キナプリル塩酸塩

Peak plasma concentrations of quinapril occur within one hour following oral administration. The extent of absorption is at least 60%. The rate and extent of quinapril absorption are diminished moderately (approximately 25-30%) when ACCUPRIL tablets are administered during a high-fat meal.

There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Quinaprilat, the principle active metabolite of quinapril, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Quinaprilat also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors.

/HUMAN EXPOSURE STUDIES/ ACE inhibitors should be avoided in 2nd and 3rd trimesters because of severe fetal and neonatal toxicity (oligohydramnios, pulmonary hypoplasia, renal failure, anuria, death); severe, persistent, neonatal hypotension may occur. Structural defects after exposure in 2nd or 3rd trimesters include fetal calvarial hypoplasia and, possibly, renal anomalies. /ACE inhibitors; from table/ /Salt not specified/

/HUMAN EXPOSURE STUDIES/ Angioedema is an infrequent but serious and potentially fatal adverse effect of all the ACE inhibitors. Thus, patients starting treatment with these drugs should be explicitly warned to discontinue their use with the advent of any signs of angioedema. /ACE inhibitors/ /Salt not specified/

/SIGNS AND SYMPTOMS/ The principal adverse effect of ACE inhibitor overdose is hypotension, although hyperkalemia & renal failure may occur. ... /ACE inhibitors/ /Salt not specified/

Drug Induced Liver Injury Rank (DILIrank 2.0)

Quinapril hydrochloride

vLess-DILI-concern

3

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or 100 mg/kg/day (50-60 times the max human daily dose, respectively, on an mg/sq m basis and 3.8-10 times the max human daily dose when based on an mg/sq m basis) for 104 weeks. Female rats given the highest dose level had an increased incidence of mesenteric lymph node hemangiomas and skin/sc lipomas.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ No teratogenic effects of ACCUPRIL were seen in studies of pregnant rats and rabbits. On a mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum recommended human dose. /Salt not specified/

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ There were no adverse effects on fertility or reproduction in rats at doses up to 100 mg/kg/day (60 and 10 times the max daily human dose when based on mg/kg and mg/sq m, respectively). /Salt not specified/

/GENOTOXICITY/ Neither quinapril nor quinaprilat were mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also negative in the following genetic toxicology studies: in vitro mammalian cell point mutation, sister chromatid exchange in cultured cells, and in an in vivo cytogenetic study with rat bone marrow. /Salt not specified/

Absorption (bioavailability) of quinapril is 60%; time to peak serum concn is 2 hr; half-life (elimination) is 2 hr; protein binding is 97%; metabolism is in the liver. /from table/ /Salt not specified/

Quinapril is rapidly absorbed (peak concns are achieved in 1 hr, but the peak may be delayed after food), & its rate but not extent of oral absorption (60%) may be reduced by food. Quinapril is metabolized to quinaprilat & to other minor metabolites, & quinaprilat is excreted in the urine (61%) & the feces (37%). Peak concns of quinaprilat in plasma are achieved in about 2 hr. Conversion of quinapril to quinaprilat is reduced in patients with diminished liver function. The initial half-life of quinaprilat is about 2 hr; a prolonged terminal half-life of about 25 hr may be due to high-affinity binding of the drug to tissue ACE. /Salt not specified/