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Exploration on Pharmacokinetics and Pharmacodynamics of Natural Molecules: Current Status and Future Perspectives

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 50759

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Prof. Dr. Fawzy A. Elbarbry

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Guest Editor

School of Pharmacy, Pacific University Oregon, Hillsboro, OR 97123, USA
Interests: drug metabolism; pharmacokinetics; natural products; pharmacodynamics; drug analysis
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Deepa A. Rao

E-Mail Website
Co-Guest Editor

School of Pharmacy, Pacific University Oregon, OR 97123, USA
Interests: natural product delivery; complementary medicine; drug delivery; nanomedicine; biopharmaceutics

Special Issue Information

Dear Colleagues,

Since the early 1990s, the research and discovery efforts of many pharmaceuticals have been focused on combinatorial chemistry and high-throughput screening to generate and identify new therapeutic agents. However, this switch did not yield the expected returns in terms of new drug candidates and might in fact have led to the current paucity of new drug candidates in the development pipeline. However, in many cultures around the world, natural product use in elixirs, tincture, and other applications have been in existence and codified in traditional Chinese medicine, Auyrveda, and African traditional medicine, among other practices. These natural products remain in active use to date. A recent focus on nature’s toolbox and existent practices has resulted in the discovery and development of promising and clinically useful drug candidates. Unfortunately, these natural products do not currently play a major therapeutic role, mostly due to the limited knowledge regarding their physicochemical, pharmacokinetic, and pharmacodynamic properties. All scientists investigating this field are cordially invited to contribute original research papers or reviews to this Special Issue of Molecules, which will focus on the latest findings in physicochemical, pharmacokinetic, and pharmacodynamic properties of promising natural products.

Prof. Dr. Fawzy A. Elbarbry
Guest Editor

Prof. Dr. Deepa A. Rao
Co-Guest Editor

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Keywords

natural products
delivery
pharmacokinetics
pharmacodynamics
molecular mechanisms
therapeutic outcomes
complementary and alternate medicine

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review

2 pages, 159 KiB

Open AccessEditorial

Natural Products; from the Laboratory to Clinical Practice

by Fawzy Elbarbry

Molecules 2023, 28(7), 3184; https://doi.org/10.3390/molecules28073184 - 3 Apr 2023

Viewed by 1061

Abstract

It has been such a great honor to serve as the Guest Editor for this Special Issue, “Exploration on Pharmacokinetics and Pharmacodynamics of Natural Molecules: Current Status and Future Perspectives” [...] Full article

(This article belongs to the Special Issue Exploration on Pharmacokinetics and Pharmacodynamics of Natural Molecules: Current Status and Future Perspectives)

Research

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12 pages, 1368 KiB

Open AccessArticle

Catechin Reduces Blood Pressure in Spontaneously Hypertensive Rats through Modulation of Arachidonic Acid Metabolism

by Fawzy Elbarbry, Gabriel Jones and Aimy Ung

Molecules 2022, 27(23), 8432; https://doi.org/10.3390/molecules27238432 - 2 Dec 2022

Cited by 8 | Viewed by 2055

Abstract

(1) Background: hypertension affects approximately half of the adults in the United States (roughly 116 million). The cytochrome P450 (CYP)-mediated metabolism of arachidonic acid (AA) in the kidney has been found to play a major role in the pathogenesis of hypertension. This study examines the anti-hypertensive effect of the natural polyphenolic compound catechin (CAT) and investigates if it impacts the metabolism of AA in the kidney in comparison to captopril (CAP): a commonly used antihypertensive drug. (2) Methods: spontaneously hypertensive rats (SHR) were randomly divided into five groups. The treatment groups were administered CAT in drinking water at doses of 10 and 50 mg/kg. A positive control group received CAP at a dose of 10 mg/kg in the drinking water, and one group received both CAP and CAT at doses of 10 mg/kg and 50 mg/kg, respectively. Blood pressure was monitored weekly for five weeks. The activity of the two major enzymes involved in AA metabolism in the kidney, namely CYP4A and soluble epoxide hydrolase (sEH), were analyzed. (3) Results: CAP monotherapy was found to reduce blood pressure compared to the control untreated rats but did not demonstrate any effect on AA metabolism. Low- and high-dose CAT resisted the rise in blood pressure observed in the untreated SHR and significantly lowered blood pressure compared to the control group, respectively. Only rats treated with high CAT doses demonstrated significant inhibition of CYP4A and sEH enzyme activities. The coadministration of CAP and a high dose of CAT resulted in more pronounced blood pressure-lowering effects, but no more significant effects on AA metabolism were found compared to a high dose of CAT alone. (4) Conclusion: the modulation of AA metabolism in the kidney contributes, at least partially, to the blood pressure-lowering effect of CAT in SHR rats. Full article

(This article belongs to the Special Issue Exploration on Pharmacokinetics and Pharmacodynamics of Natural Molecules: Current Status and Future Perspectives)

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13 pages, 1866 KiB

Open AccessArticle

The Modulation of Arachidonic Acid Metabolism and Blood Pressure-Lowering Effect of Honokiol in Spontaneously Hypertensive Rats

by Fawzy Elbarbry and Nicholas Moshirian

Molecules 2022, 27(11), 3396; https://doi.org/10.3390/molecules27113396 - 25 May 2022

Cited by 8 | Viewed by 1855

Abstract

Background: Cardiovascular diseases have consistently been the leading cause of death in the United States over the last two decades, with 30% of the adult American population having hypertension. The metabolites of arachidonic acid (AA) in the kidney play an important role in blood pressure regulation. The present study investigates the antihypertensive effect of honokiol (HON), a naturally occurring polyphenol, and examines its correlation to the modulation of AA metabolism. Methods: Spontaneously hypertensive rats (SHR) were randomly divided into four groups. Treatment groups were administered HON intraperitoneally at concentrations of 5, 20, and 50 mg/kg. Blood pressure was monitored at seven-day intervals. After a total of 3 weeks of treatment, the rats were euthanized and the kidney tissues were collected to examine the activity of the two major enzymes involved in AA metabolism in the kidney, namely cytochrome P450 (CYP)4A and soluble epoxide hydrolase (sEH). Results: Rats treated with HON did not experience the rise in blood pressure observed in the untreated SHR. High-dose HON significantly reduced blood pressure and inhibited the activity and protein expression of the CYP4A enzyme in the rat kidney. The activity of the sEH enzyme in renal cytosol was significantly inhibited by medium and high doses of HON. Conclusion: Our data demonstrate the antihypertensive effect of HON and provide a novel mechanism for its underlying cardioprotective properties. Full article

(This article belongs to the Special Issue Exploration on Pharmacokinetics and Pharmacodynamics of Natural Molecules: Current Status and Future Perspectives)

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15 pages, 3392 KiB

Open AccessArticle

Excretion, Metabolism, and Tissue Distribution of Gelsemium elegans (Gardn. & Champ.) Benth in Pigs

by Xiao Ma, Zi-Yuan Wang, Meng-Ting Zuo, Kun Yang, Zhi-Liang Sun, Yong Wu and Zhao-Ying Liu

Molecules 2022, 27(8), 2605; https://doi.org/10.3390/molecules27082605 - 18 Apr 2022

Cited by 8 | Viewed by 2239

Abstract

Gelsemium elegans (Gardn. & Champ.) Benth is a toxic flowering plant in the family Loganiaceae used to treat skin diseases, neuralgia and acute pain. The high toxicity of G. elegans restricts its development and clinical applications, but in veterinary applications, G. elegans has been fed to pigs as a feed additive without poisoning. However, until now, the in vivo processes of the multiple components of G. elegans have not been studied. This study investigates the excretion, metabolism and tissue distribution of the multiple components of G. elegans after feeding it to pigs in medicated feed. Pigs were fed 2% G. elegans powder in feed for 45 days. The plasma, urine, bile, feces and tissues (heart, liver, lung, spleen, brain, spinal cord, adrenal gland, testis, thigh muscle, abdominal muscle and back muscle) were collected 6 h after the last feeding and analyzed using high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. Five natural products in plasma, twelve natural products and five metabolites in urine, and three natural products in feces were characterized, suggesting that multiple components from G. elegans were excreted in the urine. However, ten natural products and four metabolites were detected in bile samples, which suggested that G. elegans is involved in enterohepatic circulation in pigs. A total of seven of these metabolites were characterized, and four metabolites were glucuronidated metabolites. Ten natural products and six metabolites were detected in the tissues, which indicates that G. elegans is widely distributed in tissues and can cross the blood-brain barrier. Among the characterized compounds, a highly toxic gelsedine-type alkaloid from G. elegans was the main compound detected in all biological samples. This is the first study of the excretion, metabolism and tissue distribution of multiple components from G. elegans in pigs. These data can provide an important reference to explain the efficacy and toxicity of G. elegans. Additionally, the results of the tissue distribution of G. elegans are of great value for further residue depletion studies and safety evaluations of products of animals fed G. elegans. Full article

(This article belongs to the Special Issue Exploration on Pharmacokinetics and Pharmacodynamics of Natural Molecules: Current Status and Future Perspectives)

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24 pages, 1913 KiB

Open AccessArticle

Pharmacokinetic Study of Withanosides and Withanolides from Withania somnifera Using Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS/MS)

by Siddharth J. Modi, Anshuly Tiwari, Chetana Ghule, Sandeep Pawar, Ganesh Saste, Shubham Jagtap, Ruchi Singh, Amol Deshmukh, Aboli Girme and Lal Hingorani

Molecules 2022, 27(5), 1476; https://doi.org/10.3390/molecules27051476 - 22 Feb 2022

Cited by 24 | Viewed by 6122

Abstract

Withania somnifera is a traditional Indian herb described under the ‘Rasayana’ class in Ayurveda, which gained immense popularity as a dietary supplement in the USA, Europe, Asia, and the Indian domestic market. Despite enormous research on the pharmacological effect of withanosides and withanolides, bioanalytical method development and pharmacokinetics remained challenging and unexplored for these constituents due to isomeric and isobaric characteristics. In current research work, molecular descriptors, pharmacokinetic, and toxicity prediction (ADMET) of these constituents were performed using Molinspiration and admetSAR tools. A rapid, selective, and reproducible bioanalytical method was developed and validated for seven withanosides and withanolides as per USFDA/EMA guidelines, further applied to determine pharmacokinetic parameters of Withania somnifera root extract (WSE) constituents in male Sprague Dawley rats at a dose of 500 mg/kg. Additionally, an ex vivo permeability study was carried out to explore the absorption pattern of withanosides and withanolides from the intestinal lumen. In silico, ADMET revealed oral bioavailability of withanosides and withanolides following Lipinski’s rules of five with significant absorption from the gastrointestinal tract and the ability to cross the blood-brain barrier. Upon oral administration of WSE, C_max was found to be 13.833 ± 3.727, 124.415 ± 64.932, 57.536 ± 7.523, and 7.283 ± 3.341 ng/mL for withanoside IV, withaferin A, 12-Deoxy-withastramonolide, and withanolide A, respectively, with T_max of 0.750 ± 0.000, 0.250 ± 0.000, 0.291 ± 0.102, and 0.333 ± 0.129 h. Moreover, at a given dose, withanoside V, withanolide B, and withanone were detected in plasma; however, the concentration of these constituents was found below LLOQ. Thus, these four major withanoside and withanolides were quantified in plasma supported by ex vivo permeation data exhibiting a time-dependent absorption of withanosides and withanolides across the intestinal barrier. These composite findings provide insights to design a clinical trial of WSE as a potent nutraceutical. Full article

(This article belongs to the Special Issue Exploration on Pharmacokinetics and Pharmacodynamics of Natural Molecules: Current Status and Future Perspectives)

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19 pages, 2307 KiB

Open AccessArticle

Determination of Antioxidants by DPPH Radical Scavenging Activity and Quantitative Phytochemical Analysis of Ficus religiosa

by Siddartha Baliyan, Riya Mukherjee, Anjali Priyadarshini, Arpana Vibhuti, Archana Gupta, Ramendra Pati Pandey and Chung-Ming Chang

Molecules 2022, 27(4), 1326; https://doi.org/10.3390/molecules27041326 - 16 Feb 2022

Cited by 363 | Viewed by 22792

Abstract

The use of F. religiosa might be beneficial in inflammatory illnesses and can be used for a variety of health conditions. In this article, we studied the identification of antioxidants using (DPPH) 2,2-Diphenyl-1-picrylhydrazylradical scavenging activity in Ficus religiosa, as F. religiosa is an important herbal plant, and every part of it has various medicinal properties such as antibacterial properties that can be used by the researchers in the development and design of various new drugs. The 2,2-Diphenyl-1-picrylhydrazyl (DPPH) is a popular, quick, easy, and affordable approach for the measurement of antioxidant properties that includes the use of the free radicals used for assessing the potential of substances to serve as hydrogen providers or free-radical scavengers (FRS). The technique of DPPH testing is associated with the elimination of DPPH, which would be a stabilized free radical. The free-radical DPPH interacts with an odd electron to yield a strong absorbance at 517 nm, i.e., a purple hue. An FRS antioxidant, for example, reacts to DPPH to form DPPHH, which has a lower absorbance than DPPH because of the lower amount of hydrogen. It is radical in comparison to the DPPH-H form, because it causes decolorization, or a yellow hue, as the number of electrons absorbed increases. Decolorization affects the lowering capacity significantly. As soon as the DPPH solutions are combined with the hydrogen atom source, the lower state of diphenylpicrylhydrazine is formed, shedding its violet color. To explain the processes behind the DPPH tests, as well as their applicability to Ficus religiosa (F. religiosa) in the manufacture of metal oxide nanoparticles, in particular MgO, and their influence on antioxidants, a specimen from the test was chosen for further study. According to our findings, F. religiosa has antioxidant qualities and may be useful in the treatment of disorders caused by free radicals. Full article

(This article belongs to the Special Issue Exploration on Pharmacokinetics and Pharmacodynamics of Natural Molecules: Current Status and Future Perspectives)

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14 pages, 1147 KiB

Open AccessArticle

Effects of Green Apple (Golden Delicious) and Its Three Major Flavonols Consumption on Obesity, Lipids, and Oxidative Stress in Obese Rats

by Ilknur Selek Aksoy and Semih Otles

Molecules 2022, 27(4), 1243; https://doi.org/10.3390/molecules27041243 - 12 Feb 2022

Cited by 5 | Viewed by 3125

Abstract

Obesity is becoming increasingly common all over the world and global strategies are accordingly being developed to prevent it. In order to support the strategies, the effects of green apple (Golden Delicious) and the consumption of its three major flavonols (quercetin-3-glucoside, quercetin-3-D-galactoside, and quercetin-3-rhamnoside) on body weight; the weight of liver, kidney, and spleen; some lipid parameters in serum; and total lipid ratios of liver and kidney and oxidative stress parameters of obese rats were studied. This study was conducted on two experimental groups: one of which was given an apple, and the other was given flavonols, in addition to their high-energy diet; along with a sham and a control rat group, for 4 weeks. According to results, there was no difference in body and organ weights between groups. The liver and kidney weights increased in obese rats, but there was no difference between the total lipid ratios in these organs. The addition of green apple and selected flavonols to the high-energy diet of rats was not sufficient to prevent the increase in body and organ weights, but it supported the reduction in some lipid fractions and in oxidative stress parameters of obese rats. Moreover, this study supported the argument that obesity causes most of the lipid fractions increase in serum and induces oxidative stress. Full article

(This article belongs to the Special Issue Exploration on Pharmacokinetics and Pharmacodynamics of Natural Molecules: Current Status and Future Perspectives)

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8 pages, 1040 KiB

Open AccessArticle

Determination of the Peptide AWRK6 in Rat Plasma by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) and Its Application to Pharmacokinetics

by Lili Jin, Haibo Ding, Volkan Degirmenci, Hongchuan Xin, Qifan Miao, Qiuyu Wang and Dianbao Zhang

Molecules 2022, 27(1), 92; https://doi.org/10.3390/molecules27010092 - 24 Dec 2021

Cited by 4 | Viewed by 3630

Abstract

AWRK6 was a synthesized peptide developed based on the natural occurring peptide dybowskin-2CDYa, which was discovered in frog skin in our previous study. Here, a quantitative determination method for AWRK6 analysis in rat plasma by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was established and validated following U.S. FDA guidelines. A combination of plasma precipitation and liquid–liquid extraction was applied for the extraction. For pharmacokinetics study, the rats were administrated with AWRK6 via intraperitoneal and intravenous injection. The prepared plasma samples were separated on an ODS column and analyzed by tandem MS using precursor-to-product ion pairs of m/z: 533.4→84.2 for AWRK6 and m/z: 401.9→101.1 for internal standard Polymyxin B sulfate in multiple reaction monitoring mode. AWRK6 concentrations in rat plasma peaked at about 1.2 h after intraperitoneal injections at 2.35, 4.7 and 9.4 mg/kg bodyweight. The terminal half-life was around 2.8 h. The absolute bioavailability of AWRK6 was 50% after 3 doses via injection, and the apparent volume of distribution was 4.884 ± 1.736 L. The obtained determination method and pharmacokinetics profiles of AWRK6 provides a basis for further development, and forms a benchmark reference for peptide quantification. Full article

(This article belongs to the Special Issue Exploration on Pharmacokinetics and Pharmacodynamics of Natural Molecules: Current Status and Future Perspectives)

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14 pages, 1570 KiB

Open AccessArticle

Pharmacokinetics of Azalomycin F, a Natural Macrolide Produced by Streptomycete Strains, in Rats

by Su He, Wenjia Zhao, Peibo Li, Wenqing Tu, Kui Hong, Duoduo Zhang, Tongke Zhang and Ganjun Yuan

Molecules 2021, 26(21), 6464; https://doi.org/10.3390/molecules26216464 - 26 Oct 2021

Cited by 2 | Viewed by 2116

Abstract

As antimicrobial resistance has been increasing, new antimicrobial agents are desperately needed. Azalomycin F, a natural polyhydroxy macrolide, presents remarkable antimicrobial activities. To investigate its pharmacokinetic characteristics in rats, the concentrations of azalomycin F contained in biological samples, in vitro, were determined using a validated high-performance liquid chromatography–ultraviolet (HPLC-UV) method, and, in vivo, samples were assayed by an ultra-high performance liquid chromatography–tandem mass spectrometric (UPLC–MS/MS) method. Based on these methods, the pharmacokinetics of azalomycin F were first investigated. Its plasma concentration-time courses and pharmacokinetic parameters in rats were obtained by a non-compartment model for oral (26.4 mg/kg) and intravenous (2.2 mg/kg) administrations. The results indicate that the oral absolute bioavailability of azalomycin F is very low (2.39 ± 1.28%). From combinational analyses of these pharmacokinetic parameters, and of the results of the in-vitro absorption and metabolism experiments, we conclude that azalomycin F is absorbed relatively slowly and with difficulty by the intestinal tract, and subsequently can be rapidly distributed into the tissues and/or intracellular f of rats. Azalomycin F is stable in plasma, whole blood, and the liver, and presents plasma protein binding ratios of more than 90%. Moreover, one of the major elimination routes of azalomycin F is its excretion through bile and feces. Together, the above indicate that azalomycin F is suitable for administration by intravenous injection when used for systemic diseases, while, by oral administration, it can be used in the treatment of diseases of the gastrointestinal tract. Full article

(This article belongs to the Special Issue Exploration on Pharmacokinetics and Pharmacodynamics of Natural Molecules: Current Status and Future Perspectives)

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Review

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26 pages, 1071 KiB

Open AccessFeature PaperReview

Mechanistic Basis for the Role of Phytochemicals in Inflammation-Associated Chronic Diseases

by Brianna Cote, Fawzy Elbarbry, Fiona Bui, Joe W. Su, Karen Seo, Arthur Nguyen, Max Lee and Deepa A. Rao

Molecules 2022, 27(3), 781; https://doi.org/10.3390/molecules27030781 - 25 Jan 2022

Cited by 21 | Viewed by 4220

Abstract

Chronic inflammatory diseases occur in a large portion of the population and are associated with a poor diet. Key natural products found in fruits and vegetables may assist in lowering inflammation associated with chronic diseases such as obesity, diabetes, cardiovascular diseases, and cancer. This review seeks to examine the roles of several natural products, resveratrol (RES), quercetin (QUE), curcumin (CUR), piperine (PIP), epigallocatechin gallate (EGCG), and gingerol (GIN), in their ability to attenuate inflammatory markers in specific diseases states. Additionally, we will discuss findings in past and ongoing clinical trials, detail possible phytochemical–drug interactions, and provide a brief resource for researchers and healthcare professionals on natural product and supplement regulation as well as names of databases with information on efficacy, indications, and natural product–drug interactions. As diet and over-the-counter supplement use are modifiable factors and patients are interested in using complementary and alternative therapies, understanding the mechanisms by which natural products have demonstrated efficacy and the types of drugs they interact with and knowing where to find information on herbs and supplements is important for practicing healthcare providers and researchers interested in this field. Full article

(This article belongs to the Special Issue Exploration on Pharmacokinetics and Pharmacodynamics of Natural Molecules: Current Status and Future Perspectives)

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