Safranal, a plant secondary metabolite isolated from saffron, has been reported for several promising pharmacological properties toward the management of Alzheimer's disease. In the present study, we observe and report for the first time about several druglike attributes of safranal, such as adherence to Lipinski's rule of five; optimum lipophilicity; high permeability; low blood-to-plasma ratio; less to moderate propensity to interact with P-glycoprotein (P-gp) or breast cancer-resistant protein (BCRP) transporters; and high plasma protein binding as common to most of the marketed drugs using in vitro and ex vivo models. In spite of the above attributes, in vivo oral absorption was found to be very poor, which is linked to the structural integrity of safranal in simulated gastric fluid, simulated intestinal fluid, plasma, and liver microsomes. Moreover, the presence of unsaturated aldehyde moiety in safranal remains in equilibrium with its hydroxylated acetal form. Further research work is required to find out the stable oral absorbable form of safranal by derivatization of its aldehyde group without losing its potency.
Bedaquiline (TMC-207) is a recently
approved drug for the treatment
of multidrug-resistant tuberculosis (MDR-TB). Moreover, there is a
present and growing concern for natural-product-mediated drug interaction,
as these are inadvertently taken by patients as a dietary supplement,
food additive, and medicine. In the present study, we investigated
the impact of 20 plant-based natural products, typically phenolics,
on in vivo oral bedaquiline pharmacokinetics, as previous studies
are lacking. Three natural phenolics were identified that can significantly
enhance the oral exposure of bedaquiline upon coadministration. We
further investigated the possible role of all of the phytochemicals
on in vitro P-glycoprotein (P-gp)
induction and inhibition and CYP3A4 inhibition in a single platform
as bedaquiline is the substrate for both P-gp and
CYP3A4. In conclusion, curcumin, CC-I (3′,5–dihydroxyflavone-7-O-β-d-galacturonide-4′-O-β-d-glucopyranoside), and 6-gingerol should not be
coadministered with bedaquiline to avoid untoward drug interactions
and, subsequently, its dose-dependent adverse effects.
Curcumin, a natural diarylheptanoid, is extensively used as a food additive or dietary supplement on the regular basis. It is known to have potential to encumber the drug transporters and hepatic drug metabolizing enzymes that lead to pharmacokinetic interactions with drug or food. Daclatasvir is a new orally acting drug for the treatment of chronic Hepatitis C Virus infections. This is a substrate of P-glycoprotein and CYP3A4 that are involved in the major pharmacokinetic interaction. Hence, the studies' aim is to assess for any possible pharmacokinetic interactions. Pharmacokinetic studies of daclatasvir in presence or absence of curcumin were carried out in Wistar rats following oral administration. Parallelly, the oral pharmacokinetics of daclatasvir was also determined in the presence of ketoconazole or quinidine. Studies revealed that plasma level of daclatasvir was not altered significantly during concomitant single dose administration of curcumin, whereas significantly decreased upon pretreatment for 7 days with curcumin at high dose level. Ketoconazole and quinidine markedly increase daclatasvir exposure following concomitant administration with daclatasvir. It can be concluded that dose adjustment is unlikely to be required for intermittent use of curcumin at low dose but cautious for chronic and concomitant use of curcumin at a high dose.
The complex and multifaceted nature of Alzheimer’s
disease
has brought about a pressing demand to develop ligands targeting multiple
pathways to combat its outrageous prevalence. Embelin is a major secondary
metabolite of Embelia ribes Burm f.,
one of the oldest herbs in Indian traditional medicine. It is a micromolar
inhibitor of cholinesterases (ChEs) and β-site amyloid precursor
protein cleaving enzyme 1 (BACE-1) with poor absorption, distribution,
metabolism, and excretion (ADME) properties. Herein, we synthesize
a series of embelin–aryl/alkyl amine hybrids to improve its
physicochemical properties and therapeutic potency against targeted
enzymes. The most active derivative, 9j (SB-1448), inhibits
human acetylcholinesterase (hAChE), human butyrylcholinesterase (hBChE),
and human BACE-1 (hBACE-1) with IC50 values of 0.15, 1.6,
and 0.6 μM, respectively. It inhibits both ChEs noncompetitively
with k
i values of 0.21 and 1.3 μM,
respectively. It is orally bioavailable, crosses blood–brain
barrier (BBB), inhibits Aβ self-aggregation, possesses good
ADME properties, and protects neuronal cells from scopolamine-induced
cell death. The oral administration of 9j at 30 mg/kg
attenuates the scopolamine-induced cognitive impairments in C57BL/6J
mice.
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