No effect on pharmacokinetics of tamoxifen and 4-hydroxytamoxifen by multiple doses of red clover capsule in rats.

Tamoxifen is used in clinical practice for breast cancer patients and to prevent osteoporosis. Red clover (Trifolium pratense) preparations are consumed worldwide as dietary supplements for relieving postmenopausal symptoms. In the present study we investigated the possible herb-drug interaction between red clover and tamoxifen in rats. 15 days pre-treatment with red clover did not alter the tamoxifen and its active metabolite 4-hydroxytamoxifen pharmacokinetics significantly (p > 0.05). Therefore the therapeutic efficacy of the tamoxifen may not be compromised by the co-administration with red clover. Tamoxifen metabolism is primarily mediated by CYP2D6, CYP3A4 with minor contribution from CYP2C9, CYP2E1 and CYP1A2 isoforms. Although, red clover pre-treatment significantly (p < 0.05) decreased the mRNA expression and activity of CYP3a2, no effect on CYP2d4 and increased expression and activity of CYP2c11 could be the plausible reasons for lack of effect on tamoxifen and its metabolite pharmacokinetics in rats. CYP1a1 and CYP2b2 mRNA expression and activity were also significantly reduced by red clover. To extend the clinical utility of the present study, effect of red clover extract on major CYPs using human liver microsomes and HepG2 cell lines were also determined. Similar finding were observed in the human liver preparations as in rats.

Pharmacokinetics study of arteether loaded solid lipid nanoparticles: an improved oral bioavailability in rats.

Arteether (ART), an artemisinin derivative, is a life saving drug for multiple drug resistant malaria. It has a deliverance effect in Falciparum malaria and cerebral malaria. We have prepared solid lipid nanoparticles (SLN) by high pressure homogenization (HPH) technique. ART-loaded SLN (ART-SLN) has been produced reproducibly with homogeneous particle size. ART-SLN was characterized for their size measured by Zetasizer Nano-ZS, Malvern, UK and by high resolution transmission electron microscopy (HR-TEM) and which was found to be 100 ± 11.2 nm. The maximum percentage entrapment efficiency (%EE) determined with the high-performance liquid chromatography (HPLC) has been found to be 69 ± 4.2% in ART-SLN-3. The release pattern from ART-SLN revealed that the release of ART is slow but time-dependent manner, which is desirable as it will help to protect the acid degradation of ART in stomach. The percentage cytotoxicity of blank SLN has been found within the acceptable range. The pharmacokinetics results indicated that ART-SLN-3 absorption has been significantly enhanced in comparison to ART in aqueous suspension and ART in ground nut oil (GNO) in rats. The % relative bioavailability (RB%) of ART-SLN to the ART in GNO and ART in aqueous suspension in rats was 169.99% and 7461%, respectively which was found to be significantly high in both the cases. From the results, it can be concluded that ART-SLN offers a new approach to improve the oral bioavailability of ART.

Disposition of pharmacologically active dietary isoflavones in biological systems.

Dietary isoflavones, popularly known as phytoestrogens, represent one of the most biologically active classes of flavonoids. Numerous in vitro and in vivo studies provide convincing evidence regarding their beneficial effects on human health. These isoflavones are increasingly being investigated as potential alternate therapies for a range of hormone-dependent conditions, including cancer, menopausal symptoms, osteoporosis and cardiovascular diseases. However, they exhibit poor oral bioavailability which limits their clinical utility in humans. The reason being, they are substrates of a plethora of enzymes and transporters and undergo extensive conjugative metabolism which facilitates their rapid elimination from biological systems. In addition, a number of experimental studies have also revealed that these isoflavones are potent inhibitors of various cytochrome P450 isoforms and transporters which play an important role in the disposition of many commonly prescribed drugs. Thus, there arise chances of observing clinically relevant herb-drug interactions which could sometimes be life-threatening. This review gives a comprehensive understanding of these dietary phytoestrogens with regard to their absorption, biodistribution and the role of enzyme-transporter interplay affecting their disposition in biological systems. Further, the effects of these phytoestrogens on the activity and kinetics of drug metabolizing enzymes and various clinically relevant influx/efflux transporters and the resulting diet-drug interactions have also been discussed.

Synthesis and insight into the structure-activity relationships of chalcones as antimalarial agents.

Licochalcone A (I), isolated from the roots of Chinese licorice, is the most promising antimalarial compound reported so far. In continuation of our drug discovery program, we isolated two similar chalcones, medicagenin (II) and munchiwarin (III), from Crotalaria medicagenia , which exhibited antimalarial activity against Plasmodium falciparum . A library of 88 chalcones were synthesized and evaluated for their in vitro antimalarial activity. Among these, 67, 68, 74, 77, and 78 exhibited good in vitro antimalarial activity against P. falciparum strains 3D7 and K1 with low cytotoxicity. These chalcones also showed reduction in parasitemia and increased survival time of Swiss mice infected with Plasmodium yoelii (strain N-67). Pharmacokinetic studies indicated that low oral bioavailability due to poor ADME properties. Molecular docking studies revealed the binding orientation of these inhibitors in active sites of falcipain-2 (FP-2) enzyme. Compounds 67, 68, and 78 showed modest inhibitory activity against the major hemoglobin degrading cysteine protease FP-2.