Physiologically based pharmacokinetic model (PBPK), a mechanistic mathematic model, which can simulate the absorption, distribution, metabolism and excretion of drugs, is being more widely used in pharmaceutical research and development areas. This article reviews primarily the recent advances in the procedure of establishing a PBPK model, including specifying of the PBPK model structure, specification of the tissue model, writing of equations, set of model parameters, simulation and evaluation. Application significance, major challenges and future developments of PBPK model in pharmaceutical areas are also discussed.
Animals ; Biological Transport ; Computer Simulation ; Humans ; Models, Biological ; Pharmaceutical Preparations ; chemistry ; metabolism ; Pharmacokinetics ; Software ; Tissue Distribution

Mammal multidrug and toxin extrusion proteins (MATEs) play an important role in the transport of organic cations in the body. MATEs mediate the final excretion step for multiple organic cation drug used clinically and important endogenous substances. This article reviews the discovery, type, gene coding and polymorphism, body distribution, classification of substrates and inhibitors and their research method of MATEs. The article also discusses the major research significance of MATEs with examples.
Animals ; Biological Transport ; Cations ; Organic Cation Transport Proteins ; metabolism ; Polymorphism, Genetic

Objective To evaluate the relationship between recurrence of cryptogenic ischemic cerebrovascular disease (CICVD) and patent foramen ovale (PFO),as well as to access the clinical significance of PFO in ischemic cerebrovascular disease.Methods Consecutive patients with CICVD aged 15 to 70 years who were hospitalized in Department of Neurology,Xuanwu Hospital Capital Medical University from January 2008 to March 2011 were prospectively investigated.Identified by transesophageal echocardiography,patients were divided into two groups with respect to outcome:PFO group and non-PFO group.The recurrence of cerebral ischemic events was compared between the two groups after neurological follow-up.Results A total of 91 patients were recruited,including 57 patients with PFO and 34 patients without PFO.The follow-up period of two groups was 695 (506,1142) d.The recurrence rate at 15 months in patients with PFO (24.5％ (12/49)) was higher than those without PFO (6.9％ (2/29),x2 =4.391,P =0.036).Cum hazard curve indicated that recurrence risk of cerebral ischemic events in patients with CICVD in PFO group was higher than that of patients in non-PFO group during the follow-up period (P =0.044).Cox model used for multivariate survival analysis indicated that PFO was a risk factor for cerebral ischemic event recurrence among patients with CICVD (OR =4.159,95％ CI 1.178-14.689,P =0.027).Conclusions PFO is associated with increased recurrence risk of cerebral ischemia in CICVD patients.In addition,PFO may be a significant factor for ischemic cerebrovascular disease.

Objective To analyze the risk factors for patients with cryptogenic ischemic cerebrovascular disease (CICVD) and patent foramen ovale (PFO), as well as to evaluate the relationship between common risk factors and PFO in cerebral ischemia. Methods Consecutive patients with CICVD aged 15 to 70 years who referred to Department of Neurology, Xuanwu Hospital, Capital Medical University from January 2008 to July 2011 were investigated. Identified by transesophageal echocardiography, they were divided into PFO group and non-PFO group with respect to outcome. The common risk factors of cerebral ischemic between 2 groups were compared. The relationship between these risk factors and PFO was analyzed. Results A total of 102 patients were investigated, including 61 patients (59.80%) with PFO and 41 patients (40.20%) without PFO. Positive family history of ischemic cerebrovascular disease proportion in PFO group (31.1%)was higher than that in non-PFO group (9.8%) (P=0.011). There was no significant difference in other observed indicators (P>0.05). Positive family history of ischemic cerebrovascular disease correlated with PFO among CICVD patients (r=0.251, P=0.011). Conclusion PFO was not only more common in CICVD patients, but also correlated with positive family history of ischemic cerebrovascular disease.

The present study is aimed to investigate the in vitro metabolic interconversion between baicalin (BG) and baicalein (B) in rat liver, kidney, intestine and bladder. BG and B were separately incubated with rat hepatic, renal, and intestinal microsomes, as well as bladder homogenates, for 30 min. The metabolites were identified and quantified by HPLC and metabolic kinetic parameters were obtained by fitting the data to the Michaelis-Menten equation. In hepatic microsomes, renal microsomes and bladder homogenates, but not in intestinal microsomes, BG was transformed into B, the hydrolysis metabolite of BG, with K(m) values being (44.65 +/- 6.01), (92.73 +/- 11.41), (74.60 +/- 3.68) micromol x L(-1), respectively, and V(max) values being (12.32 +/- 0.56), (3.30 +/- 0.18), (5.93 +/- 0.12) micromol x min(-1) x g(-1) (protein), respectively. In incubations with hepatic, renal, and intestinal microsomes and bladder homogenates, B was also transformed into BG, the glucuronidation metabolite of B, with K(m) values being (67.46 +/- 10.49), (226.7 +/- 71.59), (177.3 +/- 35.85), and (18.33 +/- 2.53) micromol x L(-1), respectively, and V(max) values being (14.74 +/- 0.97), (5.91 +/- 1.03), (38.14 +/- 3.60), and (1.22 +/- 0.05) micromol x min(-1) x g(-1) (protein), respectively. The results showed that the activity of UDP-glucuronosyltranferase (UGT) in intestinal microsomes was the highest among the four organs, and the activities of UGT were higher than that of glucuronidase (GUS) in hepatic, renal and intestinal microsomes, but the activity of GUS was higher than that of UGT in bladder homogenates.
Animals ; Anti-Infective Agents ; pharmacokinetics ; Antioxidants ; pharmacokinetics ; Biotransformation ; Flavanones ; pharmacokinetics ; Flavonoids ; pharmacokinetics ; Glucuronidase ; metabolism ; Glucuronosyltransferase ; metabolism ; Hydrolysis ; Intestines ; enzymology ; metabolism ; Kidney ; enzymology ; metabolism ; Liver ; enzymology ; metabolism ; Male ; Microsomes ; enzymology ; metabolism ; Rats ; Rats, Sprague-Dawley ; Urinary Bladder ; enzymology ; metabolism

Objective:Osteoprotegerin (OPG) is a key molecule negatively regulating osteoclast differentiation and activation; and the conserved mycobacterial heat shock 70 (HSP70) peptide p111-125 has also been found to inhibit inflammation reactions in chronic arthritis. BaculoDirectTM baculovirus expression system was selected to express recombinant OPG-HSP70 in insect cells.Methods:The human functional fragment (p22-194) of OPG and functional fragment (p111-125) of mycobacterial HSP70 gene were cloned into the transfer vector pENTRTM/SD/D-TOPO. The recombinant plasmid was performed an LR reaction with the BaculoDirectTM Linear DNA to generate recombinant baculovirus DNA. The cultured Sf9 insect cells were directly transferred with the recombinant baculovirus DNA,and the pure recombinant baculovirus was obtained. Then recombinant baculovirus was infected Sf9 insect cells again to express the OPG-HSP70 gene.Results:The target protein was detected at the time of 48h post infection,reached at highest yield at the time of 72h post-infection. A 28kDa protein immunostaining band was detected by Western blotting from lysate of those cells.And the purified protein was obtained by using Ni-NTA system. Functional stuies on the fusion protein showed it significantly reduce osteoclast cell number[(3.10?0.640) cells under each microscope field in treatment group by comparing to (10.70?0.817)cells in the control group] in the osteoclast inhibition test,and reduce the inflammation reaction in a delayed type hypersensitivity (DTH) mice model (P

0. 05). Conclu-sion The THT and THC have bioequivalence.

Objective To investigate the relationship between spinal neuronal microRNA 212 (miR-212) and phosphorylation of cAMP response element-binding protein (CREB) in a mouse model of bone cancer pain (BCP).Methods Thirty-two male SPF C3H/HeJ mice, aged 4-6 weeks, weighing 20-25 g, were randomly divided into 4 groups (n=8 each) using a random number table: sham operation group (group S), BCP group, BCP + intrathecal negative control locked nucleic acid (LNA) group (group BC) , and BCP + intrathecal miR-212 antisense LNA group (group BL).After the mice were anesthetized with intraperitoneal pentobarbital sodium, 20 μl of α minimal essential medium containing NCTC 2472 cells 2×105 was injected directly into the medullary cavity of the distal femur.In BC and BL groups, negative control LNA and miR-212 antisense LNA 12 pmol/5 μl were intrathecally injected, respectively, once a day for 7 consecutive days, starting from day 14 after inoculation.In S and BCP groups, the equal volume of DNAse/RNAse-free water was given instead.The number of spontaneous flinches (NSF) and mechanical paw withdrawal threshold (MWT) were measured on 1 day before inoculation and 4, 7, 10, 14 and 21 days after inoculation.The mice of each group were sacrificed after measurement of pain threshold on 21 days after inoculation, and the lumbar enlargement segments of the spinal cord were harvested to detect the expression of phosphorylated CREB (p-CREB) and CREB using Western blot.Results Compared with group S, the MWT was significantly decreased, and the NSF was increased on 7-21 days after inoculation, and the expression of p-CREB was up-regulated in BCP, BC and BL groups.Compared with group BCP, the MWT was significantly increased, and the NSF was decreased on 21 days after inoculation, and the expression of p-CREB was down-regulated in group BL, and no significant change was found in the parameters mentioned above in BC group.There was no significant difference in the expression of CREB between the four groups.Conclusion Spinal neuronal miR-212 is involved in the maintenance of BCP probably by promoting phosphorylation of CREB in mice.

Objective To investigate the effects of repeated intrathecally kinesin superfamily protein 17 (KIF17) antisense oligodeoxynucleotide (ODN) on the expression of mLin10 and NR2B in spinal cord in a mouse model of bone cancer pain.Methods Fifty-six male C3H/HeJ mice,aged 4 ～ 6 weeks,weighting 20 ～ 25 g,were randomly divided into two groups:sham operation group (group S,n=20) and bone cancer pain group (group T,n=36).20μl α-minimal essence medium (α-MEM) which containing 2× 105 NCTC2472 osteosarcoma cells was injected into the intramedullary space of the right femur in group T.In group S,no cancer cell was instead.The number of spontaneous flinches (NSF) and the paw withdrawal mechanical threshold (PWMT) were measured at the day before (base) and the days 4,7,10 and 14 after inoculation.According to the corresponding time points,twenty-four mice were sacrificed for determination the expression of KIF17,mLin10 and NR2B using Western blot.Then,the mice of group T were randomly divided into three groups (n=8,T1,T2,T3,group).In group S and group T1,Saline 5 μl was injected intrathecally.KIF17 sense ODN and antisense ODN,5 μg/5μl were respectively injected in group T2 and T3 for 6 consecutive days.Pain behaviors were assessed at the days 2-6 after the first injection.And determinated the KIF17,mLin10 and NR2B expression,again.Results Compared with group S,the NSF was increased and the PWMT was decreased at the days 7,10 and 14 after inoculation in group T (P＜0.05).Compared with the base ((0.65±0.15),(1.06±0.06),(1.01±0.14)),the expression of KIF17,mLin10 and NR2B (14d:(1.13 ±0.06),(2.17 ± 0.37),(1.85 ± 0.32)) were increased at the days 7,10 and 14 after inoculation in group T(P＜0.05).During the course of the injection,compared with group T1 and T2,the NSF was decreased and the PWMT was increased significantly in the group T3(P＜0.05),the expression of KIF17,mLin10 and NR2B((0.88±0.08),(0.96±0.11),(1.03±0.08)) were reduced in group T3 (P＜0.05).Conclusion Intrathecal KIF 17 antisense ODN in the mice of bone cancer pain improves the pain behaviors,and inhibits the up-regulated of KIF17,mLin10 and NR2B during the course of the injection.

Formula granule of traditional Chinese medicine (TCM) has been characterized as a safe medication with the advantages of accurate dosage and easy to carry.In this study,references over current status of the development of TCM formula granule were retrieved,so were those of the market situation and its application to intelligent pharmacy of TCM.Then the key problems restricting the development of the application of TCM granules were discussed,in hope of providing a reference for the development and its application to the intelligent pharmacy of TCM.