Palmatine: A review of its pharmacology, toxicity and pharmacokinetics.

Palmatine is a natural isoquinoline alkaloid and has been widely used in pharmaceutical field. The purpose of this review is to provide the latest and comprehensive information on the pharmacology, toxicity and pharmacokinetics of palmatine in the past, to explore the therapeutic potential of this compound and look for ways to reduce toxicity. Information on palmatine was collected from the internet database PubMed, Elsevier, ResearchGate, Web of Science, Wiley Online Library and Europe PMC using a combination of keywords including "pharmacology", "toxicology", "pharmacokinetics". All studies of this genus were included in this review until March 2019. Palmatine has a wide spectrum of pharmacological effects, including anti-cancer, anti-oxidation, anti-inflammatory, neuroprotection, anti-bacterial, anti-viral and regulating blood lipids. However, palmatine has obvious DNA toxicity, and has a complex effect on metabolic enzymes in the liver. Pharmacokinetic studies have demonstrated that glucuronidation and sulfation are the main metabolic pathways of palmatine. Palmatine can be used in many diseases. Future research directions include: how the concentration of palmatine affects pharmacological effects and toxicity; the mechanism of synergy between palmatine and other protoberberine alkaloid; Structural modification of palmatine is one of the key methods to enhance pharmacological activity and reduce activity.

A review on analytical methods for natural berberine alkaloids.

Berberine alkaloids, a group of protoberberine alkaloids under the classification of isoquinoline alkaloids, include berberine, coptisine, palmatine, columbamine, dehydrocorydaline, jatrorrhizine, and epiberberine from natural sources. Studies have shown that berberine alkaloids have various pharmacological functions, such as antibacterial, antiviral, blood pressure-lowering, hypoglycaemic, antiarrhythmia, and anticancer effects. Therefore, it is worthwhile to develop analytical methods to investigate the pharmacokinetics and activity mechanisms of berberine alkaloids and to study berberine alkaloids more comprehensively. Current analytical methods for berberine alkaloids include liquid chromatography, thin-layer chromatography, ultraviolet spectroscopy, capillary electrophoresis, and gas chromatography. The most widely used detection method is mass spectrometry. In order to provide a systematic and comprehensive summary and to serve as a reference for the future pharmacokinetics studies and analysis of berberine alkaloids, analytical methods for natural berberine alkaloids that have been used in the past ten years are reviewed here.

Comparison between linear and star-like HPMA conjugated pirarubicin (THP) in pharmacokinetics and antitumor activity in tumor bearing mice.

Previously we showed that linear poly(N-(2-hydroxypropyl)methacrylamide) conjugates of pirarubicin (THP), LP-THP, with MW about 39 kDa, exhibited far better tumor accumulation and therapeutic effect than that of parental free THP. To improve the pharmacokinetics of LP-THP further, high-MW conjugate of poly(amido amine) (PAMAM) dendrimer grafted with semitelechelic HPMA copolymer (PHPMA) was synthesized [star polymer (SP); 400 kDa] and conjugated with THP via hydrazone bond-containing spacer (SP-THP). THP was conjugated to SP to form SP-THP via acid cleavable hydrazone bonding, which responds to acidic milieu of tumor tissue. As a consequence, it would release free THP, by active therapeutic principle. SP-THP exhibits larger hydrodynamic diameter (25.9 nm) in aqueous solution than that of LP-THP (8.2 nm) as observed by light scattering and size exclusion chromatography. Because of the larger size, the tumor AUC5h-72 h of SP-THP was 3.3 times higher than that of LP-THP. More importantly, released free THP was retained selectively in the tumor tissue for at least up to 72 h after administration of SP-THP. We found that SP-THP exhibited superior antitumor effect to LP-THP against both S-180 tumor-bearing mice in vivo, and with chemically AOM/DSS-induced colon tumor-bearing mice, most probably due to their different molecular size. In our comparison study of in vitro and in vivo behavior of SP-THP and LP-THP we concluded that SP-THP exhibited enhanced therapeutic efficacy not only in implanted tumor but also in orthotopic/spontaneous tumor despite its higher toxicity compared to LP-THP. Upon these findings further investigation using various tumors including transgenic, and metastatic tumors is going to be conducted soon.

L-isocorypalmine reduces behavioral sensitization and rewarding effects of cocaine in mice by acting on dopamine receptors.

BACKGROUND: We previously reported isolation of l-isocorypalmine (l-ICP), a mono-demethylated analog of l-tetrahydropalmatine (l-THP), from the plant Corydalis yanhusuo. Here we characterized its in vitro pharmacological properties and examined its effects on cocaine-induced behaviors in mice. METHODS: Receptor binding, cAMP and [(35)S]GTPγS assays were used to examine pharmacological actions of l-ICP in vitro. Effects of l-ICP on cocaine-induced locomotor hyperactivity and sensitization and conditioned place preference (CPP) in mice were investigated. HPLC was employed to analyze metabolites of l-ICP in mouse serum. RESULTS: Among more than 40 targets screened, l-ICP and l-THP bound only to dopamine (DA) receptors. l-ICP was a high-affinity partial agonist of D1 and D5 receptors and a moderate-affinity antagonist of D2, D3 and D4 receptors, whereas l-THP bound to only D1 and D5 receptors, with lower affinities than l-ICP. At 10mg/kg (i.p.), l-ICP inhibited spontaneous locomotor activity for a shorter time than l-THP. Pretreatment with l-ICP reduced cocaine-induced locomotor hyperactivities. Administration of l-ICP before cocaine once a day for 5 days reduced cocaine-induced locomotor sensitization on days 5 and 13 after 7 days of withdrawal. Pretreatment with l-ICP before cocaine daily for 6 days blocked cocaine-induced CPP, while l-ICP itself did not cause preference or aversion. HPLC analysis showed that l-ICP was the main compound in mouse serum following i.p. injection of l-ICP. CONCLUSIONS: l-ICP likely acts as a D1 partial agonist and a D2 antagonist to produce its in vivo effects and may be a promising agent for treatment of cocaine addiction.

Inhibition of CYP1 by berberine, palmatine, and jatrorrhizine: selectivity, kinetic characterization, and molecular modeling.

Cytochrome P450 (P450, CYP) 1 family plays a primary role in the detoxification and bioactivation of polycyclic aromatic hydrocarbons. Human CYP1A1, CYP1A2, and CYP1B1 exhibit differential substrate specificity and tissue distribution. Berberine, palmatine, and jatrorrhizine are protoberberine alkaloids present in several medicinal herbs, such as Coptis chinensis (Huang-Lian) and goldenseal. These protoberberines inhibited CYP1A1.1- and CYP1B1.1-catalyzed 7-ethoxyresorufin O-deethylation (EROD) activities, whereas CYP1A2.1 activity was barely affected. Kinetic analysis revealed that berberine noncompetitively inhibited EROD activities of CYP1A1.1 and CYP1B1.1, whereas palmatine and jatrorrhizine caused either competitive or mixed type of inhibition. Among protoberberines, berberine caused the most potent and selective inhibitory effect on CYP1B1.1 with the least Ki value of 44±16 nM. Berberine also potently inhibited CYP1B1.1 activities toward 7-ethoxycoumarin and 7-methoxyresorufin, whereas the inhibition of benzo(a)pyrene hydroxylation activity was less pronounced. Berberine inhibited the polymorphic variants, CYP1B1.3 (V432L) and CYP1B1.4 (N453S), with IC50 values comparable to that for CYP1B1.1 inhibition. Berberine-mediated inhibition was abolished by a mutation of Asn228 to Thr in CYP1B1.1, whereas the inhibition was enhanced by a reversal mutation of Thr223 to Asn in CYP1A2.1. This result in conjugation with the molecular modeling revealed the crucial role of hydrogen-bonding interaction of Asn228 on CYP1B1.1 with the methoxy moiety of berberine. These findings demonstrate that berberine causes a selective CYP1B1-inhibition, in which Asn228 appears to be crucial. The inhibitory effects of berberine on CYP1B1 activities toward structurally diverse substrates can be different.

[Biotransformation by human intestinal flora and absorption-transportation characteristic in a model of Caco-2 cell monolayer of d-corydaline and tetrahydropalmatine].

OBJECTIVE: To study the biotransformation by human intestinal flora, and the absorption and transportation characteristic in a model of human colon adenocarcinoma cell lines (Caco-2 cell) monolayer of d-corydaline (CDL) and tetrahydropalmatine (THP). METHOD: CDL or THP was incubated with crude enzymes of human intestinal flora under the anaerobic environment and 37 degrees C conditions to transform CDL or THP. Caco-2 cell monolayer was used as an intestinal epithelial cell model for determination of the permeability of CDL or THP from apical side (AP side) to basolateral side (BL side) or from BL side to AP side. Transportation parameters and permeability coefficients (P(app)) were then calculated, and P(app) values were compared with the reported values for model compounds, propranolol as a well absorbed drug and atenolol as a poor absorbed drug. The concentration of CDL or THP was measured by HPLC coupled with photodiode array detector. RESULT: CDL or THP in the human intestinal flora incubation system did not happen biotransformation. In the Caco-2 cell monolayer model, the P(app) magnitudes of both CDL and THP were 1 x 10(-5) cm x s(-1) in the bi-directional transport, which were identical with propranolol. And their transports were concentration dependent between 0-180 min. CONCLUSION: Both CDL and THP may be stable in the human intestinal flora incubation system, and their absorption and transportation in the human Caco-2 cell monolayer model are mainly via passive diffusion mechanism.

Amphiphilic poly{[alpha-maleic anhydride-omega-methoxy-poly(ethylene glycol)]-co-(ethyl cyanoacrylate)} graft copolymer nanoparticles as carriers for transdermal drug delivery.

In this study, the transdermal drug delivery properties of D,L-tetrahydropalmatine (THP)-loaded amphiphilic poly{[alpha-maleic anhydride-omega-methoxy-poly(ethylene glycol)]-co-(ethyl cyanoacrylate)} (PEGECA) graft copolymer nanoparticles (PEGECAT NPs) were evaluated by skin penetration experiments in vitro. The transdermal permeation experiments in vitro were carried out in Franz diffusion cells using THP-loaded PEGECAT NPs as the donor system. Transmission electron microscopy and Fourier transform infrared spectroscopy were used to characterize the receptor fluid. The results indicate that the THP-loaded PEGECAT NPs are able to penetrate the rat skin. Fluorescent microscopy measurements demonstrate that THP-loaded PEGECAT NPs can penetrate the skin not only via appendage routes but also via epidermal routes. This nanotechnology has potential application in transdermal drug delivery.