Comparative Clinical Pharmacokinetics of Midodrine and Its Active Metabolite Desglymidodrine in Cirrhotic Patients with Tense Ascites Versus Healthy Volunteers.

OBJECTIVE: Midodrine is an α-agonist prodrug of desglymidodrine used for the management of hypotension, and can also be used for hepatorenal syndrome and cirrhotic patients with tense ascites. The objective of the present work was to study the clinical pharmacokinetic parameters of midodrine and its active metabolite desglymidodrine in cirrhotic patients with tense ascites, which may help in dose selection and improve treatment outcome. METHOD: This was a prospective, open-label, single-dose, parallel-group study. At first, a pilot study was performed on one healthy volunteer by taking serial blood samples at scheduled time intervals to validate the method of analysis and sampling times. The full study was then conducted by selecting 12 cirrhotic patients with tense ascites in one group and taking nine blood samples. We also selected five healthy volunteers as the control group and took 11 blood samples. RESULTS: Statistically significant differences were observed between the healthy volunteer group and the patients group in the area under the concentration versus time curve (AUC0-t) and maximum plasma concentration (Cmax) values of midodrine and desglymidodrine. Based on the results of the pharmacokinetic analysis, the patient group was further subdivided into those receiving the interacting drug ranitidine (five patients) and those not receiving the interacting drug (seven patients). CONCLUSIONS: Pharmacokinetic parameters of midodrine can differ significantly in cirrhotic patients with tense ascites from those in healthy individuals. Drug monitoring, dose adjustments, and drug-drug interactions should all be considered during therapy in this vulnerable patient group.

Predicting human exposure of active drug after oral prodrug administration, using a joined in vitro/in silico-in vivo extrapolation and physiologically-based pharmacokinetic modeling approach.

INTRODUCTION: Predicting the pharmacokinetics (PK) of prodrugs and their corresponding active drugs is challenging, as there are many variables to consider. Prodrug conversion characteristics in different tissues are generally measured, but integrating these variables to a PK profile is not a common practice. In this paper, a joined in vitro/in silico-in vivo extrapolation (IVIVE) and physiologically-based pharmacokinetic (PBPK) modeling approach is presented to predict active drug exposure in human after oral prodrug administration. METHODS: Physico-chemical and in vitro assays as well as in silico predictions were proposed to characterize key pharmacokinetic properties (e.g. clearance, volume of distribution, conversion rates) of three marketed prodrugs. These data were used to parameterize a PBPK model for simulating human PK profiles of the active drugs after prodrug administration, which were compared to literature data by evaluating the accuracy and uncertainty of the predictions. RESULTS: For mycophenate mofetil and midodrine the PK of their active moieties could be adequately predicted. The assumptions of the PBPK-IVIVE approach were valid, i.e. being hepatically cleared, converted in the gut lumen, blood and liver and not metabolized in the gut wall. However, the observed profiles after oral bambuterol administration clearly fell outside the prediction interval as the PBPK model failed to predict the observed bioavailability. DISCUSSION: Adding quantitative information about prodrug conversion in the gut, liver and blood to a PBPK model for the absorption, distribution, metabolism and excretion (ADME) properties of prodrugs and their active moieties resulted, retrospectively, in reasonable predictions of the human PK when the ADME properties are well understood. Also in a prospective compound selection process, this integrative approach can improve decision making on prodrug candidates by putting relative differences in prodrug conversion of a large number of candidates into the perspective of their human PK profile, before conducting any in vivo experiments.

Pharmacokinetic and pharmacodynamic effects of midodrine on blood pressure, the autonomic nervous system, and plasma natriuretic peptides: a prospective, randomized, single-blind, two-period, crossover, placebo-controlled study.

BACKGROUND: Midodrine is an alpha-agonist prodrug of desglymidodrine (DGM) that has been reported to be of clinical benefit in patients with neurocardiogenic syncope. Its effects may be mediated not only by its hypertensive properties but also by its neurohumoral influences independent of blood pressure (BP). OBJECTIVE: The present study aimed to simultaneously characterize the effects of midodrine on BP, plasma catecholamines, plasma atrial natriuretic peptide (ANP), and power spectral analysis of heart rate (HR) in healthy volunteers. METHODS: This was a prospective, randomized, single-blind, 2-period, crossover study in which a single, oral, 5-mg dose of midodrine was compared with placebo. The washout period between midodrine and placebo was 1 week. The study parameters included plasma DGM (as measured by high-performance liquid chromatography [HPLC]); systolic and diastolic BP (as measured with an oscillometric monitor); HR; plasma catecholamines (measured by HPLC); plasma ANP, also known as venous return (measured by a radio-immunoassay); and low- and high-frequency HR variation (calculated from computerized 5-minute electrocardiographic recordings). All study parameters were measured simultaneously 12 times just before and over a period of 8 hours after drug administration. RESULTS: Fifteen healthy nonsmoking male subjects (14 white, 1 black; mean [SD] age, 28.6 [4.7] years; weight, 74.5 [16.4] kg; seated BP, 109.9 [9.0]/73.6 [9.5] mm Hg; seated HR, 63.8 [8.4] bpm) were randomized. No significant effects of midodrine on BP were observed. At Cmax, midodrine decreased norepinephrine from 188.4 (30.6) to 162.5 (29.8) pg/mL (P = 0.011) and HR from 57.2 (7.3) to 54.9 (6.6) bpm (P = 0.022). A significant correlation was found between DGM concentration and HR ( varphi -0.61; P = 0.014). A DGM-related increase in plasma ANP (+29.6 [90.0] fmoL/mL) was observed. CONCLUSION: This study in healthy male volunteers found that midodrine has sympatholytic influences that are independent of BP but related to augmented venous return.

Liquid chromatography-tandem mass spectrometry method for the quantification of deglymidodrine in human plasma.

A simple, rapid and sensitive liquid chromatography-tandem mass spectrometry method was developed for quantification of deglymidodrine in human plasma. The plasma samples were pretreated by protein precipitation with trichloroacetate. The chromatographic separation was performed on reversed phase Aquasil C18 column, and the plasma extraction was eluted with a mobile phase solution consisting of acetonitrile (containing 0.02% formic acid) and water (containing 0.02% formic acid). The molecular ion of analyte was detected in positive ionization by multiple reaction monitoring. The mass transitions of m/z 198.4--> 148.1 and m/z 212.4--> 162.3 were used for detection of deglymidodrine and its internal standard, respectively. The assay exhibited linear ranges from 0.25 to 32 ng/ml for the analyte in human plasma. Acceptable precision and accuracy were obtained for concentrations of quality control (QC) samples. The proposed method has been successfully used to analyze human plasma samples for application in oral pharmacokinetic study.

Effects of fatty acids and iontophoresis on the delivery of midodrine hydrochloride and the structure of human skin.

PURPOSE: The purpose of this work was to investigate if fatty acids can increase the iontophoretic delivery of midodrine hydrochloride through human dermatomed skin and to observe the effects of iontophoresis and fatty acids on skin using SEM. METHODS: After prehydration for 1 h, human dermatomed skin was treated with 0-0.3 M fatty acids (oleic acid, linoleic acid, decanoic acid, and lauric acid) in propylene glycol (PG) for 1 h. Then the fatty acid solution was replaced by 1% midodrine hydrochloride aqueous solution, and 0.1 mA/cm2 constant current was applied. Samples were taken over 24 h and analyzed by HPLC. After the treatments outlined above, the epidermis was separated, fixed with glutaraldehyde, and dehydrated for SEM. RESULTS: SEM studies revealed that only 1 h of treatment with fatty acids opened up the tightly compact stratum corneum cell layer, and the permeation study showed a significant increase of the permeability of skin to midodrine hydrochloride after fatty acid treatment. CONCLUSIONS: Using 5% oleic acid pretreatment, with the electrical current offset at 0.1 mA/cm2, the daily delivery of midodrine hydrochloride can provide an adequate clinical application. The enhancement of passive and iontophoretic delivery by fatty acids may be occurring through the same mechanism.

Determination of midodrine in human plasma by high-performance liquid chromatography with fluorescence detection.

A simple and sensitive fluorometric high-performance liquid chromatographic method was developed for the determination of midodrine in human plasma. After liquid-liquid extraction from plasma, the drug and 2-phenylglycinol (internal standard) were convened into the corresponding fluorescent derivatives by reaction with 3,4-dihydro-6,7-dimethoxy-4-methyl-3-oxoquinoxaline-2-carbonyl chloride, a fluorescence derivatization reagent for amines. The derivatives were separated within 30 min on a reversed-phase column using isocratic elution with acetonitrile-methanol-water (10:30:60, v/v) and were detected spectrofluorometrically at 485 nm with excitation at 400 nm. The detection limit for midodrine was 0.3 pmol (76 pg) per mL plasma at a signal-to-noise ratio of 3.

Use of midodrine (Gutron) to treat permanent hypotension in a chronic hemodialysis patient.

Chronic hypotension, infrequent though possible in chronic renal failure patients on hemodialysis, has harmful consequences on their physical state and hence general well-being. These patients often experience acute intradialytic manifestations while non-pharmacologic interventions as pharmacologic agents are sometimes insufficient to improve symptoms. Well tolerated, midodrine appears to be a suitable and effective agent as it raises blood pressure significantly via its effect on peripheral alpha-adrenergic receptors. The authors describe their use of midodrine in a dialysis patient for the longest period of time reported up to now, documented by a pharmacokinetic study, confirming long-term both clinical efficacy and safety of the drug.

[Midodrine (Gutron) treatment of permanent arterial hypotension in a chronic hemodialysis patient]. / Traitement par midodrine (Gutron) de l'hypotension artérielle permanente d'un patient hémodialysé chronique.

Chronic hypotension, although unfrequent in uremic patients on hemodialysis, accentuates the deterioration of patients physical state and thus, their general well-being. These patients often experience acute intradialytic symptoms and respond very poorly to conventional therapies. Well tolerated, midodrine is a suitable and effective choice as it raises blood pressure significantly through its effect on peripheral alpha-adrenergic receptors. The authors report observing the use of midodrine by a dialysis patient during the longest time period published to date, documented by a pharmacokinetic study, and that confirms the excellent results and proves long term tolerance for that drug.

A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension.

OBJECTIVE: To determine the best therapeutic strategy for the use of midodrine in patients with neurogenic orthostatic hypotension (NOH). BACKGROUND: Midodrine is a peripherally acting alpha-adrenergic agonist useful in the treatment of NOH. However, neither the most effective dosage of midodrine nor the required frequency of administration is established. DESIGN/METHODS: Midodrine dose-blood pressure response, pharmacokinetics, and duration of action were examined in a double-blind, placebo-controlled, four-way crossover trial. Twenty-five patients with NOH were randomized to receive on successive days placebo or midodrine 2.5, 10, or 20 mg. Blood pressures of patients in the supine and standing positions were measured sequentially. A global assessment of the patient's overall symptom improvement after each leg of the study was performed. Blood levels of midodrine and its active metabolite, desglymidodrine, were assayed. RESULTS: Midodrine significantly increased standing systolic blood pressure, with the increase peaking at 1 hour. There was a significant linear relation between midodrine dosage and mean systolic blood pressure. The mean score for global improvement of symptoms was significantly higher for midodrine (10 and 20 mg) compared with placebo. The half-life of desglymidodrine was approximately 4 hours. CONCLUSION: A 10-mg dose of midodrine prescribed two to three times daily is effective in increasing orthostatic blood pressure and ameliorating symptoms in patients with NOH.

Midodrine efficacy and pharmacokinetics in a patient with recurrent intradialytic hypotension.

Recurrent intradialytic hypotension, a complication of hemodialysis, is a consequence of an inadequate compensatory response or a paradoxic response to ultrafiltration-induced volume reduction. We report the use of midodrine, an alpha agonist, in an 18-year-old man with Bardet-Biedl syndrome and recurrent intradialytic hypotension. The clinical features of the intradialytic hypotensive spells are consistent with a paradoxic withdrawal of sympathetic activity, although an underlying abnormality in autonomic dysfunction cannot be excluded. Midodrine significantly increased the intradialytic blood pressure and decreased the intradialytic hypotensive episodes requiring intervention. The pharmacokinetic characteristics of the prodrug midodrine and the active metabolite de-glymidodrine in this patient with end-stage renal disease approximate those reported for patients with normal renal function. However, the prolonged terminal half-life for the active metabolite, de-glymidodrine, warrants careful administration in patients with renal failure.

Pharmacokinetic parameters and haemodynamic actions of midodrine in young volunteers.

In two groups of volunteers pharmacological parameters of the antihypotensive drug midodrine have been investigated. The first group of 12 male healthy volunteers received 2.5 mg midodrine hydrochloride intravenously, as drinking solution or as tablet according to a randomized cross-over design. Plasma and urine samples were analyzed for midodrine and its main metabolite ST 1059 by high-performance liquid chromatography. The mean maximum concentration in plasma for midodrine was 10 ng/ml 20-30 min after oral administration, for ST 1059 5 ng/ml after 1 h. Midodrine was eliminated with a terminal half-life of 0.5 h, ST 1059 with a half-life of 3 hrs. The mean area under the plasma-level vs. time curve (AUC) of ST 1059 after administration of 2.5 mg midodrine i.v. was 28.7 ng x h/ml, and similar for the other formulations which are considered to be bioequivalent. In a second group of 15 volunteers with postural hypotension midodrine (M) as alpha-sympathomimetic drug and oxilofrine (O) as beta-sympathomimetic drug was given i.v. in a randomized double blind study against placebo (P). Blood pressure (BP), heart rate (HR) and circulating catecholamines (CA) were determined before and after injections of the drugs as well as before and during 10 min of tilting. Echocardiographic parameters were obtained at rest before and after the administration of the drugs. Blood pressure remained unchanged at rest and during orthostasis after all agents injected. After oral administration of midodrine heart rate was decreased and systolic blood pressure increased significantly and dose-dependently. M lowered circulating noradrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)

[The distribution and localization of alpha 1-adrenoceptor agonist on the bladder and urethra of female rats].

The distribution of selective alpha 1-adrenoceptor agonist 1-(2',5'-dimethoxyphenyl)-2-glycinamidoethanol hydrochloride, midodrine, and its active metabolite 1-(2',5'-dimethoxyphenyl)-2-aminoethanol, DMAE, was evaluated on bladder and urethra of 8-weeks and 52-weeks old female rats. Prior to the intravenous injection of 14C-labeled midodrine and DMAE, bilateral ureters were ligated to prevent drug uptake from the urinary tract. In 8-weeks rats, 14C-midodrine activity was significantly (p less than 0.01) higher in the bladder than in the femoral muscle, which served as a control for drug distribution. Similarly, higher uptake of 14C-DMAE was observed in the bladder than in the femoral muscle (p less than 0.01) and the urethra (p less than 0.05). In 52-weeks rats, there was no significant difference of midodrine uptake among these tissues. However, significantly higher uptake of 14C-DMAE was observed in the urethra than in the femoral muscle (p less than 0.05). Compared with midodrine, the concentration of DMAE was significantly increased in the bladder of 8-weeks rat and in the urethra of 52-weeks rats (respectively, p less than 0.05). In autoradiogram, the grains corresponding to midodrine and DMAE were diffusely distributed on the smooth muscles of bladder (mainly bladder neck and trigone) and urethra. The grains were also recognized on the vessels and perivascular areas of these tissues. These findings support that midodrine and DMAE could be effective for stress incontinence, because these drugs are known to bind specifically to alpha 1-adrenoceptor.