| AIM: In order to increase the liposolubility and improve oral bioavailability of paliperidone, we synthesized seven esters of derivatives for the first time. A series of studies were conducted on paliperidone and its derivatives to offer some useful references and inspirations for further development of paliperidone prodrugs.METHODS: Structural modifications by chemical syntheses at hydroxyl group were carried out to obtain seven ethers of paliperidone derivatives. Following oral administration to Beagle dogs, blood at different time points to validate that whether derivatives have the nature of prodrugs. In addition, we evaluated pharmacokinetic behavior of the prodrugs.Studies on in vivo: An LC-MS/MS method was developed and validated for the determination of paliperidone in biological samples. Paliperidone and the internal standard, tramadol, were precipitated from the matrix by acetonitrile, and separated on a Venusil MP C18 column employing acetonitrile-10mM ammonium acetate (65:35, v/v). Detection was carried out by multiple reaction monitoring (MRM) on an API 4000 LC-MS/MS system with an ESI interface in the positive ion mode. MRM was performed at low resolution using the mass transition ion-pairs m/z 427.0→m/z 207.1 and m/z 264.1→m/z 58.0 for paliperidone and tramadol, respectively. The linearity, specificity, precision, accuracy, recovery and stability were estimated for the validations of the assay. After the plasma concentration–time profile was shown, the area under the curve (AUC0-t) was determined by the linear trapezoidal rule. And then calculated the absolute bioavailabilities of the prodrugs.Studies on in vitro: HPLC methods with diode array detector (DAD) method were developed and validated for the determination of prodrugs in solutions. The prodrugs was separated on a HC-C18 using a mobile phase of acetonitrile-10mM ammonium acetate (1% formic acid) (45:55,v/v). The solubility and partition coefficient of the prodrugs were tested and their degradations were investigated in various phosphate buffers at different temperatures. RESULTS: In order to improve pharmacokinetic behavior of paliperidone, seven ethers of paliperidone derivates were designed and synthesized at the first time. It is a simple synthesized method and yield Multi-output to study their physico-chemical property. The pharmacokinetics of paliperidone and its prodrugs were investigated in dogs by the LC/MS/MS method. After oral administration of 4mg, the prodrugs were quickly absorbed and metabolized into paliperidone in dogs. The Cmax of PAP-1 ~PAP-7 were 223,116,279,208,386,90,257 ng/mL, while the Tmax were 1.5,2.0,1.0,1.0,0.5,1.5,1.5 h. The elimination half?life (T1/2) was calculated to be 6.08,9.18,7.14,7.46,7.09,11.6,6.93 h.The absolute bioavailabilities of PAP-1, PAP-2, PAP-3,PAP-4,PAP-5,PAP-6 and PAP-7 to PA at the same dose, which was intravenous injection administration, were calculated to be 60.1%,53.0%,69.0%,76.5%,120.6 %,44.8% and 105.7%, respectively. Higher absolute bioavailabilities of PAP-1,PAP-3,PAP-4,PAP-5和PAP-7 to paliperidone (absolute bioavailabilitie 28%) indicated great improvements of their pharmacokinetic behavior after structural modifications.Stability experiments showed that: with increasing temperature, the degradation of prodrugs were faster. PAP-3 and PAP-7 were degradation in 25℃during 2 h, while in 37℃were very unstable and degrade quickly. They were not suitable for the development of prodrugs. PAP-1, PAP-4 and PAP-5 showed better stability in the phosphate buffers. The partition coefficient of PAP-1, PAP-4 and PAP-5 and paliperidone were 4.2, 3.5, 4.5 and 1.9, respectively. The absorption of prodrug in the gastrointestinal tract were better than parent drug. The solubility of the prodrugs in organic solvents were the same as partition coefficient: PAP-5>PAP-1>PAP-4, while the solubility in water were just the opposite. This experiment identified three prodrugs (PAP-1, PAP-4 and PAP-5) that have good prospects for development of drug precursors.
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