Micellar enhanced spectrofluorimetric approach for nanogram detection of certain α1 -blocker drugs: Application in pharmaceutical preparations and human plasma.

Alpha1-adrenergic-blocking drugs, namely; alfuzosin hydrochloride (ALF), doxazosin mesylate (DOX) and terazosin hydrochloride (TER) are effective as antihypertensive agents as well as in management of benign prostatic hypertrophy. In this study, a simple, very fast, highly sensitive and cheap technique was optimized for assay of these drugs in pure states and pharmaceutical tablets. The proposed method is dependent on enhancement of the native fluorescence of investigated drugs using the polyoxyethylene 50 stearate (POE50S) micellar system. The method showed excitation at 325, 340 and 250 nm for ALF, DOX and TER, respectively and an emission maxima at 382 nm. The fluorescence intensity-concentration charts of studied drugs were attained utilizing concentration ranges (2.0-60.0 ng mL-1 ) for DOX and (4.0-100.0 ng mL-1 ) for ALF and TER with quantitation limits 2.9, 1.6 and 2.5 ng mL-1 for ALF, DOX and TER, respectively. The suggested technique was approved according to International Council for Harmonisation (ICH) standards and the United States Food and Drug Administration (US FDA) bioanalytical method validation and has been effectively applied for assay of these medications in their dosage forms as well as for content uniformity test. The developed procedure was also efficiently applied for determination of these drugs in real human plasma with high accuracy.

Utility of Hantzsch reaction for development of highly sensitive spectrofluorimetric method for determination of alfuzosin and terazosin in bulk, dosage forms and human plasma.

A highly sensitive, cheap, simple and accurate spectrofluorimetric method has been developed and validated for the determination of alfuzosin hydrochloride and terazosin hydrochloride in their pharmaceutical dosage forms and in human plasma. The developed method is based on the reaction of the primary amine moiety in the studied drugs with acetylacetone and formaldehyde according to the Hantzsch reaction, producing yellow fluorescent products that can be measured spectrofluorimetrically at 480 nm after excitation at 415 nm. Different experimental parameters affecting the development and stability of the reaction products were carefully studied and optimized. The fluorescence-concentration plots of alfuzosin and terazosin were rectilinear over a concentration range of 70-900 ng ml-1 , with quantitation limits 27.1 and 32.2 ng ml-1 for alfuzosin and terazosin, respectively. The proposed method was validated according to ICH guidelines and successfully applied to the analysis of the investigated drugs in dosage forms, content uniformity test and spiked human plasma with high accuracy.

Unconjugated bilirubin elevation impairs the function and expression of breast cancer resistance protein (BCRP) at the blood-brain barrier in bile duct-ligated rats.

AIM: Liver failure is associated with dyshomeostasis of efflux transporters at the blood-brain barrier (BBB), which contributes to hepatic encephalopathy. In this study we examined whether breast cancer resistance protein (BCRP), a major efflux transporter at the BBB, was altered during liver failure in rats. METHODS: Rats underwent bile duct ligation (BDL) surgery, and then were sacrificed after intravenous injection of prazosin on d3, d7 and d14. The brains and blood samples were collected. BCRP function at the BBB was assessed by the brain-to-plasma prazosin concentration ratio; Evans Blue extravasation in the brain tissues was used as an indicator of BBB integrity. The protein levels of BCRP in the brain tissues were detected. Human cerebral microvessel endothelial cells (HCMEC/D3) and Madin-Darby canine kidney cells expressing human BCRP (MDCK-BCRP) were tested in vitro. In addition, hyperbilirubinemia (HB) was induced in rats by intravenous injection of unconjugated bilirubin (UCB). RESULTS: BDL rats exhibited progressive decline of liver function and HB from d3 to d14. In the brain tissues of BDL rats, both the function and protein levels of BCRP were progressively decreased, whereas the BBB integrity was intact. Furthermore, BDL rat serum significantly decreased BCRP function and protein levels in HCMEC/D3 cells. Among the abnormally altered components in BDL rat serum tested, UCB (10, 25 µmol/L) dose-dependently inhibit BCRP function and protein levels in HCMEC/D3 cells, whereas 3 bile acids (CDCA, UDCA and DCA) had no effect. Similar results were obtained in MDCK-BCRP cells and in the brains of HB rats. Correlation analysis revealed that UCB levels were negatively correlated with BCRP expression in the brain tissues of BDL rats and HB rats as well as in two types of cells tested in vitro. CONCLUSION: UCB elevation in BDL rats impairs the function and expression of BCRP at the BBB, thus contributing to hepatic encephalopathy.

Pharmacokinetics of terazosin enantiomers in healthy Chinese male subjects.

The purpose of this study was to elucidate the pharmacokinetics of terazosin enantiomers in healthy Chinese male subjects. After a single oral dose of 2-mg terazosin, the plasma concentrations of terazosin enantiomers were measured over the course of 48 h in 12 healthy subjects. The plasma concentrations of (+)-(R)-terazosin at all time points were higher than those of (-)-(S)-terazosin. The area under the plasma concentration-time curve (AUC(0-∞) ) and maximum plasma concentration of (+)-(R)-terazosin were significantly greater than those of the (-)-(S)-terazosin (P < 0.01, respectively). The R/S ratio of AUC(0-∞) of terazosin was 1.68. For the first time, it was proven that the pharmacokinetics of terazosin was stereoselective in healthy Chinese male subjects.

Simple and fast LC-MS/MS method for quantification of terazosin in human plasma and application to bioequivalence study.

A simple, fast and sensitive LC-MS/MS method was developed to quantify terazosin in human plasma. The mobile phase consisted of acetonitrile-0.1% (v/v) formic acid (70:30, v/v). Prazosin was used as internal standard (IS). As deproteinization agent, acetonitrile produced a clean sample. A higher response intensity with more symmetrical peak was obtained using Agilent Poroshell 120 EC-C18 - Fast LC column (100 × 2.1mmID, 2.7 µm) compared with Kinetex XB-C18 (100 × 2.1 mm, 2.6 µm) column. The response of terazosin and IS were approximately two times in citrate phosphate dextrose (CPD) plasma compared with dipotassium ethylenediaminetetraacetic acid (K2EDTA) plasma. Plasma calibration curve was linear from 1.0 to 100.0 ng/mL, with coefficient of determination r2 ≥ 0.99. The within-run and between-run precision values (CV, %) were <5.2% and <7.8%, while accuracy values were 102.8-112.7% and 103.4-112.2%. The extended run accuracy was 98.6-102.8% and precision (CV, %) 4.3-10.4%. The recovery of analyte was >98% and IS >94%. Terazosin in plasma kept at benchtop was stable for 24 h, in autosampler tray for 48 h, in instrumentation room for 48 h, for 7 freeze-thaw cycles and in freezer for 140 days. Terazosin and IS stock standard solutions were stable for 140 days at room temperature and in the chiller. The high throughput method was successfully utilized to measure 935 samples in a bioequivalence study of terazosin.

Direct analysis of dried blood spots utilizing desorption electrospray ionization (DESI) mass spectrometry.

A novel approach to the quantitative determination of xenobiotics in whole blood samples without sample preparation or chromatography is described. This method is based on direct analysis of microlitre volumes of blood which are spotted onto specialized paper cards and dried, with the resulting dried blood spots (DBS) analyzed directly via desorption electrospray ionization (DESI) mass spectrometry (MS). Using sitamaquine, terfenadine, and prazosin as model compounds with verapamil as a common internal standard, this methodology demonstrated detection of each compound down to 10 ng mL(-1) from DBS where standard calibration curves show linearity from 10-10,000 ng mL(-1) with r(2) > 0.99. Three (3) different untreated types of filter papers (Whatman 903 and 31ETF as well as Ahlstrom 237) and two (2) treated types of filter paper (Whatman FTA and FTA Elute) were examined and the effect of each surface on the recovery of each analyte was evaluated. The results show that the untreated papers provide the best substrates for DBS analysis by DESI. A more in depth study of the quantitation of sitamaquine on 31ETF paper stock provided bias and error measurements of less than 20%. The promising results shown in this study may have important implications in the areas of therapeutic drug monitoring (TDM), clinical and forensic toxicology, and pharmacology.

Magnetic-Dispersive Solid Phase Extraction Based on Graphene Oxide-Fe3O4 Nanocomposites Followed by High Performance Liquid Chromatography-Fluorescence for the Preconcentration and Determination of Terazosin Hydrochloride in Human Plasma.

In the present study, a facile modified impregnation method was employed to synthesize superparamagnetic graphene oxide-Fe3O4 (GO-Fe3O4) nanocomposites. Based on the GO-Fe3O4 as adsorbent, a simple and fast magnetic-dispersive solid phase extraction followed by high performance liquid chromatography with fluorescence detection (M-dSPE-HPLC-FL) method was established and validated for the preconcentration and determination of terazosin hydrochloride (TRZ) in human plasma samples. The obtained nanomaterials were characterized by X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, energy dispersive X-ray spectroscopy and vibrating sample magnetometry. Different parameters affecting the extraction efficiency, such as sample pH, amount of sorbent, extraction time, elution solvent and its volume and desorption time, were evaluated and optimized. The linearity of the proposed method was excellent over the range 0.3-50.0 ng mL-1 with an acceptable coefficient of determination (R2 = 0.9989). The limit of quantification and limit of detection were found to be 0.3 and 0.09 ng mL-1, respectively, and the preconcentration factor of 10 was achieved. Intra- and inter-day precision expressed as relative standard deviation (RSD %, n = 6) were between 2.2-3.8% and 4.7-6.4%, respectively. Accuracy, estimated by recovery assays, was 97.7-106.6% with RSD ≤ 5.2%. Ultimately, the applicability of the method was successfully confirmed by the extraction and determination of TRZ in human plasma samples.

Applications of shun shell column and nanocomposite sorbent for analysis of eleven anti-hypertensive in human plasma.

High-performance liquid chromatography (HPLC) and solid phase micro membrane tip extraction (SPMMTE) methods are developed for the simultaneous analysis of eleven cardiovascular drugs in human plasma. Iron nanoparticles were obtained by the green method, characterized by XRD, FT-IR, TEM, and EDS and utilized in SPMMTE for sample preparation. The mobile phase used was ammonium acetate buffer-methanol-acetonitrile (65:18:17) with a 1.0 mL/min flow rate at 260 nm detection. Column used was Sunshell C18 150 × 4.6 mm, 2.6 µm. The values of k, α, and Rs were ranged from 040 to109.22, 1.20 to 2.67 and 1.0 to 26.18. SPMMTE and HPLC methods were fast, reproducible, precise, robust, economic and rugged for analysis of methyldopa, hydrochlorothiazide, prazosin hydrochloride, furosemide, labetalol, propranolol, valsartan, losartan potassium, diltiazem, irbesartan and spironolactone in human plasma. The recoveries (%) of methyldopa, hydrochlorothiazide, prazosin hydrochloride, furosemide, labetalol, propranolol, valsartan, losartan potassium, diltiazem, irbesartan, and spironolactone were 91.0, 85.2, 92.3, 90.4, 90.1, 85.6, 86.6, 86.2, 85.1, 86.6, and 85.7, respectively. These results showed that SPMMTE and HPLC methods can be applied to test the described drugs in several matrices.

Pharmacokinetic and pharmacodynamic modelling of arterial haemodynamic effects of terazosin in healthy volunteers.

OBJECTIVE: This study aimed to investigate, in healthy volunteers, the relationship between the plasma concentrations of the alpha(1)-adrenoceptor antagonist terazosin and its effects on arterial blood pressure after a single oral administration of terazosin 2 mg. M ethods: Twenty-four healthy volunteers participated in this study. Pharmacokinetic and pharmacodynamic modeling were performed subject by subject. First, plasma concentrations were fitted according to a one-compartment model with first-order absorption and monoexponential elimination. Then the maximum drug-induced decrease (E(max)) effect compartment-model was developed to describe the pharmacodynamic relationships between systolic and diastolic blood pressure and plasma concentrations using the pharmacokinetic parameters that were previously estimated. RESULTS: For systolic blood pressure, E(max) was 29.9 +/- 10.6 mmHg. The corresponding value for decrease in diastolic blood pressure was 39.7 +/- 8.6 mmHg. The effects of terazosin on systolic and diastolic blood pressure could be quantified by an inhibitory E(max) effect compartment model. The obtained first-order rate constant values (0.40 +/- 0.006 h(-)(1) for systolic blood pressure and 0.47 +/- 0.012 h(-)(1) for diastolic blood pressure) were consistent with the rapid development of pharmacological effect. EC(50) (concentration of terazosin that induces an effect at 50% of E(max) values) values were similar for systolic (29.9 +/- 4.3 microg/L) and diastolic (28.7 +/- 4.0 microg/L) blood pressure. A decrease in diastolic blood pressure was the most sensitive response after oral administration of a single dose of terazosin. CONCLUSION: The direct haemodynamic effects of terazosin can be characterized by an E(max) effect compartment model.

A novel electrochemical sensor based on electrode modified with gold nanoparticles and molecularly imprinted polymer for rapid determination of trazosin.

A novel molecularly imprinted polymer sensor for fast and direct determination of trazosine (TR) was studied. The voltammetric sensor based on molecularly imprinted polymer (MIP) with disposable gold nanoparticles modified screen printed carbon electrode (MIP/AuNPs/SPCE) is developed for the determination of TR. Under the optimum conditions, the peak current of the sensor and TR concentration showed a good linear relationship over the range from 2.0 to 250.0 µM, with a low detection limit (S/N = 3) of 0.3 µM. The modified electrode demonstrated good electrocatalytic properties toward the oxidation of TR. This sensor selectively detected TR even in the presence of high concentration of similar compounds and MIP/AuNPs/SPCE was also confirmed successfully for the determination of TR in the various real samples including human blood serum, urine and trazosin tablet.

[Analysis of 37 drugs in whole blood by HPLC after solid phase extraction].

OBJECTIVE: To develop a specific, sensitive, reproducible SPE-HPLC method for the determination of 37 drugs in whole blood. METHODS: With the doxapram as internal standard, Oasis column was used to extract drugs from whole blood. Two kinds of mobile phases were used in this study. Separations were achieved by a LiChrospher 100 RP-C18 (250 mm x 4.0 mm x 5 microm) column kept at 50 degrees C, the DAD detector was set at 230 nm and 250 nm. RESULTS: The limit of detection were 1-30 ng/mL. The method showed excellent linearity and the linear correlation coefficient was > or =0.997 98. The relative standard deviation for between-day and within-day assay were <10%. CONCLUSION: The method is effective, simple, reliable and has been used in real cases.

Prazosin plasma concentration and blood pressure reduction.

Prazosin was administered to 16 patients with essential hypertension in an initial dose of 0.5 mg, after which the blood pressure (BP), pulse, and plasma concentrations of prazosin were measured at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 24 hours. The dose of prazosin was then increased over 16 to 20 weeks, and similar sequences of measurements were obtained twice. Eleven patients completed the 20-week course. All patients did not respond in a similar way; two distinct patterns of BP and pulse response emerged, although there was no significant difference in the pharmacokinetic parameters, namely, absorption rate constant (Ka), maximum plasma concentration (Cpmax), time to reach the maximum concentration (Tmax), prazosin plasma half-life (T 1/2), elimination rate constant (kel), prazosin plasma concentration-time curve (AUC), and clearance. Patients in Group 1 had a marked reduction (52/30 mm Hg) of BP after the first dose of prazosin, no pulse increase, and needed a small dose of prazosin to maintain an adequate BP response. Patients in Group 3 had a minimal reduction in BP (14/13 mm Hg) after a first dose, a significant pulse increase, and needed a high dose of prazosin to control their BP. We conclude that this effect might be due to a different drug-receptor interaction, and the BP response and dose could be predicted from the response of the first dose of prazosin.

Influence of congestive heart failure on prazosin kinetics.

The kinetics of oral prazosin was studied in 10 healthy normal subjects (NS) and in 9 patients with congestive heart failure (CHF). NS received a single 5-mg dose, and blood concentrations of prazosin (CB) were measured, using a specific HPLC assay, during an 8-hr period. CHF patients received a 2-mg dose after which CB was measured for 10 hr. These patients then received 2 to 5 mg prazosin every 8 hr for 48 hr. After the last dose of prazosin, CB was measured for 24 hr. After the initial dose, time to peak CB did not differ significantly between that of the NS (123 +/- 19 SEM min) and of patients with CHF (132 +/- 31.3 min). AUC/mg prazosin was greater (p less than 0.001) in patients with CHF (3,385 +/- 380 Ng x min/ml) than in NS (1,603 +/- 208 ng x min/ml). Elimination of prazosin from blood was slower in CHF patients (t1/2 = 374 +/- 33.4 min) than in NS (t1/2 = 144.5 +/- 4.3 min) (p less than 0.001). These data suggest that in patients with CHF the elimination of prazosin is substantially slower than in NS and therefore higher steady-state prazosin concentrations can be expected in CHF patients than in NS.

Alpha-receptor function changes after the first dose of prazosin.

The effect of oral prazosin on blood pressure and antagonism of phenylephrine-induce blood pressure increase was investigated in six healthy subjects during a dosing interval after the first dose and 3 days after the first dose of the drug. Prazosin lowered standing blood pressure more after the first dose than after the same dose 3 days later, despite similar plasma levels. Blood pressure decrease correlated with plasma prazosin levels during the elimination phase at the first dose, but not after 3 days of therapy. The phenylephrine log dose-response curves shifted to the right after prazosin, which indicates alpha-receptor antagonism of the drug. On day 4, the phenylephrine curve before prazosin dose shifted to the right of the pretreatment curve on day 1, despite very low prazosin plasma levels. On day 4 after after prazosin dosing the phenylephrine dose-response curves were shifted to the left of that on day 1. Our data indicated tolerance to prazosin effect on blood pressure and to phenylephrine agonism after 3 days dosing. Our data suggest that this might be due to desensitization of alpha-adrenoceptors with differential effects of agonists and antagonists.

Prazosin dynamics in hypertension: relationship to plasma concentration.

The antihypertensive effects of prazosin in relation to its kinetics were studied after single doses (intravenous and oral, 0.5 mg) and during increasing multiple doses (0.5 to 5 mg three times a day). There was a fall in systolic and diastolic blood pressures of 10% to 14%, which was greater in the standing than in the sitting position. Prazosin plasma concentrations correlated with dose (P less than 0.001). After intravenous prazosin the fall in systolic and diastolic blood pressure and prazosin plasma concentration correlated (P less than 0.01) during the beta-elimination phase in all patients. In only five of eight patients, however, did mean plasma concentration and antihypertensive effect during continuous treatment with different doses correlate. The maximal fall in systolic blood pressure correlated (P less than 0.01) with that after the first oral steady-state dose (0.5 mg three times daily), which indicates limited possibility of early identification of prazosin responders. There were no signs of overshoot of blood pressure when prazosin was withdrawn for a week. On rechallenge with a single oral dose of 2.5 mg prazosin there were no signs of enhanced hypotensive effect.

Clinical pharmacology of doxazosin in patients with essential hypertension.

Doxazosin is a new quinazoline derivative that, like prazosin, has selectivity for alpha 1-receptors. A three-way crossover, randomized, open study in 18 patients with essential hypertension was conducted to investigate the clinical pharmacokinetics of 2, 4, and 8 mg doxazosin at steady state. The pharmacokinetics of the initial 2 mg dose was also studied. Doxazosin showed linear pharmacokinetics. Increases in doses from 2 to 8 mg (steady state) produced proportional increases in doxazosin serum levels (maximum plasma drug concentration [Cmax] minimum plasma drug concentration [C min], and O-24-hour area under the curve [AUC(p-24)], whereas half-life (t1/2) (19.4, 18.7, and 19.7 hours, respectively), volume of distribution (3.4, 3.4, and 3.6 L/kg, respectively), clearance from serum (2.2, 2.2, and 2.1 ml/min/kg, respectively), and degree of protein binding (1.2%, 1.0%, and 1.0% unbound, respectively) were dose independent. Similar t1/2 and time to reach peak concentration (tmax) were obtained with 2 mg initial dose and 2 mg steady state. alpha 1-Acid glycoprotein levels were unchanged during doxazosin treatment. Doxazosin lowered supine and standing systolic and diastolic blood pressure. The blood pressure reduction was associated with an increase in heart rate. Peak hypotensive and tachycardic effects occurred 5.7 +/- 0.1 hours after administration, whereas Cmax was achieved at 2.4 +/- 0.7 hours (tmax). Greater decreases in systolic blood pressure and increases in heart rate were seen in standing than in supine position. The reduction in standing systolic and diastolic blood pressure with 8 mg was greater than with 2 mg (P less than 0.05); however, the increases in heart rate were not different. Dizziness, headaches, and dry mouth were the most frequent side effects. This study indicates that doxazosin shows linear pharmacokinetics between 2 and 8 mg and that because of its long t1/2, once-a-day administration should be adequate for the treatment of hypertension.

Relationship between plasma prazosin concentration and alpha-antagonism in humans: comparison of conventional and rate-controlled (Oros) formulations.

A single-dose comparative evaluation in young normotensive men of the plasma concentrations and alpha-adrenoceptor antagonism after conventional prazosin and a new slow-release formulation (Oros) is described. Whereas conventional prazosin (2 mg) produced a maximum reduction in erect blood pressure at 3 hours (80/46 mm Hg compared with 110/65 mm Hg with placebo), the lowest blood pressure of 94/48 mm Hg with Oros prazosin (5.5 mg) was not observed until 8 hours after administration. Twenty-four hours after Oros prazosin, prazosin was still detectable in plasma and erect blood pressure was reduced to 107/58 mm Hg compared with 110/71 mm Hg after placebo. alpha 1-Antagonism (assessed by the pressor responses to intravenous phenylephrine) was maximal, with a 4.8-fold shift in dose-response 24 hours after Oros prazosin, and persisted at least until 30 hours after administration, with a 2.3-fold shift. There were significant correlations between alpha 1-antagonism and plasma prazosin concentrations for both Oros and conventional prazosin. The slopes of these relationships were significantly different, but this is thought to be consistent with the differences in the rates of drug release from the two formulations. Overall this study provides further evidence in humans that the duration and extent of the alpha 1-antagonism and the blood pressure response reflect the plasma prazosin concentrations. Additionally these data suggest the potential suitability of this type of a slow-release formulation for single daily administration.

Immediate cardiovascular responses to oral prazosin--effects of concurrent beta-blockers.

Initiation of prazosin therapy may be complicated by the first-dose response of acute postural hypotension and tachycardia. The effects of beta-blocker on the responses to oral prazosin were studied in eight normotensive men. After 1 mg oral prazosin there was a marked postural fall in blood pressure to a lowest mean standing systolic pressure of 88 +/- 7 mm Hg (mean +/- SD), associated with a tachycardia of 117 +/- 13 bpm, and an increase in mean plasma norepinephrine concentration to 9.6 +/- 7.9 nmole/l. There was a linear relationship (r = 0.93) between plasma prazosin concentration and hypotensive effect. Concurrent propranolol 80 mg or primidolol 100 mg (a cardioselective beta-blocker) increased the severity and duration of the postural hypotensive response, with lowest mean systolic blood pressure (BP) of 79 +/- 7 and 75 +/- 9 mm Hg. There was no effect on the orthostatic release of norepinephrine but there was attenuation of the postural tachycardia. Concurrent beta-adrenergic blocking therapy, selective or nonselective, intensifies the immediate postural hypotensive response to the initial dose of prazosin.

Alpha adrenoceptor blockade with oral prazosin.

alpha-Adrenoceptor blockade after placebo and 5-mg oral doses of prazosin was assessed in five normal subjects over a range of phenylephrine infusion rates. Systolic blood pressure during a 400-microgram/min infusion of phenylephrine at 3 hr after placebo or prazosin was 172.8 +/- 6.2 and 108.7 +/- 4.4 mm Hg (p less than 0.05). The phenylephrine effects were blocked from 1 hr to at least 7 hr after prazosin. The drug-sensitivity ratio, an indicator of alpha-adrenoceptor blockade, before prazosin was 1.1, rising to 4 at 1 hr, 4.9 at 3 hr, 5.7 at 5 hr, and 4 at 7 hr after oral prazosin. The highest prazosin plasma concentration after a 5-mg oral dose was 29.3 +/- 6.6 ng/ml. It occurred 1 hr after prazosin. The elimination half-life was 2.9 +/- 0.3 hr. After oral prazosin the alpha-adrenoceptor blockade response did not correlate with prazosin plasma concentration.

Prazosin kinetics and effectiveness in renal failure.

Single and repeated doses of prazosin were given to 17 hypertensive patients, 5 with normal renal function and 12 with impaired renal function. Blood for prazosin assay was drawn after a 1-mg single dose and after patients reached steady-state levels with their long-term maintenance dose. As blood was drawn blood pressure was recorded. Prazosin absorption was not altered in patients with impaired renal function, and there is no cumulation of the drug when given repeatedly to patients with impaired renal function. Elimination kinetics were virtually identical regardless of degree of renal function. Effect on blood pressure was significantly better at the dosage range of 3 to 8 mg/day than at higher doses of 9 to 20 mg/day. There does not appear to be a direct relationship between the peak plasma prazosin level and the nadir of antihypertensive response. This would seem to indicate that the drug leaves the plasma and goes to the vascular smooth muscle receptor site of action. There appears to be no impairment in prazosin elimination in patients with impaired renal function, and its effectiveness (with diuretic or dialysis) is optimum at 3 to 8 mg/day.