Pinacidil monohydrate

Disposition of [14C]pinacidil in humans

Pinacidil [(+/-)-2-cyano-1-(4-pyridyl)-3-(1,2,2-trimethylpropyl)guanidine monohydrate] is a novel, direct-acting vasodilator antihypertensive agent. The cyano 14C-labeled drug is rapidly and completely absorbed after an oral 12.5-mg dose in solution. The blood:plasma concentration ratios (0.8-0.9) indicate transient penetration of radioactivity into blood cells. Blood and plasma tmax (0.5 h) and t 1/2 (4 h) of [14C]pinacidil equivalents are similar. Pinacidil (51%), pinacidil N-oxide (28%), and unidentified polar metabolites (21%) comprise the plasma radioactivity. The plasma t 1/2 of pinacidil is 2-3 h, and that of pinacidil N-oxide is 4-5 h. Renal excretion of radioactivity is the major route (80-90% dose) of drug elimination; fecal elimination accounted for 4% of the dose. Renal clearance of the N-oxide is 10 times the renal clearance of the parent drug and exceeds the creatinine clearance. Biotransformation products in 0-24-h urine samples include pinacidil (10%), pinacidil N-oxide (60%), and free and conjugated analogues of pinacidil and metabolites (30%). Stereoselective metabolism is not a major biotransformation pathway of pinacidil or the N-oxide metabolite.

In vivo characterization of monolithic matrix type transdermal drug delivery systems of pinacidil monohydrate: a technical note

The present work aimed to characterize transdermal drug delivery systems of pinacidil monohydrate in vivo by monitoring the effect of the TDDS on blood pressure of methyl prednisolone acetate induced hypertensive rats. The blood pressure of rats was measured using a noninvasive rat BP instrument based on cuff tail technique. A significant fall in rat BP (P<.01) was observed in treatment of hypertensive rats with all the formulations, which was maintained for 48 hours. Interformulation comparison revealed that formulation B-4 was the most effective with 37.96% reduction in BP (160.33±4.96 vs 99.44±4.46 mmHg). It was concluded that a single patch application of pinacidil TDDS (B-4) can effectively control hypertension in rats for 2 days. The system holds promise for clinical studies.

Monolithic matrix type transdermal drug delivery systems of pinacidil monohydrate: in vitro characterisation

The monolithic matrix type transdermal drug delivery systems of pinacidil monohydrate (PM) were prepared by film casting technique on mercury substrate and characterised in vitro by drug release studies using paddle over disc assembly, skin permeation studies using Keshary and Chein diffusion cell on albino rat skin and drug-excipient interaction analysis. Four formulations were developed which differed in the ratio of matrix forming polymers, Eudragit RL-100 and PVP K-30, i.e. 8:2, 4:6, 2:8 and 6:4 and were coded as B-1, B-2, B-3 and B-4, respectively. All the four formulations carried 20% w/w of PM, 5% w/w of plasticiser, PEG-400 and 5% w/w of DMSO (based on total polymer weight) in isopropyl alcohol: dichloromethane (40:60) solvent system. Cumulative % of drug released in 48 h from the four formulations was 63.96, 55.95, 52.26 and 92.18%. The corresponding values for cumulative amount of drug permeated for the said formulations were 57.28, 50.35, 46.38 and 86.54%, respectively. On the basis of in vitro drug release and skin permeation performance, formulation B-4 was found to be better than the other three formulations and it was selected as the optimised formulation. The interaction studies carried out by comparing the results of assay, ultraviolet, infrared and TLC analyses for the pure drug, medicated and placebo formulations indicated no chemical interaction between the drug and excipients.

In vivo characterization of monolithic matrix type transdermal drug delivery systems of pinacidil monohydrate: A technical note

The present work aimed to characterize transdermal drug delivery systems of pinacidil monohydrate in vivo by monitoring the effect of the TDDS on blood pressure of methyl prednisolone acetate induced hypertensive rats. The blood pressure of rats was measured using a noninvasive rat BP instrument based on cuff tail technique. A significant fall in rat BP (P<.01) was observed in treatment of hypertensive rats with all the formulations, which was maintained for 48 hours. Interformulation comparison revealed that formulation B-4 was the most effective with 37.96% reduction in BP (160.33±4.96 vs 99.44±4.46 mmHg). It was concluded that a single patch application of pinacidil TDDS (B-4) can effectively control hypertension in rats for 2 days. The system holds promise for clinical studies.

Postjunctional effect of pinacidil on contractility of isolated bovine trachealis

Potassium channel openers hyperpolarize the smooth muscle cell membrane and relax airway smooth muscle. In this study, pre- and postjunctional effects of pinacidil ((+/-) N-cyano-N'-(4-pyridil)-N"-(1,2,2-trimethylpropyl)-guanidine monohydrated), an adenosine triphosphate (ATP)-sensitive K(+)-channel opener, were determined in isolated bovine trachealis. The effects of pinacidil on the frequency-response to electrical field stimulation (EFS), 0.1-32 Hz, and on the concentration response to acetylcholine (ACh), 10(9)-10(-4) M, were compared in muscle strips from six animals. In addition, the effect of pinacidil on the inhibitory nonadrenergic noncholinergic (iNANC) system was evaluated in histamine-contracted muscle strips from another eight animals. Pinacidil (10(-6) or 10(-5) M) shifted both the EFS frequency-response and the ACh concentration-response curves significantly (p < 0.01) to the right. Glibenclamide (10(-7)-10(-5) M) antagonized these responses in a concentration-dependent manner. The inhibitory effects of pinacidil on contractions of the same magnitude induced by EFS or exogenous ACh were not significantly different (p = 0.11), suggesting that pinacidil had only a postjunctional effect. Pinacidil had no effect on iNANC-mediated muscle relaxation. We conclude that pinacidil attenuates the contraction of isolated bovine tracheal smooth muscle by postjunctional mechanisms.