ABSTRACT
The aim of this study was to present a deductive compartment pharmacokinetic (PK) model to predict the concentration profiles of drugs in plasma and peritoneal fluid in peritoneal dialysis (PD) rats. PK parameters of model drugs in normal and experimentally induced acute renal failure (ARF) rats not undergoing PD were obtained inductively in a common regression manner with a two-compartment model. In PD normal and ARF rats, PK parameters relating to the transfer of drugs to the peritoneal dialysate and the progress of renal failure were deductively modified to simulate the drug concentration-time profiles in plasma and in the peritoneal fluid in PD rats. The deductively introduced modifiers were the volume of distribution in the peripheral compartment, plasma protein binding, and solvent movement factor to the peritoneal fluid. Predicted profiles of tolbutamide, propranolol and cefazolin in PD normal and ARF rats were compared with the corresponding observed data. This minimal deductive approach yielded satisfactory accuracy in the prediction of both the plasma and peritoneal fluid concentrations of tolbutamide and propranolol.
Subject(s)
Acute Kidney Injury/therapy , Ascitic Fluid/metabolism , Cefazolin/pharmacokinetics , Models, Biological , Peritoneal Dialysis , Propranolol/pharmacokinetics , Tolbutamide/pharmacokinetics , Acute Kidney Injury/blood , Animals , Cefazolin/blood , Disease Models, Animal , Male , Propranolol/blood , Protein Binding , Rats, Wistar , Reproducibility of Results , Tolbutamide/bloodABSTRACT
Triterpenes, a diverse group of natural products comprising six isoprene units, are distributed across various organisms from bacteria to higher plants. Ferns are sporophytes that produce triterpenes and are lower on the evolutionary scale than higher plants. Among ferns that produce triterpenes analogous to bacterial hopanoids, Polypodiodes niponica produces migrated dammaranes and oleananes, which are also widely found in higher plants. Because the study of terpene-producing ferns could help us to understand the molecular basis of triterpene biosynthesis, cDNA cloning of squalene cyclases (SCs) from P. niponica was carried out. Two SCs (PNT and PNG) were obtained. The heterologously expressed PNT produces tirucalla-7,21-diene (67% major), and PNG produces germanicene (69%). Phylogenetic analysis revealed that PNT and PNG, which produce higher-plant-type migrated dammaranes and oleananes, are closely related to bacterial-type SCs. Furthermore, analysis of the minor products indicated that fern SCs gained the ability to directly form dammarenyl cations, which are key intermediates in oleanane formation during molecular evolution.
