A sensitive and efficient LC-MS/MS method for the bioanalysis of fosinopril diacid from human plasma and its application for a bioequivalence study in humans.

Fosinopril diacid is an angiotensin converting enzyme inhibitor with efficient antihypertensive action. It is an active metabolic product formed in the body from hydrolysis of its prodrug Fosinopril. A sensitive, rapid method with high recovery for Fosinopril diacid from human plasma was developed. Solid-phase extraction technique employing Waters Oasis SPE cartridges gave clean samples with very high recovery of 97%. The analyte along with its internal standard (Benazepril hydrochloride) were chromatographed on an XTerra RP8 column (4.6 × 50 mm, 5 µm) using methanol-ammonium acetate buffer (10 mm; 90:10, v/v) as the mobile phase. A triple quadrupole mass spectrometer equipped with electrospray ionization source operated in the negative ion mode was used for detection. Multiple reaction monitoring scan mode was used for monitoring the transitions from m/z 434.00 → 237.15 for Fosinopril diacid and m/z 423.10 → 174.00 for Benazepril hydrochloride. Beer-Lambert's law was obeyed in the range of 0.50-1,500.00 ng/ml (r = 0.9993). The stability of the drugs in human plasma and in stock solution was proved by performing stability tests as per US Food and Drug Administration guidelines. The method was successfully applied for a bioequivalence study of Fosinopril diacid in 36 healthy, adult, male volunteers under fasting conditions.

Angiotensin Converting Enzyme Inhibitor Dialyzability and Outcomes in Older Patients Receiving Hemodialysis.

BACKGROUND/AIMS: Some angiotensin converting enzyme (ACE) inhibitors are efficiently removed from circulation by hemodialysis ('high dialyzability'), whereas others are not ('low dialyzability'). In patients receiving hemodialysis, this may influence the effectiveness of ACE inhibitors. METHODS: Using linked healthcare databases we identified older patients receiving chronic hemodialysis who filled new ACE inhibitor prescriptions. The low dialyzability group (n = 3,369) included fosinopril and ramipril. The high dialyzability group (n = 5,974) included enalapril, lisinopril, and perindopril. The primary outcome was all-cause mortality within 180 days of first ACE inhibitor prescription. RESULTS: There were 361 deaths among 5,974 patients (6.0%) prescribed with low dialyzability ACE inhibitors and 179 deaths among 3,369 patients (5.3%) prescribed with high dialyzability ACE inhibitors (relative risk 1.1, 95% CI 0.9-1.3, p = 0.6). CONCLUSION: In this study of older patients receiving hemodialysis, the dialyzability of ACE inhibitors was not associated with mortality or cardiovascular outcomes.

Mrp2 is involved in the efflux and disposition of fosinopril.

The multidrug-resistance-associated proteins 1 and 2 (MRP1/MRP2) are transporters responsible for the efflux of drugs and endogenous compounds. Madin Darby canine kidney (MDCK) cells transfected with the human MRP1 or MRP2 genes were used to assess whether several widely used pharmaceuticals are potential substrates by examining their differential toxicity, accumulation and efflux. Loratadine, an antihistamine, was 1.4-fold less toxic to MRP1 cells and its retention was 1.3-fold lower than that from MDCK control cells. Fosinopril, an angiotensin converting enzyme inhibitor, was 2.4-fold less toxic and its retention was 4.5-fold lower in MRP2-transfected cells compared with control cells. To determine whether fosinopril contributed to a drug-drug interaction, fosinopril efflux was examined in vitro in combination with other known or suspected MRP2 substrates over a period of 20 min. When fosinopril was coincubated with desloratadine, loratadine or methotrexate, its retention was increased by 2-, 4.7- and 2-fold, respectively, which likely indicates that a drug-drug interaction is occurring. In vivo studies were conducted, in which FVB wild-type and FVB/Mrp2(-/-) mice were dosed with fosinopril and the known MRP2 substrate methotrexate, and tissues collected after 1 h. In mice lacking Mrp2, drug levels were reduced in the intestine by 1.5-fold, but increased in the liver, serum and kidneys, by 2.1-, 2.9- and 3-fold, respectively. These data suggest that, in the absence of Mrp2, fosinopril alters the retention of a second drug. These findings will help increase our understanding of the role that MRP2 plays in altering the retention and disposition of coadministered pharmaceuticals.

Respuesta de los autores: Densidad ósea e hipertensión arterial / Authors’ reply: Bone density and hypertension

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Densidad ósea e hipertensión arterial / Bone density and hypertension

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Development and validation of liquid chromatography-tandem mass spectrometric method for simultaneous determination of fosinopril and its active metabolite fosinoprilat in human plasma.

A highly sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for simultaneous determination of the prodrug fosinopril and its major active metabolite fosinoprilat for pharmacokinetic studies in healthy subjects. In order to get the lower limit of quantification (LLOQ), especially for analysis of fosinopril, key points of the method have been investigated including chromatographic conditions and selection of LC-MS/MS conditions. The analytes were extracted from plasma samples by liquid-liquid extraction, separated on a reversed-phase C(8) column using gradient procedure, and detected by tandem mass spectrometry with a triple quadrupole ionization interface. The analytes and internal standard zaleplon were detected using positive electrospray ionization (ESI) in the SRM mode. The LLOQ of the method down to 0.1 ng mL(-1) for fosinopril and 1.0 ng mL(-1) for fosinoprilat were identifiable and reproducible. The standard calibration curves for both fosinopril and fosinoprilat were linear over the ranges of 0.1-15.0 and 1.0-700 ng mL(-1) in human plasma, respectively. The within- and between-batch precisions (relative standard deviation (RSD)%) and the accuracy were acceptable. The validated method was successfully applied to reveal the pharmacokinetic properties of fosinopril and fosinoprilat after oral administration.

Evolución de la densidad ósea de mujeres menopáusicas hipertensas en tratamiento con fosinopril / Evolution of the bone mass of hypertense menopausal women in treatment with fosinopril

Fundamento y objetivo: El sistema renina-angiotensina-aldosterona (SRAA) actúa en el metabolismo óseo disminuyendo la mineralización. Las mujeres menopáusicas frecuentemente son hipertensas y tienen riesgo de desarrollar osteoporosis. La inhibición del SRAA podría favorecer la mineralización y proteger la masa ósea de mujeres hipertensas en tratamiento con fármacos antihipertensivos inhibidores de la enzima de conversión de la angiotensina. Pacientes y método: Estudio observacional y prospectivo de cohortes. Se incluyó a 50 mujeres menopáusicas, divididas en una cohorte de pacientes normotensas y una cohorte de mujeres hipertensas, que iniciaron tratamiento antihipertensivo con fosinopril por vía oral. Se realizó una densitometría ósea de columna lumbar y cadera, basal y al cabo de 1 año. Resultados: No se observaron diferencias significativas de la masa ósea entre ambos grupos. En la cohorte expuesta no se evidenciaron cambios significativos antes y después del tratamiento. El grupo de mujeres no expuestas mostró diferencias en columna lumbar (densidad ósea basal, 0,874 g/cm2; final, 0,854 g/cm2; p = 0,002) y en cuello de fémur (densidad ósea basal, 0,743 g/cm2; final, 0,725 g/cm2; p = 0,016). Conclusiones: Las mujeres menopáusicas e hipertensas que siguieron tratamiento con fosinopril no presentaron la pérdida fisiológica de masa ósea que sí afectó a mujeres menopáusicas normotensas sin tratamiento

Background and objective: The renin-angiotensin system (SRA) acts on the bone metabolism and decreases the mineralization. Menopausal women frequently are hypertense and have risk of developing osteoporosis. The inhibition of SRA could favour the mineralization and protect the bone mass of hypertense women in treatment with antihypertensive drugs that are angiotensin converting enzyme inhibitors. Patients and method: Cohorts prospective study. 50 menopausal women were recruited and divided in one cohort of non hypertense patients and one cohort of hypertense women who initiated antihypertensive treatment with oral fosinopril. Baseline and after 1 year bone mineral density of lumbar spine and femoral neck was made. Results: There were no significant differences between the bone mass of both groups. Significant changes between the baseline and after the treatment were not demonstrated in the cohort exposed. In the group of non exposed women were demonstrated differences in lumbar spine (baseline, 0.874 g/cm2; final, 0.854 g/cm2; p = 0.002) and femoral neck (baseline, 0.743 g/cm2; final, 0.725 g/cm2; p = 0.016). Conclusions: The menopausal and hypertense women who followed treatment with fosinopril did not present the physiological loss of bone mass that affected to menopausal women without treatment

Mechanism of intestinal absorption and renal reabsorption of an orally active ace inhibitor: uptake and transport of fosinopril in cell cultures.

The objective of this study was to delineate the transepithelial transport mechanisms of fosinopril in cultured cell lines expressing the intestinal and renal peptide transporters. Lineweaver-Burk, Dixon, and dose-response analyses revealed that GlySar uptake was competitively inhibited by fosinopril in both Caco-2 (K(i), 35.5 microM) and SKPT cells (K(i), 29.6 microM). Intracellular accumulations of fosinopril were 3 to 4 times higher from apical versus basolateral surfaces of the membrane, as was the apical-to-basal flux of the drug. The apical peptide transporter had a significantly greater affinity for fosinopril than did the basolateral peptide transporter in Caco-2 cells (K(m), 154 versus 458 microM, respectively; p < 0.001) and SKPT cells (K(m), 22 versus 104 microM, respectively; p < 0.001). Moreover, fosinopril uptake by the basolateral peptide transporter was less sensitive to changes in medium pH than the apical peptide transporter in both cell lines. Although Caco-2 cells are known to express PEPT1 protein (and not PEPT2), our immunoblot analyses provide definitive evidence that SKPT cells express PEPT2 protein (and not PEPT1). Taken as a whole, our findings demonstrate that fosinopril is transported intact by PEPT2 and PEPT1, with high-affinity and by a proton-coupled, saturable process. Our results also suggest that distinct peptide transporters exist at the basolateral and apical membranes and that they play an important role in modulating the intestinal absorption and renal reabsorption of peptides and peptide-like drugs.

Is the tissue affinity of ACE inhibitors of relevance for the remodeling of the left ventricular wall following myocardial infarction? Estimations with cine magnetic resonance imaging.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors have been shown to be of value in the treatment of postinfarction remodeling. The question whether substances with a greater tissue affinity are associated with advantages for the acute and the chronic course is, however, still unclear. AIM: The aim of the present study was to investigate the influence of ACE inhibitors with differing tissue affinities on the remodeling of the left ventricular wall in patients recovering from myocardial infarction. METHODS: 52 patients (17 women, aged 38-73 years) suffering their first acute myocardial infarction were randomized to receive a daily dose of either 25-75 mg captopril or 10-20 mg fosinopril, beginning on the 7th postinfarction day. 28 patients had an anterior wall infarction and 24 patients an inferior wall infarction. The size of the infarct was determined using the creatine kinase integral method. 50 patients were investigated by cine magnetic resonance imaging 1 and 26 weeks after the infarction. The following parameters were determined: infarct weight and diastolic diameter of the infarcted zone, systolic wall stress, muscle mass, diastolic and systolic diameters, systolic wall thickening, and motility of the noninfarcted myocardium. RESULTS: The infarct weight increased under captopril by 5.7% (p < 0.05) and under fosinopril by 6.1% (p < 0.05). The diastolic diameter of the infarcted zone decreased by 12% under captopril (p < 0.001) and by 11% under fosinopril (p < 0.001). The systolic wall thickness increased by 12.1% (p < 0.001) and the muscle mass by 12.7% (p < 0.001) under captopril and by 15.4% (p < 0.001) and 9.6% (p < 0.01), respectively, under fosinopril. Under captopril, the diastolic diameter increased by 2.3% (p < 0.05) and the systolic diameter by 17.8% (p < 0.01) and under fosinopril by 2.8% (n.s.) and 17.5% (p < 0.001), respectively. The systolic wall thickening increased by 73.9% under captopril (p < 0.001) and by 129.4% under fosinopril (p < 0.001). The motility decreased by 13.8% (p < 0.05) under captopril and by 6.0% (n.s.) under fosinopril. For all parameters, the results seen in anterior wall infarction were appreciably poorer than those seen in inferior wall infarction. All the differences between captopril and fosinopril were not significant. CONCLUSIONS: Captopril and fosinopril show no major differences in their influence on left ventricular wall remodeling following myocardial infarction. On the basis of the present results, the tissue affinity of an ACE inhibitor does not appear to be of a significant relevance for postinfarction treatment.

Comparison of the pharmacokinetics of fosinoprilat with enalaprilat and lisinopril in patients with congestive heart failure and chronic renal insufficiency.

AIMS: To compare the serum pharmacokinetics of fosinoprilat with enalaprilat and lisinopril after 1 and 10 days of dosing with fosinopril, enalapril and lisinopril. METHODS: Patients with congestive heart failure (CHF, NYHA Class II-IV) and chronic renal insufficiency (creatinine clearance

Fosinopril/hydrochlorothiazide: single dose and steady-state pharmacokinetics and pharmacodynamics.

AIMS: Fosinoprilat, the active product of fosinopril, is eliminated by an hepatic pathway in addition to the renal pathway shared by other angiotensin converting enzyme inhibitors (ACEIs). This study aimed to determine whether impaired renal function affects the pharmacokinetics and pharmacodynamics of a combination of fosinopril and hydrochlorothiazide (HCTZ). METHODS: The study had a parallel-group design comparing patients with renal impairment and body-mass-index-matched normal controls. The study was done in a University clinic in 13 patients with renal impairment (mean creatinine clearance 55.7+/-15.6 ml min-1 1.73 m-2 ) and 13 age-, sex-, and body-mass-index-matched normal controls (mean creatinine clearance 102.4+/-8.9 ml min-1 1.73 m-2 ). All patients and normal controls received fosinopril sodium 20 mg and HCTZ 12.5 mg as a daily oral administration on days 1-5. Non-compartmental pharmacokinetic parameters of fosinoprilat and HCTZ were determined from blood and urine samples obtained over 48 h starting on Day 1 (single dose) and Day 5 (steady state): maximum serum concentration (Cmax ), time to maximum serum concentration (tmax ), area under the serum concentration-time curve during the dosing interval (AUC), cumulative urinary excretion (CUE) and the accumulation index (AI; ratio of AUC-day 5/AUC-day 1). Pharmacodynamic parameters were also measured over 24 h on day 1 and over 48 h on day 5: serum ACE activity and arterial blood pressure. RESULTS: Fosinoprilat pharmacokinetic parameters on day 1 in renally impaired vs normal patients: Cmax=387+/-0.19 vs 324+/-0.25 ng ml-1 (P=0.07); tmax=3.5 vs 3.0 h (P=0.58); AUC=3510+/-0.29 vs 2701+/-0.35 ng ml-1 h (P=0. 072); CUE=5.08+/-2.70 vs 7.40+/-2.56% (P=0.009). Fosinoprilat parameters on day 5: Cmax=517+/-0.40 vs 357+/-0.19 ng ml-1 (P=0. 007); tmax=3.0 vs 3.0 h (P >0.99); AUC=4098+/-0.43 vs 2872+/-0.30 ng ml-1 h (P=0.027); CUE=6.81+/-3.53 vs 8.10+/-2.80% (P=0.068). AI=1. 17+/-0.33 vs 1.06+/-0.23 (P=0.29). In both groups ACE inhibition and blood pressure response were similar over 24 h and slightly greater 48 h after last dosing. CONCLUSIONS: In renally impaired subjects fosinopril and HCTZ can be coadministered without undue increases in fosinoprilat concentrations or any clinically significant pharmacodynamic effects. This is probably due to the dual excretory pathways for fosinoprilat.

Fosinopril and hydrochlorothiazide combination versus individual components: lack of a pharmacokinetic interaction.

OBJECTIVE: To evaluate the pharmacokinetic interaction and bioequivalence of a combination formulation of the angiotensin-converting enzyme inhibitor fosinopril and the diuretic hydrochlorothiazide (HCTZ). METHODS: In an open-label, balanced, randomized incomplete block, three-way crossover fashion, healthy men received single doses of three of four regimens in one of two independent studies. Regimens for study A (36 subjects): (1) fosinopril 10-mg tablet, (2) HCTZ 12.5-mg tablet, (3) a combination tablet of fosinopril 10 mg plus HCTZ 12.5 mg, or (4) coadministered tablets of fosinopril 10 mg and HCTZ 12.5 mg. Study B (40 subjects) received: (1) fosinopril 20-mg tablet, (2) HCTZ 12.5-mg tablet, (3) a combination tablet of fosinopril 20 mg plus HCTZ 12.5 mg, or (4) coadministered tablets of fosinopril 20 mg and HCTZ 12.5 mg. 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. Fosinoprilat had no clinically important effect on the pharmacokinetics of HCTZ only slightly decreasing its AUC by 14% in study A. Coadministration was well tolerated; no new adverse events were reported with the combination tablet. CONCLUSIONS: Fosinopril and HCTZ in a combination tablet display pharmacokinetic profiles similar to those achieved when either drug is administered alone or when coadministered in separate tablets. When used with HCTZ, the favorable pharmacokinetic feature of fosinopril, dual and compensatory pathways of renal and hepatic elimination, is preserved.

Fosinopril: pharmacokinetics and pharmacodynamics in Chinese subjects.

This study examined thepharmacokinetics and pharmacodynamics of fosinopril (IVand oral) in Chinese subjects to determine whether they were different from a group of somewhat heavier and older Western control subjects previously published using the same methods. 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. Standard pharmacokinetics, including AUC, Cmax Tmax, T 1/2, Vss, bioavailability, total clearance, and renal and nonrenal clearance, were determined as well as pharmacodynamic effects on angiotensin-converting enzyme (ACE) activity. Following oral administration of 10 mg fosinopril, AUC0-T and AUCinf were 1,556 +/- 586 ng x hr/mL and 1,636 +/- 620 ng x hr/mL, respectively; T 1/2 was 17.4 +/- 11.4 hr; Cmax was 183.4 +/- 59.4 ng/mL; and median Tmax was 4.0 hr, with > 99% protein binding. 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. Bioavailability was 22.3% +/- 7.9%. Percent urinary excretion was 7.6% +/- 2.6% after oral dosing and 42.6% +/- 6.1% after IV dosing. After IV, dosing total clearance was 1,088 +/- 439 mL/hr, renal clearance was 472 +/- 213 mL/hr, and nonrenal clearance was 617 +/- 246 mL/hr. ACE inhibition was essentially complete through 12 hours and markedly reduced through 24 hours. Compared to a somewhat heavier and older previously reported control group, pharmacokinetic values were similar except for a slightly lower AUC and total clearance in Chinese and a statistically significantly lower nonrenal clearance. Pharmacodynamic effects on ACE activity were essentially identical. There is no reason to expect significant differences in fosinopril dosing or effect in a Chinese population compared to a Western population.

Treatment of heart failure with fosinopril: an angiotensin converting enzyme inhibitor with a dual and compensatory route of excretion.

Congestive heart failure (CHF) is one of the most common and clinically important cardiovascular diseases. This pathologic state is characterized not only by well-defined hemodynamic alterations, but also by complex abnormalities involving the sympathetic nervous system, the renin-angiotensin system, and other hormones involved in cardiovascular homeostasis. In addition, there is an abnormality in the homeostatic cardiovascular control exerted by arterial baroreceptors and the viscoelastic properties of medium-size arteries are altered, causing a reduction in arterial compliance. All of these abnormalities can be favorably affected by angiotensin converting enzyme (ACE) inhibitors, which have been shown to improve not only the hemodynamic and neurohumoral profiles of CHF, but also patient survival. CHF is accompanied with a decline or some sort of effect on renal function. An ACE inhibitor with a dual route of excretion, such as fosinopril, may be especially useful in treating patients with CHF.

Treatment of congestive heart failure: experience with fosinopril.

The prevalence of congestive heart failure (CHF), a debilitating condition associated with impaired quality of life and markedly shortened life expectancy, is increasing. The goals of therapy for CHF are reducing symptoms, improving functional capacity, and slowing the progression of the condition. In most cases, this is best achieved with a combination of diuretic and vasodilator therapy. Angiotensin-converting enzyme (ACE) inhibitors have several advantages over other vasodilatory agents and are becoming widely used for treating CHF. The most recently introduced ACE inhibitor, fosinopril, is at least as effective as enalapril, and its dual and compensatory route of excretion is particularly advantageous in patients with renal insufficiency. Fosinopril may also have particular benefits in the prevention of CHF, as it has beneficial effects on cardiac function that may help delay the onset of overt cardiac failure.

Fosinopril. A review of its pharmacology and clinical efficacy in the management of heart failure.

Fosinopril is the prodrug of the active diacid ACE inhibitor fosinoprilat. In patients with heart failure, fosinopril reduces pulmonary capillary wedge pressure, mean arterial blood pressure, mean right atrial pressure and heart rate, and increases stroke volume index and cardiac index. The drug has compensatory dual elimination routes via renal and hepatic systems and accumulates to a lesser extent than enalapril and lisinopril in patients with chronic renal insufficiency with or without heart failure. Comparative studies of 3 or 6 months' duration with fosinopril 10 to 40 mg/day have demonstrated clinical efficacy significantly superior to that of placebo in patients with heart failure [mostly New York Heart Association (NYHA) functional class II or III]. Fosinopril treatment consistently increased exercise duration and improved heart failure symptoms in these patients. Significantly fewer fosinopril than placebo recipients withdrew or were hospitalised because of worsening heart failure. Additionally, significantly more fosinopril than placebo recipients showed improvement, and fewer patients had deteriorated, in terms of NYHA functional class. Fosinopril and enalapril showed similar clinical efficacy over 6 and 12 months' treatment in patients with NYHA functional class II to IV heart failure. As yet, there are no data showing a mortality benefit with fosinopril. Fosinopril was well tolerated in clinical trials in patients with heart failure. Dizziness (11.9 vs 5.4% for placebo), cough (9.7 vs 5.1%) and hypotension (4.4 vs 0.8%) were the most commonly reported adverse events. In 6- or 12-month comparative studies, fosinopril therapy was associated with a lower incidence of dizziness and hypotension, but a higher incidence of vertigo, than enalapril therapy. 0.8% of patients discontinued the drug because of cough, which occurred to a similar extent with fosinopril and enalapril. Thus, based on available clinical evidence, fosinopril is an effective and well tolerated option for the management of patients with heart failure. Although clinical data are limited, fosinopril may be especially useful in patients with renal or hepatic impairment.

Fosinopril. Clinical pharmacokinetics and clinical potential.

Fosinopril is a phosphorus-containing ester prodrug of an angiotensin-converting enzyme (ACE) inhibitor. It is hydrolysed mainly in the gastrointestinal mucosa and liver to the active diacid, fosinoprilat, which has unique pharmacological properties. The majority of the active moieties of other ACE inhibitors are excreted in the urine. This means that an adjustment in either the dosage and/or the administration interval is needed in patients with moderate to severe renal dysfunction, in order to reduce drug accumulation and the possibility of an excessive decrease in blood pressure or other adverse effects. On the other hand, fosinoprilat is excreted both in urine and bile (as with temocaprilat, zofenoprilat and spiraprilat), and thus an adjustment of dosage and/or administration interval may be unnecessary in patients with moderate to severe renal dysfunction, as impaired renal function influences little of the pharmacokinetics of fosinoprilat. Furthermore, the available evidence suggests that the pharmacokinetic variables of fosinoprilat in patients receiving haemodialysis were similar to those in patients with moderate to severe renal dysfunction. Dosage modifications or supplemental dose administration following dialysis may be unnecessary. The hypotensive effect of the combination of fosinopril and a diuretic is synergistic. Pharmacokinetic interactions with fosinopril are unlikely in patients receiving thiazide or loop diuretics. Fosinopril has beneficial effects for patients with hypertension and left ventricular hypertrophy because it produces an adequate reduction in blood pressure and reversal of left ventricular hypertrophy. There are a large number of studies of the pharmacokinetics of fosinopril. However studies of its pharmacokinetic drug interactions with other drugs are far fewer. Further investigations are needed in several clinical settings.

Pharmacokinetics of fosinoprilat in Chinese and whites after intravenous administration.

The pharmacokinetics of fosinoprilat was studied in 12 healthy Chinese men after a 7.5 mg intravenous dose of fosinoprilat. The data were compared with those from an earlier study using the same protocol in nine healthy white men. Blood and urine samples were obtained before and at various time intervals after fosinoprilat administration up to 24 hours and 48 hours, respectively. Pharmacokinetic parameters were calculated by fitting the plasma or serum concentrations to a three-compartment model. The total clearance (Clt), renal clearance (ClT), and nonrenal clearance (ClNR) were significantly lower in Chinese (16.29 +/- 6.92, 6.85 +/- 2.97, and 9.44 +/- 5.08 mL.hr-1.kg-1) than those obtained in whites (29.88 +/- 6.36, 13.55 +/- 3.45, and 16.33 +/- 5.07 mL.hr-1.kg-1). The Chinese subjects had a significantly lower volume of distribution (Vc [volume of distribution of central compartment] and Vdss [volume of distribution at steady state]) (29.38 +/- 21.12 and 73.67 +/- 40.20 mL/kg) than white men (58.14 +/- 15.01 and 152.49 +/- 24.89 mL/kg). The Chinese men also had a shorter elimination half-life than whites, although not statistically significant. The respective half-lives in Chinese and whites were 5.51 +/- 1.53 and 8.24 +/- 1.99 hours. The significant differences in ClNR and ClR may be related to lower liver elimination function and lower kidney excretory function, respectively. Plasma protein binding may contribute to part of the difference in the volume of distribution. Chinese men have smaller volume of distribution and clearances of fosinoprilat after intravenous administration compared with white men. The cumulative urine excretion of fosinoprilat was not different between Chinese and whites. Chinese may require a lower fosinoprilat dosage to obtain plasma concentrations similar to whites after intravenous administration. However, since a relatively high variation was found in fosinopril oral absorption, the oral dosage of fosinopril for Chinese and whites may not be different. Further study is obviously needed to elucidate whether the pharmacodynamic effect may be different between Chinese and whites.

Fosinopril: a reappraisal of its pharmacology and therapeutic efficacy in essential hypertension.

Fosinopril is a phosphinic acid derivative which undergoes rapid hydrolysis after oral administration to the active diacid ACE inhibitor fosinoprilat. Cardiotropic effects have been associated with the drug, and the compensatory dual elimination route of fosinopril via renal and hepatic systems offers an opportunity for ACE inhibitor treatment of hypertension in patients with renal or hepatic impairment. Comparative trials of monotherapy with fosinopril 10 to 40 mg/day have demonstrated antihypertensive efficacy equivalent to that of sustained release nifedipine 40 mg/day, hydrochlorothiazide 25 to 50 mg/day, enalapril 5 to 10 mg/day amlodipine 5 to 10 mg/day and sustained release verapamil 240 to 480 mg/day, and superior to that of isradipine 5 mg/day. The efficacy of combination therapy with fosinopril 10 to 20 mg/day and hydrochlorothiazide 12.5 mg/day was significantly superior to that of hydrochlorothiazide alone, tended to be superior to that of fosinopril 20 mg/day alone and was similar to that of sustained release nifedipine 40 mg/day alone. The combination of fosinopril/chlorthalidone 20 to 40/25 mg/day was as effective as propranolol/chlorthalidone 80 to 160/25 mg/day. The incidence of adverse effects associated with fosinopril is low, and cough may possibly occur less often with this drug than with other ACE inhibitors. Fosinopril thus offers an effective and well tolerated option for the treatment of hypertension in adult and elderly patients, including those with renal or hepatic impairment.