Abstract
The prototype 1,4βdihydropyridine (1,4βDHP) nifedipine, indicated for the management of hypertension and angina pectoris, has disadvantages including photodegradation and a short halfβlife. Several newer 1,4βDHPs, including mβnifedipine 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 nonβcompartmental 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~0βt~) of mβnifedipine, MN9201, MN9202 and MN9203 was 45.1βΒ±β13.6, 51.7βΒ±β15.2, 70βΒ±β16 and 62βΒ±β12.4 Β΅mol/l*min, respectively. The elimination halfβlife (t~1/2~) was 98βΒ±β24, 129βΒ±β55, 190βΒ±β21 and 92βΒ±β25min, 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. Copyright Β© 2008 John Wiley & Sons, Ltd.