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Among the large family of cyclodepsipeptides, the simplest members are the cyclodidepsipeptides which have an ester group and an amide group in the same six-membered ring. To point out the pharmacological potential of this class of compounds, the present article reviews structure, isolation, synthesis and biological properties of the known cyclodidepsipeptides. Synthesis of cyclodidepsipeptides is achieved by two general approaches--by initial formation of the amide bond, or initial formation of the ester bond; and subsequent intermolecular cyclization to cyclodidepsipeptide structure. It is closely related to the condensation and ring-closure strategies applied in the preparation of the larger members of the cyclodepsipeptide family. However, due to synthesis of the smaller heretocycles it allows for the use of more versatile building blocks. There are data on antimicrobial, antioxidant and immunomodulatory activities of cyclodidepsipeptides as well as their inhibitory activities toward α-glucosidase, acyl-CoA:cholesterol acyltransferase, xanthine oxidase and platelet aggregation. Because we have recently found that two 6-(propan-2-yl)-4-methyl-morpholine-2,5-diones, as novel non-purine xanthine oxidase inhibitors, may give promise to be used in the treatment of gout, in this review we have included a study of molecular interactions of the selected cyclodidepsipeptides with xanthine oxidase using idTarget web server. Cyclodidepsipeptides showed promising pharmacological activities and meet all criteria for good solubility and permeability. However, further research of their medical application is necessary. In addition to this, the diversity of natural cyclodidepsipeptides, simplicity for synthesis and convenience for rational drug design indicate the cyclodidepsipeptide as promising scaffold in medicinal chemistry.

The aim of this study was to develop a population pharmacokinetic (PK) model for clearance of mycophenolic acid (MPA) in adult renal transplant recipients, to quantify the PK parameters and the influence of covariates on the MPA pharmacokinetic parameters. Parameters associated with plasma concentrations of MPA at steady-state were analyzed in 70 renal transplant recipients (mean age 42.97 years; mean total body weight 75.33 kg) using nonlinear mixed-effect modeling (NONMEM). Characteristics of patients screened for influence on the pharmacokinetic parameters were gender, age, body weight, time after transplantation, whether the patient was diagnosed as having diabetes mellitus, organ source (living or deceased donor), biochemical parameters and co-therapy (tacrolimus, cyclosporine, prednisolone, omeprazole, bisoprolol, carvedilol, nifedipine). A validation set of 25 renal transplant recipients was used to estimate the predictive performance of population pharmacokinetic model. Typical mean value of MPA oral clearance, estimated by base model (without covariates) was 0.741 L h(-1). During population modeling, the full model showed that clearance of the MPA was significantly influenced by age, total daily dose of MPA, creatinine clearance, albumin level, status and gender of a donor, and the nifedipine and tacrolimus co-therapy. In the final model, clearance of MPA was reported to be significantly influenced by age, total daily dose of MPA and thenifedipine co-therapy. The derived model describes adequately MPA clearance in terms of characteristics of our patients, offering basis for individual pharmacotherapy approach.

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SPE-HPLC method has been developed and validated for rapid analysis of carbamazepine and its two metabolites carbamazepine epoxide and carbamazepine trans-diol in human plasma. The analysis was performed using C18 Bakerbond-BDC analytical column (250 mm x 4.6 mm i.d., particle size 5 μm). The optimal conditions for the separation were established with the mobile phase acetonitrile - 10 mM phosphate buffer, pH 7.0 (30:70, v/v) at the flow rate of 1.5 mL min-1, temperature 35°C, and UV detection at 210 nm. Total run time was about 8 minutes. SPE procedure for extraction of the analytes from plasma sample was developed using Oasis HLB cartridges and subsequently eluate was injected into the HPLC system for analysis. Afterwards, SPE-HPLC method was subjected to validation. Linearity was obtained over the concentration range of 0.2-25 μg/mL for carbamazepine, carbamazepine epoxide and carbamazepine trans-diol with correlation coefficients higher than 0.995. The method showed good intra-day and inter-day precision with relative standard deviation below 7.96%, while accuracy ranged from 92.09% to 108.5% for all analytes. Finally, the method was successfully applied to analysis of plasma samples of epileptic patients in monotherapy and polytherapy. [Acknowledgments. Projekat Ministarstva nauke Republike Srbije, br. OI 172033]