Discussion
The purpose of thisstudy was to compare the PK properties to examine
whether the new lisinopril/amlodipinebesylate FDC product was equivalent
to the reference for a new drug application to the NMPA.In this study,
the GMR and its 90% CI for the
Cmax,
AUC0-t, AUC0-72 (only lisinopril) and
AUC0-∞ of lisinopril and
amlodipinerespectively,
under both fasting and fed conditions,
fell
within the conventional bioequivalence criteria of 0.80-1.25.In
addition, compared with the reference drug, the incidence of AEs of the
test drug had no difference, and showedsimilar safety and tolerance.
These results indicated that the two lisinopril/amlodipinebesylate FDC
preparations were bioequivalent and exchangeable in clinical practice.
In this study, food appeared to greatly decrease the extent of
lisinopril absorption by more than half and affect the antihypertensive
effect for both the reference and test products. These results are
inconsistent with the instructions of the original lisinopril tablet
(Zestril® produced by AstraZeneca UK limited) and the reference
Lisonorm(produced by Gedeon Richter Ltd). The instructions say the
gastrointestinal absorption of lisinopril is not affected by food.A
previous study investing the influence of food consumption on the rate
or extent of absorption of orally administered lisinopril in healthy
volunteers observed that, a breakfast (524kcal, consisting of one fried
egg, two pieces of toast or bread, 20g of orange marmalade or jelly, two
stripes of bacon, 150ml of skimmed milk and 100ml of orange juice)did
not affect the bioavailability of
lisinopril[16]. This inconsistency
may probably be due to the fact that (i) high-caloric and high-fat foods
have a more obvious impact on the physiology of the gastrointestinal
tract and lead to more significant changes in the bioavailability of
pharmaceuticals[17]; (ii)spinach in
breakfast is rich in oxalic acid, which may change gastrointestinal PH
and gastrointestinal peristalsis
[18]; and (iii) the participants of
this study were all young Chinese adults, and there may be ethnic
differences in the pharmacokinetics of lisinopril. Among ACE inhibitors,
lisinopril has a unique property that does not require hydrolysis to
exert ACE inhibition, and only lisinopril and captopril are not ester
prodrugs and less lipophilic[19].
Food has been shown to reduce the bioavailability of captopril by 35%
to 50% after a single oral administration, but not the bioavailability
of inhibitors administered as ester
prodrugs[20].With high solubility,
low membrane permeability and poor metabolism, the pharmacokinetic of
lisinopril may be dominated by absorptive transporter
effects[21].Only about a quarter of
the administered dose is absorbed and the low bioavailability is due to
poor gastrointestinal absorption rather than first-pass hepatic
metabolism, as demonstrated by the factthat mean fecal recovery of
lisinopril was 69% of intact
drug[22].
In order to better understand the possible reasons for the decrease of
lisinopril absorption in the fed study, we searched for various factors
that affect lisinopril bioavailability.Little is known about
pharmacokinetic interaction of lisinopril so far.Drugs that often used
with lisinopril,such as nifedipine, digoxin,hydrochlorothiazide, have no
substantial effect on the pharmacokinetics of
lisinopril[23-25].No drug-drug
interactions (DDIs) were found between the active components amlodipine
and lisinopril. One of the factors that has been reported to affect the
kinetic properties of lisinopril was age. Drug concentrations of elderly
patients (>65 years) have been reported to be approximately
double those of younger patients[26].
And a recent study demonstrated that a concomitant ingestion of
epigallocatechin gallate(EGCG)-concentrated green tea extract
significantly decreased lisinopril Cmax, AUC0-24 and
AUC0-∞by 71%,69% and 67%, without altering renal clearance of
lisinopril[27]. However, in the
present study, the enrolled subjects was all between 18 and 50 years
old, and those who have drink too much tea were excluded. Moreover, it
was forbidden to taketeawithin 48 hours before taking the first
administration and during the test.Therefore, larger studies are needed
to evaluate the effect of food on the pharmacokinetics of lisinopril in
Chinese.