Disease relevance of Fosinopril diacid

• CONCLUSIONS: Fosinoprilat exhibits significantly less accumulation than enalaprilat or lisinopril in patients with CHF and renal insufficiency, most probably because fosinoprilat is eliminated by both the kidney and liver, and increased hepatic elimination can compensate for reduced renal clearance in patients with kidney dysfunction [1].
• Comparison of the pharmacokinetics of fosinoprilat with enalaprilat and lisinopril in patients with congestive heart failure and chronic renal insufficiency [1].

High impact information on Fosinopril diacid

• The IC50 of captopril and fosinoprilat for LTA4 hydrolase activity were 500 microM and 1 mM, respectively [2].
• Omapatrilat inhibited similarly both N- and C-domain hydrolysis, whereas fosinoprilat was slightly more specific for the N-domain [3].
• After oral 14C-fosinopril (10 mg), plasma kinetics and bioavailability of fosinoprilat were similar for the three groups of renally impaired patients [4].
• The dipeptidyl carboxypeptidase activity towards benzoyl-Gly-His-Leu was inhibited by captopril (IC50 50 nM) and fosinoprilat (IC50 251 nM), two inhibitors of mammalian ACE, and was activated by Cl- (optimal Cl- concentration 600 mM) [5].
• Fosinopril is a phosphinic acid derivative which undergoes rapid hydrolysis after oral administration to the active diacid ACE inhibitor fosinoprilat [6].

Biological context of Fosinopril diacid

• Pharmacokinetics of fosinoprilat in Chinese and whites after intravenous administration [7].
• Peak blood levels of fosinoprilat occurred at about 3 hours after dosing, and linear kinetics of the diacid were observed [8].
• Following IV administration of 7.5 mg fosinoprilat, AUC0-T and AUCinf were 7,727 +/- 2,638 ng x hr/mL and 7,816 +/- 2,693 ng x hr/mL, respectively; T 1/2 was 13.0 +/- 5.2 hr; and median Tmax was 4.0 hr, with 99.5% +/- 0.22% protein binding and a Vss of 5,850 +/- 2,780 mL [9].
• Serum aldosterone levels, ACE activity, and sitting blood pressure were determined, as were pharmacokinetic parameters of fosinoprilat, the active diacid of fosinopril [8].
• RESULTS: There was no evidence of any significant effect of HCTZ on the pharmacokinetics of fosinoprilat, based on maximum concentration value, AUC, or cumulative urinary recovery over 24 hours [10].

Anatomical context of Fosinopril diacid

• Binding of the potent radiolabeled ACE inhibitor 125I-351A to ACE in the lung and aorta of gd 19 fetuses of fosinopril-treated dams was reduced by 56 and 44%, respectively, compared to fetuses from vehicle-treated dams, indicating that fosinopril or its active metabolite, fosinoprilat, crosses the placental barrier and inhibits fetal ACE [11].

Associations of Fosinopril diacid with other chemical compounds

• We demonstrate that captopril, lisinopril, and fosinoprilat are potent inhibitors of AcSDKP hydrolysis by wild-type ACE, with K(i) values in the subnanomolar range [12].
• In vitro, omapatrilat was 5 times more potent than fosinoprilat in inhibiting angiotensin I hydrolysis [3].
• The phosphinyl ester prodrug fosinopril, a new angiotensin converting enzyme (ACE) inhibitor, is fully hydrolysed after oral administration to the pharmacologically active diacid, fosinoprilat [13].
• Fosinopril is a phosphinic acid prodrug which, after oral administration, undergoes rapid hydrolysis to its active diacid, the angiotensin converting enzyme (ACE) inhibitor fosinoprilat [14].
• Concentration-inhibition curves to captopril, bestatin, and fosinoprilat revealed IC50 values of 430 microM, 7 microM, and 1 mM, respectively, for disrupted-cell LTA4 hydrolase activity [15].

Gene context of Fosinopril diacid

• Acer was inhibited by captopril, trandolaprilat and enalaprilat, with apparent Ki values in the nanomolar range, whereas lisinopril and fosinoprilat were less potent [16].
• Pharmacokinetic profiles of patient sera containing SQ 27,519 obtained by RIA and [14C]TLRC are identical [17].
• The relative contribution of the gut, liver, and lung to the first-pass hydrolysis (bioactivation) of the orally administered prodrug, fosinopril sodium (FS), to the active angiotensin-converting enzyme (ACE) inhibitor, SQ 27,519 (S), was determined [18].
• In conscious dogs, intravenous infusion of SQ 27,519 [0.5 mg/kg (1.1 mumol/kg) bolus plus 0.1 mg/kg/min (0.22 mumol/kg/min)], the active moiety of the prodrug fosinopril, increased PAH clearance and GFR by 25 and 16%, respectively (p less than 0.05, each) without changing arterial pressure (AP) [19].

Analytical, diagnostic and therapeutic context of Fosinopril diacid

• Liquid chromatography/electrospray tandem mass spectrometry method for the quantitation of fosinoprilat in human serum using automated 96-well solid-phase extraction for sample preparation [20].
• A specific radioimmunoassay (RIA) for the measurement of SQ 27,519 in human serum has been developed [17].
• Determination of SQ 27,519, the active phosphinic acid-carboxylic acid of the prodrug SQ 28,555, in human serum by capillary gas chromatography with nitrogen-phosphorus detection after a two-step derivatization [21].
• It was an open-label, randomized, balanced, two-way crossover study comparing oral and IV pharmacokinetics in 12 healthy Chinese subjects in a clinic in Taiwan. Each subject received 10 mg of oral fosinopril or 7.5 mg of IV fosinoprilatin a randomized sequence with sampling for fosinoprilat concentrations over 48 hours [9].

References