Characterization of Silvestrol Pharmacokinetics in Mice Using Liquid Chromatography–Tandem Mass Spectrometry

Abstract

A sensitive and specific liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of the plant natural product silvestrol in mice, using ansamitocin P-3 as the internal standard. The method was validated in plasma with a lower limit of quantification of 1 ng/mL, accuracy ranging from 87 to 114%, and precision (coefficient of variation) below 15%. The validated method was used to characterize pharmacokinetics in C57BL/6 mice and metabolism in mouse, human and rat plasma, and liver microsomes. Mice were dosed with silvestrol formulated in hydroxypropyl-β-cyclodextrin via intravenous, intraperitoneal, and oral routes followed by blood sampling up to 24 h. Intraperitoneal systemic availability was 100%, but oral administration resulted in only 1.7% bioavailability. Gradual degradation of silvestrol was observed in mouse and human plasma, with approximately 60% of the parent drug remaining after 6 h. In rat plasma, however, silvestrol was completely converted to silvestric acid (SA) within 10 min. Evaluation in microsomes provided further evidence that the main metabolite formed was SA, which subsequently showed no cytotoxic or cytostatic activity in a silvestrol-sensitive lymphoblastic cell line. The ability of the analytical assay to measure tissue levels of silvestrol was evaluated in liver, brain, kidney, and spleen. Results indicated the method was capable of accurately measuring tissue levels of silvestrol and suggested it has a relatively low distribution to brain. Together, these data suggest an overall favorable pharmacokinetic profile of silvestrol in mice and provide crucial information for its continued development toward potential clinical testing.

Overexpression of eIF4F components in meningiomas and suppression of meningioma cell growth by inhibiting translation initiation

“…We have demonstrated that silvestrol exhibits consistent strong suppression of the growth of meningioma cells in culture (Figure 3). Previous pharmacokinetic analysis showed that silvestrol requires intraperitoneal or intravenous delivery for maximal bioavailability (Saradhi et al, 2011). However, even with these delivery methods, the distribution to the brain is relatively low, suggesting that silvestrol may not readily cross the blood-brain barrier.…”

Rocaglamide, silvestrol and structurally related bioactive compounds from Aglaia species

“…65 These results were achieved in the absence of obvious toxicity, thus leaving conditions used was 100%, and that in mouse and human plasma gradual degradation of silvestrol occurred, leading to about 60% of the parent drug remaining after 6 h. It was considered that an overall favorable pharmacokinetic profile was observed for silvestrol ( 2 ) in mice. 61 …”

Targeting the eIF4A RNA helicase as an anti-neoplastic approach

“…Preclinical pharmacokinetic studies of silvestrol indicated an overall favorable profile, as it is relatively stable in mouse and human plasma, well tolerated in animals (up to 1.5 mg/ kg in mice) and highly potent (effective at nanomolar concentrations in in vitro cell culture and less than 0.5 mg/kg daily dosing in murine cancer models) [147][148][149]. When delivered IP, 60% of silvestrol is bioavailable 6 hours after injection.…”

“…When delivered IP, 60% of silvestrol is bioavailable 6 hours after injection. However, there are shortcomings with respect to the delivery and absorption of the compound; although the systemic availability of silvestrol when delivered via IP is near 100%, the bioavailability achieved from oral administration is dramatically inferior (1.7%) [147]. The inefficiency of oral delivery is thought to be attributed to the fact that silvestrol is a substrate for the multi-drug resistance 1 (MDR1) efflux pump [150]-a drug transporter present in the intestinal mucosa lining and which can prevent efficient drug absorption [151].…”