164 Genetic differences in the renin- Cilazapril angiotensin system (RAS) and in RAS- Cilazapril is a carboxyl-containing ACEI designed related treatment for once-a-day administration and given as the prodrug which is converted to cilazaprilat, the active There is significant genetic variation in the RAS 32 based on an insertion/deletion (I/D) polymorphism ACEI. It is excreted by the kidneys. Cilazapril in intron 16 of the ACE gene.4 This variation may pharmacokinetics were studied in 12 healthy Chi- 5 nese and 13 healthy Caucasians using single 2.5 mg affect circulating levels of ACE as well as suscepti- 28 bility to myocardial infarction, among other con- oral doses. Plasma concentrations were similar ditions.6 In Caucasians, 44% of the variance in cir- across time for both races (Table 1, rows 1 and 2 and culating ACE activity is accounted for by genetic Figure 1a). The only difference between the groups polymorphism.5 In a meta-analysis of studies com- was in plasma clearance which was significantly posed mostly of Caucasians, the distribution of the higher in Chinese even when adjusted for weight. I/D polymorphism was 22.7% II, 49% ID, and 28.3% No data were obtained to determine a dose- DD, with the ACE levels of DDs about twice that of response. IIs6 (for further review see Singer et al).7 Plasma ACE activity is also genetically determined in the Chi- Fosinopril nese population,8 but there is a much higher prevalence of the I allele (0.70 among Chinese9 compared Fosinopril is a phosphinic acid ACEI designed for to 0.43 in a Caucasian population5), and fewer have once-a-day administration and given as the prodrug the D/D phenotype among Chinese than Cauca- which is converted to fosinoprilat, the active ACEI. sians.9–12 The association of I/D polymorphism with It has dual excretory pathways, renal and hepatic.33 hypertension in Chinese appears weak13 and per- Fosinopril pharmacokinetics have been studied in haps confined to males over 40 years of age,14 or 12 healthy Chinese and 10 healthy Caucasians using absent.8 There appears to be no association with cor- single 10.0 mg oral doses.29,34 Data were combined onary artery disease (CAD), myocardial infarction, from two studies which used the same methods and and ischaemic cardiomyopathy,9–12,15,16 nor with analytic techniques (one in Chinese29 and one in insulin resistance17 in Chinese. Unlike Caucasi- Caucasians34). Plasma concentrations across time ans,18,19 the T174M and M235T polymorphisms of (Table 1, rows 5 and 6 and Figure 1b) and renal the angiotensinogen (AGT) gene appear not to be clearance were similar in Chinese and Caucasians. associated with MI or CAD in Chinese.20,21 Finally, Percent urinary excretion was identical.29 genetic polymorphisms may unexpectedly influence Pharmacokinetics have also been obtained from the action of a drug22 and, independent of the ACE 23 Chinese with heart failure (CHF) who received gene I/D polymorphism, a possible polymorphic randomly allocated doses of 10, 20 or 40 mg/d oral response of ACE to the ACEI enalaprilat has been fosinopril in three sequences of 10–14 days each.30 reported in Chinese subjects.23 Because of the protocol design no single-dose para- In addition to genetic factors influencing the RAS, meters could be obtained. At steady-state, following genetic factors involving the disease substrate may the 10 mg daily dose, pharmacokinetic values of also influence the response to treatment. For AUC, Cmax, and Tmax were similar to values derived instance, data from MIDAS24 and GLANT25 from 12 Caucasians with CHF and renal insuf- (conducted in Europe and the US), suggest that ficiency who were studied separately30 (Table 1, short-acting dihydropyridines, while controlling rows 9 and 10). Higher doses were not studied in blood pressure, do not reduce mortality and may the Caucasian group. In order to assess the compar- increase cardiovascular events at higher doses. In ability of the steady-state data with single dose data, contrast, data from a Chinese megatrial (STONE)26 one can compare single-dose data from the same with dihydropyridines demonstrate effective blood CHF/renal insufficiency Caucasians with single- pressure reduction and a reduction in mortality. Per- dose data from other Caucasian subjects with CHF34 haps these differential effects are related to the low (Table 1, rows 7 and 8) and with single-dose data in prevalence of coronary artery disease in Chinese healthy Chinese29 (Table 1, row 5). Taken together, compared to that in Europe and the US.27 no significant differences appear among any of these groups nor with the dose-independent parameters of Pharmacokinetics of ACEIs in Chinese Tmax (3.0 h) and elimination t. (11.3 h) in Caucasian CHF patients from another single-dose study.35 and Caucasians In CHF, where either the hepatic or renal elimin- Oral pharmacokinetic data from various studies of ation pathways may be affected, higher drug doses Chinese and Caucasian subjects are available for cil- could produce adverse effects in the absence of dose azapril,28 fosinopril,29,30 and perindopril31 (Table 1). proportionality. However, at steady state, over the These data make possible comparisons of single- oral fosinopril doses of 10, 20 and 40 mg/d there was dose pharmacokinetics between normal Chinese and dose proportionality in the Chinese CHF patients as Caucasian subjects for cilazapril, perindopril and indicated by both AUC and Cmax (Table 2). fosinopril. For fosinopril there are additional single- Finally, in studies of fosinoprilat after i.v. admin- dose and steady-state comparisons of pharmacoki- istration in 12 healthy Chinese and nine healthy netics available among Chinese and Caucasian whites, there were statistically significantly lower patients with congestive heart failure (CHF) as well values for renal clearance, non-renal clearance and as with CHF and renal insufficiency. total clearance in Chinese than white subjects.36

Journal of Human Hypertension Pharmacokinetics and use of ACE inhibitors in Chinese PYA Ding et al 165 Table 1 Pharmacokinetic parameters for various ACEIs in Chinese

a b c Group Dosing Cmax Tmax AUC t. CL (ng/ml) (h) (ng.h/mL) (h) (mL/kg/h)

Cilazaprilat 1 Chinese Single dose 28.2 2.0 181 1.9 270* (n = 12)28 2.5 mg (3.1) (1.0, 3.0) (15) (0.1) (30) 2 Caucasian Single dose 28.4 2.0 241 2.1 187 (n = 13)28 2.5 mg (3.3) (1.5, 3.0) (16) (0.2) (14)

Perindoprilat e 3 Chinese Single dose 3.6 4.0 119 4.4 630 (n = 12)31 4.0 mg (2.0–13.0) (3.0, 8.0) (95–144) (3.5–5.3) (530–730) 4 Caucasian Single dose 2.7 7.0 132 5.4 420 (n = 10)31 4.0 mg (1.9–8.2) (3.0, 12.0) (119–145) (3.3–7.5) (360–480)

Fosinoprilat 5 Chinese Single dose 183 4.0 1556 17.4 15.9 (n = 12)29 10 mg (59) (2.0, 5.0) (586) (11.4) (6.3) 6 Caucasian Single dose 177 4.0 1489 11.0 20.3 (n = 10)34 10 mg (64) (3.0, 6.0) (619) (5.2) (8.6) 7 Caucasian Single dose 196 4.0 1716 14 18.1 CHF 10 mg (67) (2.0, 8.0) (808) (7) (7.6) (n = 10)34 8 Caucasian Single dose 173d 4.0 2099d NA NA CHF & RI 10 mg (0.1) (3.0, 8.0) (0.1) (n = 12)39 9 Caucasian Steady-state 225d 4.1 2956d NA NA CHF & RI 10 mg (0.1) (2.0, 8.1) (0.2) (n = 12)39 10 Chinese CHF Steady-state 287 4.0 3113 13 NA (n = 23)30 10 mg (69) (1.0, 6.0) (756) (4) aMedian (range). b = AUC AUCinf for cilazapril and AUC(t) for perindopril and fosinopril. cFor fosinopril, weight-adjusted value obtained using mean weight. dExpressed as geometric mean (s.e. in log scale of geometric mean). e Mean (95% CI), except for Tmax. =± ± () s.e. for cilazaprilat and s.d. for fosinoprilat except for Tmax and Cmax/AUC for fosinoprilat. *P = Ͻ0.05 Chinese vs Caucasian. This difference was not signiﬁcant when adjusted for weight. All other differences = NS. NA = not available; CHF = congestive heart failure; RI = renal insufﬁciency.

Perindopril Pharmacodynamic effects of ACEIs on the RAS in Chinese Perindopril is a carboxyl-containing ACEI designed for once-a-day administration and given as the pro- Cilazapril drug which is converted to perindoprilat, the active ACEI. It is predominantly metabolically eliminated At a 2.5 mg dose, ACE inhibition was similar in Chi- and excreted by the kidneys.37 Perindopril pharma- nese and Caucasians with almost 100% inhibition cokinetics were studied in 12 healthy Chinese and at 2 h, greater than 90% inhibition at 6 h, about 75% 10 healthy Caucasians using single 4.0 mg oral at 12 h, and about 50% at 24 h (Table 3). Baseline doses.31 For perindopril, the rate of the absorption plasma aldosterone concentrations tended to be phase was signiﬁcantly higher in Chinese, perhaps higher in Chinese and the increase in plasma renin due to more rapid gastric emptying. Plasma concen- activity (PRA) in response to ACE-inhibition trations remained slightly higher for Chinese, but appeared to be greater. The authors speculated that this could reﬂect dietary differences or racial differ- this was, for the most part, accounted for by body- 28 weight adjustment (Table 1, rows 3 and 4 and Figure ences in the sensitivity of the RAS. 1c). Percent urinary excretion was similar in Chi- nese and Caucasians. There were no other pharma- Fosinopril cokinetic differences. No dose-response data were obtained. A small food effect,38 which reduces the At a 10 mg dose, ACE inhibition of 100% was extent of ACE inhibition in Caucasian populations, achieved at 1 h, maintained at 99% through 8 h, and was not evaluated in Chinese. 84% at 24 h in normals.29 In heart failure patients,

Journal of Human Hypertension Pharmacokinetics and use of ACE inhibitors in Chinese PYA Ding et al 166 Perindopril Maximum ACE inhibition with the 4.0 mg dose studied was 88% at 5–6 h and appeared to fall below 80% after 8 h.31 Aldosterone and PRA were reduced in both groups by 8 h but had returned to baseline by 48 h. The authors concluded that minor differences in pharmacokinetics between healthy Chinese and Caucasians have no signiﬁcant effects on the pharmacodynamics of perindopril, although weight adjustment may be more commonly required in the lighter weight Chinese population.

Clinical pharmacodynamics of ACEIs in Chinese Eleven studies3,28,31,40–47 have reported clinical pharmacodynamic results of ACEIs in Chinese using eight different ACEIs (Table 4). Eight of these 11 studies have been in hypertensives,28,31,42–47 one in post-MI patients,3 one in chronic renal failure patients,40 and one has examined the occurrence of cough.41 Among the eight hypertensive studies, three compared an ACEI with a calcium antagonist and found: enalapril less effective than nifedipine;42 lisinopril equal to diltiazem;43 and spirapril equal to isradip- ine46 in antihypertensive effect. Benazepril and captopril were equal in a Chinese group.45 In single- dose studies comparing Chinese and Caucasian groups perindopril was equally effective,31 but cilazapril appeared to have a lesser effect28 in Chinese. In both the cilazapril and perindopril trials there was a signiﬁcant and prolonged increase in heart rate in Chinese not found in the comparative Caucasian group. The authors speculated that this effect may have resulted in part from higher weight-related doses in Chinese, although the blood pressure effect was similar. In an 8-week trial in mild to moderate Chinese hypertensives, fosinopril lowered average blood pressure 23/15 mm Hg by cuff and 18/13 mm Hg by ambulatory blood pressure measure- ment.47 Heart rate was unchanged from baseline. An early (4 week) report from the large Chinese Figure 1 (a) Concentration-time relationship following oral Cardiac Study in post-MI patients showed a non- administration of 2.5 mg cilazapril, (b) 10 mg fosinopril, and (c) signiﬁcant reduction in death with captopril.3 A 4.0 mg perindopril. study comparing a Chinese herbal drug, Rheum E, with captopril for the prevention of renal failure Table 2 Dose-response parameters at steady-state with fosinopril found Rheum E superior to captopril, but the combi- in Chinese patients with congestive heart failure (± s.d.) nation of the two drugs superior to either alone.40 In a case-control study in the Chinese population Dose AUC(t) Cmax the incidence of persistent cough in patients taking (ng.h/mL) (ng/mL) ACEIs (captopril and enalapril) was 44% (among ± ± 191 patients) compared to 11.1% (among 382 10 mg 3113 756 287 69 Ͻ 41 20 mg 6378 ± 1422 630 ± 161 patients) in controls not taking ACEIs (P 0.001). 40 mg 12063 ± 4320 1207 ± 320 In a case-control study comparing ACEI-associated (captopril and enalapril) cough in Hong Kong Chi- nese and Auckland Caucasians the incidence of cough in ACEI-users vs non-ACEI-users was 53% steady-state ACE inhibition was 82% at the 10 mg/d and 10% for Chinese and 18% and 5% for Caucasi- dose and Ͼ90% at higher doses30 (Table 3). Other ans (P Ͻ 0.001).41 In a lisinopril study the incidence indices of RAS activity have not been reported. of cough following drug rechallenge was 31%,43 and These results were similar to those found for Cauca- in a benazepril study 21% withdrew because of sians, both normal34 and with heart failure, and in cough.45 In contrast, in a study of 79 hypertensive single or steady-state dosing.39 patients given fosinopril, the total reported inci-

Journal of Human Hypertension Pharmacokinetics and use of ACE inhibitors in Chinese PYA Ding et al 167 Table 3 Pharmacodynamic effects on the RAS in Chinese populations using ACEIs

Group Dosing ACE inhibition Chinese PRA Aldosterone concentration vs Caucasian

Cilazaprilat Normals Single 2.5 mg 100% Ȱ 2 h; Similar ↑ both groups, ↓ in both groups 2–8 h, then ↑ in Chinese (n = 24)28 dose у90% Ȱ 6 h; signiﬁcantly more but ↓ in Caucasians through 48 h. ෂ75% Ȱ 12 ha; in Chinese ෂ50% Ȱ 24 ha

Fosinoprilat Normals Single 10 mg 100% Ȱ 1 h; Similar to NA NA (n = 12)29 dose 99% Ȱ 8 h; separately studied 84% Ȱ 24 h; group34 58% Ȱ 48 h. CHF Steady-state Steady-state at NA NA (n = 23)30 10–40 mg/d trough: 82% at dosing 10 mg, Ͼ90% at higher doses

Perindoprilat Normals Single 4.0 mg Max. 88% Ȱ 5– Similar Inconclusive ↓ in both groups by 8 h; (n = 24)31 dose 6 h; back to baseline by 48 h. Ͻ80% after 8 hb aEstimated from graph of activity.28 bExtrapolated from plasma concentration/activity plot.31 dence of cough was 29%,47 and none were with- subjects and in those with heart failure, whether drawn for cough. This appears to be a lower inci- after a single dose or at steady state. ACE inhibition dence of cough in Chinese than found with the other is preserved beyond 24 h following dosing, as is ACEIs cited above. In two separate studies (not antihypertensive efficacy. among Chinese), which involved 24 patients each, In Chinese with CHF or other conditions in which patients with ACEI-induced cough were switched the elimination pathway may be affected, there is from another ACEI to fosinopril. In both studies data only for fosinopril, the only ACEI with a dual there was a significant reduction in cough occur- (hepatic and renal) elimination mode. In this case, rence, frequency and severity (P Ͻ 0.00148 and there appeared to be no hazard induced by the heart P р 0.000249) for each of the measurements. Cough failure condition and no significant differences with captopril has been related to higher doses and among normal, hypertensive or heart failure renal impairment leading to accumulation50,51 patients, whether Chinese or Caucasian, in pharma- which could be lessened with fosinopril because of cokinetics or pharmacodynamics, following single dual (renal/hepatic) excretory pathways.49 Perhaps doses or at steady state. these observations explain the differences noted In normal or hypertensive subjects ACEIs gener- above. ally showed good blood pressure lowering efficacy in Chinese with the exception of perindopril and cil- Discussion azapril (single dose studies in normotensives) where there appeared to be comparatively less blood press- Based on these data, and with the exception of some ure lowering (cilazapril) compared to Caucasians or pharmacokinetic measurements in the selected a relatively short-term effect for either group ACEIs which have been studied, there appears to be (perindopril). The blood pressure lowering efficacy few differences among the pharmacokinetics of in Chinese of benazepril, enalapril, fosinopril and ACEIs between Chinese and Caucasians. spirapril was adequately demonstrated in these Only single-dose pharmacokinetic studies in nor- studies. mal volunteers were carried out with cilazapril and Chinese experience more cough from ACEIs perindopril. With perindopril, and to a lesser extent (captopril and enalapril) than Caucasians. Why this cilazapril, there was a relatively short duration of may be so remains to be explained. Data suggest that effective ACE inhibition (Ͻ80% after 12 h) and for fosinopril may not induce cough in as many subjects perindopril more rapid absorption and a higher con- as other ACEIs,49,52 and this seems to be true of Chi- centration-time curve for Chinese than for Cauca- nese as well.47 The mechanism underlying this sians. These kinetics were also associated with a effect and the actual significance of it also await relatively poor blood pressure lowering effect. For further investigation. cilazapril, plasma clearance was higher among Chi- It appears, then, that ethnic differences between nese. It is possible that these conclusions would Chinese and Caucasians with respect to ACE and have been different had steady-state pharmacoki- AGT gene polymorphism, which might be expected netic data been available. Fosinopril pharmacokinet- to differentially affect the action of ACEIs in these ics are similar in normal Chinese and Caucasian two ethnic groups, do not, in fact, have such an

Journal of Human Hypertension Pharmacokinetics and use of ACE inhibitors in Chinese PYA Ding et al 168 Table 4 Clinical pharmacodynamic effects in Chinese populations using ACEIs

Chinese Group Trial drugs Duration BP effect of ACEI Other effect Studiedref

Benazepril HTN45 Benazepril 12 wk; 1 yr benazepril BP ↓ 21/10 Ȱ 12 wk 21% withdrew from 10 mg vs captopril 25 mg only (benazepril) and ↓ 21/13 benazepril long-term due to t.i.d. (captopril); maintained for cough 1 yr by benazepril

Captopril or Enalapril Post-MI3 Captopril 4-wk early report Non-signiﬁcant reduction Excess early hypotension 12.5 mg t.i.d. in death Chronic renal failure40 Captopril & Rheum E 6–22 mos NA Rheum E prevented deterioration better than captopril, but combination was best Various patients41 Captopril or enalapril Variable NA Persistent cough in 46% captopril and 41.8% enalapril NIDDM & HTN42 Enalapril vs nifedipine 12 wk Mean BP ↓ 11.1 mm Hg ApoB and glycaemic control with enalapril, 23.1 with better with enalapril nifedipine

Cilazapril Normal28 Cilazapril single 2.5 mg 72 h BP signiﬁcantly ↓ only at 5 hHR signiﬁcantly ↑ from 6–72 h dose in Chinese vs post-dose in Chinese and in Chinese cf. Caucasians Caucasians persistently ↓ to 48 h in Caucasians

Fosinopril Chinese HTN47 Fosinopril 10–20 mg/d 8 wk BP ↓ 149/104 to 126/89 HR unchanged at 79 and 80 with or without HCTZ mm Hg by cuff and 143/93 bpm in clinic and 79 and 82 to 125/80 mm Hg by ABPM by ABPM; cough noted in 29% (no withdrawals).

Lisinopril HTN44 Lisinopril 10–40 mg/d 4–7 wk BP ↓ 150/98 to 134/87 Elderly HTN43 Diltiazem vs lisinopril 12 wk Lisinopril 10 mg had 31% cough with lisinopril intermediate efﬁcacy after rechallenge between 120 and 240 mg diltiazem

Perindopril Normal31 Perindopril single 4 mg 24 h BP signiﬁcantly ↓ only at HR signiﬁcantly ↑ at 12 and dose in Chinese vs 4 & 8 h in both groups 24 h in Chinese and Caucasians unchanged in Caucasians

Spirapril Elderly isolated Spirapril vs isradipine 8 wk BP ↓ 20/10 (isradipine) systolic vs 24/6 (spirapril) HTN46

ABPM = ambulatory blood pressure monitoring; HTN = hypertension; NA = not applicable.

effect. There are data which may explain this para- significantly reduced.53 This seems to set the clini- dox. Gene titration studies in mice using both the cally significant level of ACE inhibition at 80+%, a angiotensinogen (AGT) and ACE genes have shown percent that correlates with clinical efficacy. that variations of angiotensin II (Ang II) levels are In conclusion, among the three ACEIs in which linked to changes in blood pressure, while vari- there are pharmacokinetic and pharmacodynamic ations in ACE levels, which may be considerable, data, fosinopril has no significant differences are not associated with such changes.53 As ACE lev- between Chinese and Caucasians and has a long dur- els decrease, the level of Ang I increases and with ation of ACE inhibition. Cilazapril and perindopril it the rate of its conversion to Ang II, thus main- show some minor differences in pharmacokinetics taining Ang II levels. Why, then, does ACE inhi- between Chinese and Caucasians and a somewhat bition lower Ang II levels? Because once ACE in- lesser duration of ACE inhibition which may or may hibition at the level of 80–90% occurs, the not be related to these ethnic differences. There compensatory increase in Ang I levels approaches a appears to be evidence of the blood pressure lower- plateau, at which point Ang II levels may then be ing efficacy of a number of these ACEIs in Chinese,

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