Pharmacokinetics of the analogs at C3 and C5 of m‐nifedipine in beagle dogs

Abstract

The prototype 1,4-dihydropyridine (1,4-DHP) nifedipine, indicated for the management of hypertension and angina pectoris, has disadvantages including photodegradation and a short half-life. Several newer 1,4-DHPs, including m-nifedipine and its analogs at the C3, C5 position such as MN9201, MN9202 and MN9203, have been designed to offset these problems. The aim of this study was to investigate the pharmacokinetic characteristics of these derivatives to provide reference for their further evaluation and modification. Derivatives were intravenously bolus administered to beagle dogs. The drug concentration in the plasma was determined by the HPLC method. The pharmacokinetic parameters were calculated by the non-compartmental method. The analysis of variance (ANOVA) was used to compare the pharmacokinetic parameters of the derivatives. The results showed that the area under the curve from time zero to the last sampling time (AUC(0-t)) of m-nifedipine, MN9201, MN9202 and MN9203 was 45.1 +/- 13.6, 51.7 +/- 15.2, 70 +/- 16 and 62 +/- 12.4 micromol/l*min, respectively. The elimination half-life (t(1/2)) was 98 +/- 24, 129 +/- 55, 190 +/- 21 and 92 +/- 25 min, respectively. The t(1/2) of MN9202 was significantly longer than those of the others (p<0.05 or p<0.01). These results suggest that the length of the carbon chain at the C3 or C5 position in the derivatives had a marked effect on its metabolism, and M9202 is a promising new drug candidate worth further evaluation.

Fucoidan from Undaria pinnatifida prevents vascular dysfunction through PI3K/Akt/eNOS-dependent mechanisms in the l-NAME-induced hypertensive rat model

“…These results correlate with a recent study that showed rapid loss of vasculoprotective effect following the withdrawal of nifedipine, which was expressed in systolic blood pressure returning back to abnormal values in SHR within 24 h. 58 One possible reason was that nifedipine, as an L-type Ca 2+ channel antagonist, is reported to have an initial disadvantage of shorter half-life in vivo. 59 The results demonstrated that there were different mechanisms between fucoidan and nifedipine. In addition, further research on possible reasons for fucoidan's effective and prolonged chronic blood pressure modulation is necessary.…”

Association of Plasma Nucleotide levels with severity of Coronary Arterial lesion and left ventricular systolic Function in Acute Myocardial infarction

“…The concentration of AMP, UTP and ATP in patient plasma was measured as our protocol 19 with modification of protocol. 20,21 Briefly, venous blood was collected at admission (within 2 hours before coronary angiography).…”

Different pharmacological properties of the optical isomers of MN9202, a novel 1,4‐dihydropyridine Ca2+ channel modulator, in rat ventricular myocytes

“…MN9202 has a chiral carbon at position 4 of the dihydropyridine ring and shares a similar structure with nitrendipine, except for the number of carbons at position 3. Earlier studies in dogs have revealed that MN9202 has beneficial effects on the smooth muscle and myocardium 7,8 . In addition, it has been shown that MN9202 concentration‐dependently relaxes rat and rabbit thoracic arteries, 9 an effect that is endothelium independent.…”

“…Earlier studies in dogs have revealed that MN9202 has beneficial effects on the smooth muscle and myocardium. 7,8 In addition, it has been shown that MN9202 concentrationdependently relaxes rat and rabbit thoracic arteries, 9 an effect that is endothelium independent. MN9202 also has favourable pharmacokinetic characteristics.…”