Mohsen A. Hedaya, Pharm.D., Ph.D., is the Vice Dean for Academic and Student Affairs, Faculty of Pharmacy, Kuwait University, Kuwait. Dr. Hedaya has taught basic and advanced pharmacokinetic classes to professional pharmacy students and graduate students in Egypt, USA and Kuwait. His research interest includes pharmacokinetic drug interactions, drug delivery to the brain, pharmacokinetic computer simulations, and bioequivalent study design and data analysis. This is in addition to his interest in the development and assessment of computer-aided instructional materials in the area of pharmacokinetics. The computer-based educational materials developed by Dr. Hedaya in the area of pharmacokinetics are currently being used by more than 300 educational, research and industrial institutions around the world.
Purpose: Linezolid (Lzd) is the first approved oxazolidinone antibiotic, while PH027, and PH051 are novel triazolyl oxazolidinone derivatives with in vitro activity comparable or superior to that of Lzd. Preliminary results showed that these novel compounds have lower in vivo activities compared to Lzd, when assessed in a mice S. aureus (Giorgio) systemic infection model after oral administration. This study was designed to determine if the discrepancy between the in vitro and in vivo activities of these compounds is due to differences in their oral bioavailability. Method: Six groups of White New Zealand Rabbits (n=4, each) were used, three groups received 5 mg/kg IV, and three groups received 20 mg/kg oral as suspension in water, each group received one compound. After administration, serial blood samples were obtained through an IV catheter inserted in the ear vein, over a period of 10 hr. Plasma was obtained from blood by centrifugation, and samples were kept at -20 °C until analysis with validated UPLC-MS/MS. The pharmacokinetic parameters for Lzd, PH027 and PH051 were calculated and compared. Results: The plasma concentration-time profile after IV administration showed a distribution phase, followed by an elimination phase. The AUC for Lzd, PH027, and PH051 after 5mg/kg IV were 4.038±1.28, 5.67±0.933, and 1.95±0.986 mg-hr/L, respectively. After oral administration, the AUC for Lzd, PH027, and PH051 were 6.25±3.62, 5.01±2.43, and 0.369±0.378 mg-hr/L which correspod to bioavailability of 38.7%, 22.1%, and 4.73%, respectively. Conclusions: PH027 and PH051 have oral bioavailability lower than that of Lzd, which may have contributed to their reduced in vivo activity after oral administration. Formulations with enhanced oral bioavailability should be used in the in vivo assessment of these novel compounds. This study was supported by a grant from Kuwait University Research Sector (PP01/13).
Tetsuo Narumi studied organometallic chemistry at Waseda University in Shinjuku, Tokyo, where he worked in the research group of Prof. Isao Shimizu. After PhD studies at Waseda University with Prof. Shimizu followed by Kyoto University with Prof. Nobutaka Fujii, he spent a year in US as a JSPS postdoctoral fellow with Prof. Jeffrey W. Bode at the University of Pennsylvania. In 2009, he began his academic career in Japan, at Tokyo Medical and Dental University with Prof. Hirokazu Tamamura. In 2013, he began his independent career at Shizuoka University, in Japan, as a associate professor in the Bioorganic Chemistry.
Naturally occurring pentacyclic triterpenoid derivatives, such as betulinic acid derivatives, have been shown to exhibit various biological activities including anti-HIV activity. IC9564 [Mayaux, JF. Et al, PNAS. 1994] and RPR103611 [Dereu, N. et al., JMC, 1996] are statin derivatives of betulinic acid tethered by 8-aminooctanoic acid linker, which was reported as a novel class of HIV-1 entry inhibitors. Although those betulinic acid derivatives show nanomolar order potency agains diverse HIV-1 strains, relatively high cytotoxicity is one of the drawbacks of them. In this study, the structure-activity relationship study of a series of triterpenoid derivatives was conducted to identify the potential triterpenoid-based HIV entry inhibitors with lower cytotoxicity than betulinic acid derivatives. Significant potency gains were made by replacing the betulinic acid moiety with the oleanoic acid, resulting in the discovery of several potent compounds. This study identified a novel lead compound OKS3-019 with significant anti-HIV activity against 89.6 strain of HIV-1 and lower cytotoxicity than those of known betulinic acid derivatives. Design, syntheses, bioevaluation and docking models of the newly identified oleanoic acid derivatives will be discussed.