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
1
Department of Internal Medicine, Veterans General Hospital–Taipei, Taipei, Taiwan, Republic of China;
2
Department 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
of angiotensin-converting enzyme inhibitors (ACEIs)
has come from subjects who are mostly male and Cau-
casian, but the use of ACEIs extends to populations
worldwide. Significant differences between Chinese in
general and male Caucasians have been demonstrated
in the pharmacokinetics/dynamics of other drug classes
that could have implications for the use of ACEIs in the
Chinese population. These include: significant
Chinese/Caucasian genetic variation in the renin-angio-
tensin system based on an insertion/deletion (O/D) poly-
morphism of the ACE gene; the genetic determination
of plasma ACE activity in the Chinese population; and
genetic factors involving the disease substrate which
may also influence the response to treatment. Oral and
IV pharmacokinetic data from various studies of Chi-
nese and Caucasian subjects are available for cilazapril,
fosinopril, and perindopril, and pharmacodynamic data
are available for eight different ACEIs. Based on these
data, there are few differences among the pharmacoki-
netics of ACEIs between Chinese and Caucasians. Most
ACEIs showed good blood pressure lowering efficacy in
Chinese (benazepril, enalapril, fosinopril and spirapril),
with perhaps less blood pressure lowering with cilaza-
pril or a relatively shorter-term effect with cilazapril or
perindopril compared to Caucasions. Chinese experi-
ence more cough from ACEIs (captopril and enalapril)
than Caucasians. Data suggest that fosinopril may not
induce cough in as many subjects as other ACEIs, and
this seems to be true of Chinese as well. The mech-
anism, currently unknown, could involve fosinopril’s
dual elimination pathway (hepatic and renal). Pharmaco-
kinetic data also support the use of fosinopril in conges-
tive heart failure where elimination pathways may be
impaired. In conclusion, ethnic differences between Chi-
nese and Caucasians with respect to ACE and AGT gene
polymorphism, which might be expected to differentially
affect the action of ACEIs in these two ethnic groups,
do not, in fact, have such an effect. Rather, differences
among the ACEIs appear to be more important. Journal
of Human Hypertension (2000) 14, 163–170.

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

Introduction ing. The vast majority of information from clinical

Benefits from the use of angiotensin-converting
enzyme inhibitors (ACEIs) have far exceeded the
expectations of their early developers, and their
numbers and indications have proliferated. The
compounds differ in whether they: are or are not
prodrugs; contain a sulfhydryl, carboxyl, or phos-
phinyl group as the zinc ligand with ACE; are
metabolised by kidney (most of them), partially by
liver or not at all; are excreted by kidney or, in one
case, by kidney and liver; and are short- or long-act-
Correspondence: Philip YA Ding, Head, Division of Cardiology,
Veterans General Hospital–Taipei, 201, Section 2, Shih-Pai Road,
Taipei, Taiwan 112, Republic of China
Received 1 June 1998; revised 15 October 1998; accepted 21
March 1999
studies of ACEIs has come from subjects who are
male and Caucasian, but the use of ACEIs extends
to populations worldwide. Only a modest number
of studies have been carried out in the Chinese
population, the world’s largest single ethnic group,
and significant differences between Chinese in gen-
eral and male Caucasians have already been demon-
strated in the pharmacokinetics/dynamics of other
drug classes.1 These differences could have impli-
cations for the use of ACEIs in the Chinese popu-
lation where they are already involved in large trials
along with nifedipine (Syst-China hypertension
study in elderly Chinese2) and in post-myocardial
infarction (MI) patients using captopril (Chinese
Cardiac Study (CCS-1)3.)
 Pharmacokinetics and use of ACE inhibitors in Chinese
PYA Ding et al
164
Genetic differences in the renin-
angiotensin system (RAS) and in RAS-
related treatment
There is significant genetic variation in the RAS
based on an insertion/deletion (I/D) polymorphism
in intron 16 of the ACE gene.4 This variation may
affect circulating levels of ACE5 as well as suscepti-
bility to myocardial infarction, among other con-
ditions.6 In Caucasians, 44% of the variance in cir-
culating ACE activity is accounted for by genetic
polymorphism.5 In a meta-analysis of studies com-
posed mostly of Caucasians, the distribution of the
I/D polymorphism was 22.7% II, 49% ID, and 28.3%
DD, with the ACE levels of DDs about twice that of
IIs6 (for further review see Singer et al).7 Plasma ACE
activity is also genetically determined in the Chi-
nese population,8 but there is a much higher preva-
lence of the I allele (0.70 among Chinese9 compared
to 0.43 in a Caucasian population5), and fewer have
the D/D phenotype among Chinese than Cauca-
sians.9–12 The association of I/D polymorphism with
hypertension in Chinese appears weak13 and per-
haps confined to males over 40 years of age,14 or
absent.8 There appears to be no association with cor-
onary artery disease (CAD), myocardial infarction,
and ischaemic cardiomyopathy,9–12,15,16 nor with
insulin resistance17 in Chinese. Unlike Caucasi-
ans,18,19 the T174M and M235T polymorphisms of
the angiotensinogen (AGT) gene appear not to be
associated with MI or CAD in Chinese.20,21 Finally,
genetic polymorphisms may unexpectedly influence
the action of a drug22 and, independent of the ACE
gene I/D polymorphism, a possible polymorphic
response of ACE to the ACEI enalaprilat has been
reported in Chinese subjects.23
In addition to genetic factors influencing the RAS,
genetic factors involving the disease substrate may
also influence the response to treatment. For
instance, data from MIDAS24 and GLANT25
(conducted in Europe and the US), suggest that
short-acting dihydropyridines, while controlling
blood pressure, do not reduce mortality and may
increase cardiovascular events at higher doses. In
contrast, data from a Chinese megatrial (STONE)26
with dihydropyridines demonstrate effective blood
pressure reduction and a reduction in mortality. Per-
haps these differential effects are related to the low
prevalence of coronary artery disease in Chinese
compared to that in Europe and the US.27
Pharmacokinetics of ACEIs in Chinese
and Caucasians
Oral pharmacokinetic data from various studies of
Chinese and Caucasian subjects are available for cil-
azapril,28 fosinopril,29,30 and perindopril31 (Table 1).
These data make possible comparisons of single-
dose pharmacokinetics between normal Chinese and
Caucasian subjects for cilazapril, perindopril and
fosinopril. For fosinopril there are additional single-
dose and steady-state comparisons of pharmacoki-
netics available among Chinese and Caucasian
patients with congestive heart failure (CHF) as well
as with CHF and renal insufficiency.
Journal of Human Hypertension
Cilazapril
Cilazapril is a carboxyl-containing ACEI designed
for once-a-day administration and given as the pro-
drug which is converted to cilazaprilat, the active
ACEI. It is excreted by the kidneys.32 Cilazapril
pharmacokinetics were studied in 12 healthy Chi-
nese and 13 healthy Caucasians using single 2.5 mg
oral doses.28 Plasma concentrations were similar
across time for both races (Table 1, rows 1 and 2 and
Figure 1a). The only difference between the groups
was in plasma clearance which was significantly
higher in Chinese even when adjusted for weight.
No data were obtained to determine a dose-
response.
Fosinopril
Fosinopril is a phosphinic acid ACEI designed for
once-a-day administration and given as the prodrug
which is converted to fosinoprilat, the active ACEI.
It has dual excretory pathways, renal and hepatic.33
Fosinopril pharmacokinetics have been studied in
12 healthy Chinese and 10 healthy Caucasians using
single 10.0 mg oral doses.29,34 Data were combined
from two studies which used the same methods and
analytic techniques (one in Chinese29 and one in
Caucasians34). Plasma concentrations across time
(Table 1, rows 5 and 6 and Figure 1b) and renal
clearance were similar in Chinese and Caucasians.
Percent urinary excretion was identical.29
Pharmacokinetics have also been obtained from
23 Chinese with heart failure (CHF) who received
randomly allocated doses of 10, 20 or 40 mg/d oral
fosinopril in three sequences of 10–14 days each.30
Because of the protocol design no single-dose para-
meters could be obtained. At steady-state, following
the 10 mg daily dose, pharmacokinetic values of
AUC, Cmax, and Tmax were similar to values derived
from 12 Caucasians with CHF and renal insuf-
ficiency who were studied separately30 (Table 1,
rows 9 and 10). Higher doses were not studied in
the Caucasian group. In order to assess the compar-
ability of the steady-state data with single dose data,
one can compare single-dose data from the same
CHF/renal insufficiency Caucasians with single-
dose data from other Caucasian subjects with CHF34
(Table 1, rows 7 and 8) and with single-dose data in
healthy Chinese29 (Table 1, row 5). Taken together,
no significant differences appear among any of these
groups nor with the dose-independent parameters of
Tmax (3.0 h) and elimination t. (11.3 h) in Caucasian
CHF patients from another single-dose study.35
In CHF, where either the hepatic or renal elimin-
ation pathways may be affected, higher drug doses
could produce adverse effects in the absence of dose
proportionality. However, at steady state, over the
oral fosinopril doses of 10, 20 and 40 mg/d there was
dose proportionality in the Chinese CHF patients as
indicated by both AUC and Cmax (Table 2).
Finally, in studies of fosinoprilat after i.v. admin-
istration in 12 healthy Chinese and nine healthy
whites, there were statistically significantly lower
values for renal clearance, non-renal clearance and
total clearance in Chinese than white subjects.36
 Pharmacokinetics and use of ACE inhibitors in Chinese
PYA Ding et al

Table 1 Pharmacokinetic parameters for various ACEIs in Chinese 165

Group Dosing Cmax Tmaxa AUCb t. CLc

(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)

a
Median (range).
b
AUC = AUCinf for cilazapril and AUC(t) for perindopril and fosinopril.
c
For fosinopril, weight-adjusted value obtained using mean weight.
d
Expressed 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 = ⬍0.05 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

Perindopril is a carboxyl-containing ACEI designed
for once-a-day administration and given as the pro-
drug which is converted to perindoprilat, the active
ACEI. It is predominantly metabolically eliminated
and excreted by the kidneys.37 Perindopril pharma-
cokinetics were studied in 12 healthy Chinese and
10 healthy Caucasians using single 4.0 mg oral
doses.31 For perindopril, the rate of the absorption
phase was significantly higher in Chinese, perhaps
due to more rapid gastric emptying. Plasma concen-
trations remained slightly higher for Chinese, but
this was, for the most part, accounted for by body-
weight adjustment (Table 1, rows 3 and 4 and Figure
1c). Percent urinary excretion was similar in Chi-
nese and Caucasians. There were no other pharma-
cokinetic differences. No dose-response data were
obtained. A small food effect,38 which reduces the
extent of ACE inhibition in Caucasian populations,
was not evaluated in Chinese.
the RAS in Chinese
Cilazapril
At a 2.5 mg dose, ACE inhibition was similar in Chi-
nese and Caucasians with almost 100% inhibition
at 2 h, greater than 90% inhibition at 6 h, about 75%
at 12 h, and about 50% at 24 h (Table 3). Baseline
plasma aldosterone concentrations tended to be
higher in Chinese and the increase in plasma renin
activity (PRA) in response to ACE-inhibition
appeared to be greater. The authors speculated that
this could reflect dietary differences or racial differ-
ences in the sensitivity of the RAS.28
Fosinopril
At a 10 mg dose, ACE inhibition of 100% was
achieved at 1 h, maintained at 99% through 8 h, and
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 differ-
ences 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 phar-
macodynamic 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 com-
pared 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 cap-
topril were equal in a Chinese group.45 In single-
dose studies comparing Chinese and Caucasian
groups perindopril was equally effective,31 but cilaz-
april 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
20 mg 6378 ± 1422 630 ± 161 patients) in controls not taking ACEIs (P ⬍ 0.001).41
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 ⬎90% at higher doses30 (Table 3). Other ans (P ⬍ 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

Table 3 Pharmacodynamic effects on the RAS in Chinese populations using ACEIs 167

Group Dosing ACE inhibition Chinese PRA Aldosterone concentration

vs
Caucasian

Cilazaprilat
Normals Single 2.5 mg 100% 얀 2 h; Similar ↑ both groups, ↓ in both groups 2–8 h, then ↑ in Chinese
(n = 24)28 dose ⭓90% 얀 6 h; significantly more but ↓ in Caucasians through 48 h.
苲75% 얀 12 ha; in Chinese
苲50% 얀 24 ha

Fosinoprilat
Normals Single 10 mg 100% 얀 1 h; Similar to NA NA
(n = 12)29 dose 99% 얀 8 h; separately studied
84% 얀 24 h; group34
58% 얀 48 h.
CHF Steady-state Steady-state at NA NA
(n = 23)30 10– 40 mg/d trough: 82% at
dosing 10 mg, ⬎90% at
higher doses

Perindoprilat
Normals Single 4.0 mg Max. 88% 얀 5– Similar Inconclusive ↓ in both groups by 8 h;
(n = 24)31 dose 6 h; back to baseline by 48 h.
⬍80% after 8 hb

a
Estimated from graph of activity.28
b
Extrapolated from plasma concentration/activity plot.31

dence of cough was 29%,47 and none were with-
drawn for cough. This appears to be a lower inci-
dence of cough in Chinese than found with the other
ACEIs cited above. In two separate studies (not
among Chinese), which involved 24 patients each,
patients with ACEI-induced cough were switched
from another ACEI to fosinopril. In both studies
there was a significant reduction in cough occur-
rence, frequency and severity (P ⬍ 0.00148 and
P ⭐ 0.000249) for each of the measurements. Cough
with captopril has been related to higher doses and
renal impairment leading to accumulation50,51
which could be lessened with fosinopril because of
dual (renal/hepatic) excretory pathways.49 Perhaps
these observations explain the differences noted
above.
Discussion
Based on these data, and with the exception of some
pharmacokinetic measurements in the selected
ACEIs which have been studied, there appears to be
few differences among the pharmacokinetics of
ACEIs between Chinese and Caucasians.
Only single-dose pharmacokinetic studies in nor-
mal volunteers were carried out with cilazapril and
perindopril. With perindopril, and to a lesser extent
cilazapril, there was a relatively short duration of
effective ACE inhibition (⬍80% after 12 h) and for
perindopril more rapid absorption and a higher con-
centration-time curve for Chinese than for Cauca-
sians. These kinetics were also associated with a
relatively poor blood pressure lowering effect. For
cilazapril, plasma clearance was higher among Chi-
nese. It is possible that these conclusions would
have been different had steady-state pharmacoki-
netic data been available. Fosinopril pharmacokinet-
ics are similar in normal Chinese and Caucasian
subjects and in those with heart failure, whether
after a single dose or at steady state. ACE inhibition
is preserved beyond 24 h following dosing, as is
antihypertensive efficacy.
In Chinese with CHF or other conditions in which
the elimination pathway may be affected, there is
data only for fosinopril, the only ACEI with a dual
(hepatic and renal) elimination mode. In this case,
there appeared to be no hazard induced by the heart
failure condition and no significant differences
among normal, hypertensive or heart failure
patients, whether Chinese or Caucasian, in pharma-
cokinetics or pharmacodynamics, following single
doses or at steady state.
In normal or hypertensive subjects ACEIs gener-
ally showed good blood pressure lowering efficacy
in Chinese with the exception of perindopril and cil-
azapril (single dose studies in normotensives) where
there appeared to be comparatively less blood press-
ure lowering (cilazapril) compared to Caucasians or
a relatively short-term effect for either group
(perindopril). The blood pressure lowering efficacy
in Chinese of benazepril, enalapril, fosinopril and
spirapril was adequately demonstrated in these
studies.
Chinese experience more cough from ACEIs
(captopril and enalapril) than Caucasians. Why this
may be so remains to be explained. Data suggest that
fosinopril may not induce cough in as many subjects
as other ACEIs,49,52 and this seems to be true of Chi-
nese as well.47 The mechanism underlying this
effect and the actual significance of it also await
further investigation.
It appears, then, that ethnic differences between
Chinese and Caucasians with respect to ACE and
AGT gene polymorphism, which might be expected
to differentially affect the action of ACEIs in these
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 얀 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 h HR 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
43
Elderly HTN 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-
dox. Gene titration studies in mice using both the
angiotensinogen (AGT) and ACE genes have shown
that variations of angiotensin II (Ang II) levels are
linked to changes in blood pressure, while vari-
ations in ACE levels, which may be considerable,
are not associated with such changes.53 As ACE lev-
els decrease, the level of Ang I increases and with
it the rate of its conversion to Ang II, thus main-
taining Ang II levels. Why, then, does ACE inhi-
bition lower Ang II levels? Because once ACE in-
hibition at the level of 80–90% occurs, the
compensatory increase in Ang I levels approaches a
plateau, at which point Ang II levels may then be
significantly reduced.53 This seems to set the clini-
cally significant level of ACE inhibition at 80+%, a
percent that correlates with clinical efficacy.
In conclusion, among the three ACEIs in which
there are pharmacokinetic and pharmacodynamic
data, fosinopril has no significant differences
between Chinese and Caucasians and has a long dur-
ation of ACE inhibition. Cilazapril and perindopril
show some minor differences in pharmacokinetics
between Chinese and Caucasians and a somewhat
lesser duration of ACE inhibition which may or may
not be related to these ethnic differences. There
appears to be evidence of the blood pressure lower-
ing efficacy of a number of these ACEIs in Chinese,

Journal of Human Hypertension


and there are pharmacokinetic data to support the
use of fosinopril in congestive heart failure where
elimination pathways may be impaired.
Acknowledgement
Supported by a grant from the Bristol-Myers Squibb
Pharmaceutical Research Institute, Princeton, NJ,
USA.
References
1 Zhou H-H et al. Racial differences in drug response.
Altered sensitivity to and clearance of propranolol in
men of Chinese descent as compared with American
whites. N Engl J Med 1989; 320: 565–570.
2 Wang JG et al. Long-term blood pressure control in
older Chinese patients with isolated systolic hyperten-
sion: a progress report on the Syst-China trial. J Hum
Hypertens 1996; 10: 735–742.
3 Hall AS, Ball SG. Oral captopril versus placebo among
13,634 patients with suspected acute myocardial
infarction: interim report from the Chinese Cardiac
Study (CCS-1). Lancet 1995; 345: 686–687.
4 Rigat B et al. An insertion/deletion polymorphism in
the angiotensin I-converting enzyme gene accounting
for half the variance of serum enzyme levels. J Clin
Invest 1990; 86: 1343–1346.
5 Tiret L et al. Evidence, from combined segregation and
linkage analysis, that a variant of the angiotensin I-
converting enzyme (ACE) gene controls plasma ACE
levels. Am J Hum Genet 1992; 51: 197–205.
6 Samani NJ et al. A meta-analysis of the association of
the deletion allele of the angiotensin-converting
enzyme gene with myocardial infarction. Circulation
1996; 94: 708–712.
7 Singer DR, Missouris CG, Jeffery S. Angiotensin-con-
verting enzyme gene polymorphism. What to do about
all the confusion? Circulation 1996; 94: 236–239.
8 Chiang FT et al. Lack of association of the angiotensin
converting enzyme polymorphism with essential
hypertension in a Chinese population. Am J Hypertens
1997; 10: 197–201.
9 Lee EJ. Population genetics of the angiotensin-con-
verting enzyme in Chinese. Br J Clin Pharmacol 1994;
37: 212–214.
10 Chuang LM et al. Insertion/deletion polymorphism of
the angiotensin I-converting enzyme gene in patients
with hypertension, non-insulin-dependent diabetes
mellitus, and coronary heart disease in Taiwan. Metab-
olism 1997; 46: 1211–1214.
11 Jeng JR et al. Angiotensin I converting enzyme gene
polymorphism in Chinese patients with hypertension.
Am J Hypertens 1997; 10: 558–561.
12 Sanderson JE et al. Lack of association between
insertion/deletion polymorphism of the angiotensin-
converting enzyme gene and end-stage heart failure
due to ischemic or idiopathic dilate cardiomyopathy
in the Chinese. Am J Cardiol 1996; 77: 1008–1010.
13 Jian M et al. Polymorphism of angiotensin I converting
enzyme gene in the older Chinese: linked to ambulat-
ory blood pressure levels and circadian blood pressure
rhythm. Int J Cardiol 1996; 55: 33– 40.
14 Chiang FT et al. Age- and gender-dependent associ-
ation of the angiotensin-converting enzyme gene with
essential hypertension in a Chinese population. J Hum
Hypertens 1996; 10: 823–826.
15 Chiang FT et al. Lack of association between angioten-
sin-converting enzyme gene polymorphism and coron-
ary heart disease in a Chinese population. Jpn Heart
J 1997; 38: 227–236.
Pharmacokinetics and use of ACE inhibitors in Chinese
PYA Ding et al
169
16 Saha N et al. Lack of association of angiotensin-con-
verting enzyme (ACE). Gene insertion/deletion poly-
morphism with CAD in two Asian populations. Clin
Genet 1996; 50: 121–125.
17 Jeng JR et al. Angiotensin I converting enzyme gene
polymorphism and insulin resistance in patients with
hypertension. J Hypertens 1997; 15: 963–968.
18 Hegele RA, Brunt JH, Connelly PW. A polymorphism
of the angiotensinogen gene associated with variation
in blood pressure in a genetic isolate. Circulation
1994; 90: 2207–2212.
19 Caulfield M et al. Linkage of the angiotensinogen gene
to essential hypertension. N Engl J Med 1994; 330:
1629–1633.
20 Ko YL et al. Angiotensinogen and angiotensin-I con-
verting enzyme gene polymorphisms and the risk of
coronary artery disease in Chinese. Hum Genet 1997;
100: 210–214.
21 Cheung B, Leung R. M235T polymorphism of the angi-
otensinogen gene is not associated with hypertension
in Chinese. Circulation 1997; 96 (Suppl): I-227
(abstract #562).
22 Kuivenhoven JA et al. The role of a common variant
of the cholesteryl ester transfer protein gene in the pro-
gression of coronary atherosclerosis. N Engl J Med
1998; 338: 86–93.
23 Lee EJ. Polymorphic inhibition of human angiotensin
I-converting enzyme by enalaprilat. Eur J Clin Pharma-
col 1995; 49: 173–175.
24 Borhani NO et al. Final outcome results of the Multi-
center Isradipine Diuretic Atherosclerosis Study
(MIDAS). A randomized controlled trial [see com-
ments]. J Am Med Assoc 1996; 276: 785–791.
25 Study Group on Long-term Antihypertensive Therapy.
A 12-month comparison of ACE inhibitor and CA
antagonist therapy in mild to moderate essential
hypertension—The GLANT Study. Hypertens Res
1995; 18: 235–244.
26 Gong L et al. Shanghai trial of nifedipine in the elderly
(STONE). J Hypertens 1996; 14: 1237–1245.
27 Maisch B et al. Retrospective studies and prospects of
therapy for hypertension. Herz 1995; 20: 370–389.
28 Anderson PJ, Critchley JA, Tomlinson B. A compari-
son of the pharmacokinetics and pharmacodynamics
of cilazapril between Chinese and Caucasian healthy,
normotensive volunteers. Eur J Clin Pharmacol 1996;
50: 57–62.
29 Ding PYA et al. Fosinopril: pharmacokinetics and
pharmacodynamics in Chinese subjects. J Clin Pharm-
acol 1999; 39: 155–160.
30 Chen J-H et al. Pharmacokinetics of fosinopril in Chi-
nese patients with congestive heart failure. Clin Drug
Invest 1998; 16: 377–385.
31 Anderson PJ, Critchley JA, Tomlinson B, Resplandy G.
Comparison of the pharmacokinetics and pharmacody-
namics of oral doses of perindopril in normotensive
Chinese and Caucasian volunteers. Br J Clin Pharma-
col 1995; 39: 361–368.
32 Waeber B, Brunner HR. Cilazapril. In: Messerli FH
(ed). Cardiovascular Drug Therapy. 2nd edn. W.B.
Saunders Company: Philadelphia, 1996, pp 810–813.
33 Sica DA. Fosinopril. In: Messerli FH (ed). Cardio-
vascular Drug Therapy. 2nd edn. W.B. Saunders Com-
pany: Philadelphia, 1996, pp 801–809.
34 Kostis JB et al. Fosinopril: pharmacokinetics and phar-
macodynamics in congestive heart failure. Clin Pharm-
acol Ther 1995; 58: 660–665.
35 Ford NF et al. Invasive pharmacodynamics of fosinop-
ril in patients with congestive heart failure. J Clin
Pharmacol 1995; 35: 785–793.
36 Hu OY-P et al. Pharmacokinetics of fosinoprilat in Chi-
Journal of Human Hypertension
 Pharmacokinetics and use of ACE inhibitors in Chinese
PYA Ding et al
170
nese and Whites after intravenous administration.
J Clin Pharmacol 1997; 37: 834 –840.
37 Lees KR, Reid JL. Perindopril. In: Messerli FH (ed).
Cardiovascular Drug Therapy. 2nd edn. W.B. Saun-
ders Company: Philadelphia, 1996, pp 775–784.
38 Physicians’ Desk Reference. Medical Economics Co:
Montvale, NJ, 1998, p 2357.
39 O’Grady P, Mangold B, Yee K-F, Liao W-C. Fosinopri-
lat and enalaprilat pharmacokinetics in patients with
congestive heart failure and renal insufficiency. J Heart
Failure 1995; 2: Abstract 1058.
40 Zhang JH, Li LS, Zhang M. Clinical effects of rheum
and captopril on preventing progression of chronic
renal failure. Chin Med J (Engl) 1990; 103: 788–793.
41 Woo KS, Nicholls MG. High prevalence of persistent
cough with angiotensin converting enzyme inhibitors
in Chinese. Br J Clin Pharmacol 1995; 40: 141–144.
42 Chan JC et al. The effects of enalapril and nifedipine
on carbohydrate and lipid metabolism in NIDDM. Dia-
betes Care 1994; 17: 859–862.
43 Chan P et al. Additive effects of diltiazem and lisinop-
ril in the treatment of elderly patients with mild-to-
moderate hypertension. Am J Hypertens 1997; 10:
743–749.
44 Hwang YS, Yen HW. Efficacy of once-daily lisinopril
monotherapy in systemic hypertension. Clin Cardiol
1993; 16: 129–132.
45 Chen CH et al. Short-term and long-term effects of
benazepril in mild to moderate hypertensives. Chung
Hua I Hsueh Tsa Chih (Taipei) 1995; 56: 12–22.
Journal of Human Hypertension
46 Tomlinson B et al. Sustained-release isradipine com-
pared with spirapril in the treatment of elderly
patients with isolated systolic hypertension. Am J
Hypertens 1994; 7: 35S–39S.
47 Chen CH et al. Different effects of fosinopril and ateno-
lol on wave reflections in hypertensive patients.
Hypertension 1995; 25: 1034 –1041.
48 Germino FW et al. Evaluation of the cough profile of
fosinopril in hypertensive patients with ACE inhibi-
tor-associated cough—a pilot study. Curr Therap Res
Clin Exp 1993; 54: 469– 475.
49 Punzi HA. Safety update: focus on cough. Am J Cardiol
1993; 72: 45H– 48H.
50 Brogden RN, Todd PA, Sorkin EM. Captopril. An
update of its pharmacodynamic and pharmacokinetic
properties, and therapeutic use in hypertension and
congestive heart failure. Drugs 1988; 36: 540–600.
51 Sorooshian M, Eynon CA, Webb DJ, Eastwood JB.
Cough associated with angiotensin converting enzyme
inhibitors: increased frequency in renal failure. Eur J
Int Med 1991; 2: 15–17.
52 Clementy J. Double-blind, randomized study of fosino-
pril vs nifedipine SR in the treatment of mild-to-mod-
erate hypertension in elderly patients. Drug Invest
1991; 3 (Suppl 4): 45–53.
53 Smithies O. A mouse view of hypertension. Circu-
lation 1997; 30: 1318–1324.