Pharmacokinetics - Dr. Christopher Hobbs

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Pharmacokineticsof Herbal Active ConstituentsChristopher Hobbs, Ph.D., L.Ac., A.H.G.from Ancient Greekpharmakon "drug" andkinetikos "moving, putting inmotion“ (Wikipedia)The use of traditional cookingwith oil and spices led the wayfor absorption-enhancement ofthe medicinal qualities ofherbal medicines

Pharmacokinetics OverviewFrom: Psychophrmacology,Fig. 1.12006. Sinauer Associates

Pharmacokinetics & Pharmacodynamicsof Herbal Active Constituents Pharmacokinetics– “the branch ofpharmacology concernedwith the movement ofdrugs within the body.”1.First, the active constituentsneed to be identified,characerized2.First, the active constituentshave to be absorbed3.Second, the ingredients insupplements or herbs need tohave active constituents4.The product has to have enoughof the ingredients that haveconstituents to do anything(pixie dust) Pharmacodynamics– “the branch ofpharmacology concernedwith the effects of drugsand the mechanism oftheir action.”

Why Study Herbal Pharmacokinetics? Efficacy—helps determine– The best type of preparation (tincture, water-based extract, enhanced extract)– How the body’s organs, tissues, and cells are affected by the herb– The dose and dosage! Safety—a better understanding of the pharmacokinetics of herbalmedicines is needed to support the predictability of botanical – druginteractions. How to maximize herbal formulas to increase effectiveness Why study pharmacodynamics? Efficacy, safety, identify biologicalactivity, the mechanisms by which it acts

Scientific Basis—Herbal ResearchResearch articles on Scholar with key words related to pharmacokineticsOriginal Research, C. Hobbs, 3-25-16

PharmacodynamicsAgonists & Antagonists Agonist—increases Antagonist—blocks Agonist antagonist herbs andherb formulas Herbs bind more reversiblythan designed drugmonosubstances Herbs—more complex actions

Basics of Pharmacodynamics Drugs affect only the rate at which existing biologicfunctions proceed Drugs do not change the basic nature of thesefunctions or create new functions Drugs can speed up or slow down the biochemicalreactions muscles to contract kidney cells to regulate the volume of water and saltsretained Hormone secretion Nerve transmission Drugs cannot restore structures or functions alreadydamaged beyond repair by the body Most interactions between a drug and areceptor or between a drug and an enzyme arereversible Sometimes an interaction is largely irreversible,and the drug’s effect persists until the bodymanufactures more enzyme For instance, omeprazole, a drug used in themanagement of gastroesophageal reflux and ulcers,irreversibly inhibits an enzyme involved in thesecretion of stomach acid However, eventually the body will create more ofthe enzyme

Active transport Requires the use of energy tomove an active chemical Carrier-mediated diffusion oror facilitated diffusion—i.e.a carrier protein Passive transport—diffusion osmosisSource: YouTube standard license (ParaCarell)

From: Munira et al., 2015. Physiological Factors Affecting Drug /physiological-factors-of-drug-absorption-45020626

Active Transport Against the concentration gradient Energy (ATP) is required shape change transports solute fromone side of membrane to other protein “pump” conformationalchange Active transport, other examples:– Pinocytosis– Endocytosis– Phagocytosis

Phagocytosis, Pinocytosis, EndocytosisFrom: Reece et al., 2011. Campbell BiologyMembrane Structure and Function:slideshare.net

Example-Mushroom beta-glucans β-glucans dock to immune receptorsincluding Dectin-1, complementreceptor (CR3) and TLR-2/6– Trigger a group of immune cellsincluding macrophages, neutrophils,monocytes, natural killer cells anddendritic cells– Fungal beta-glucans are taken up bymacrophages– Then digested to fragments– Taken up and distributed inside the body– These bind to CR3 receptors– Inducing granulocytes to produceSource: Chan et al., 2009

Cross-section of fungalcell wall(β(1,3)(1,6) D-glucanSource: Chan et al., 2009

Figure 3 Immune activation induced by β-glucans(From: Chan et al., 2009) β-glucans can act on a variety of membrane receptors foundon the immune cells may act singly or in combine with other ligands Various signaling pathway are activated and their pathwaysare shown Reactor cells include monocytes, macrophages, dendriticcells, natural killer cells and neutrophils Corresponding surface receptors are listed Immunomodulatory functions induced by β-glucans involveboth innate and adaptive immune response β-glucans also enhance opsonic and non-opsonicphagocytosis and trigger a cascade of cytokines release tumor necrosis factor(TNF)-α and various types ofinterleukins (ILs).

Blood serum levels and Tissue LevelsA study in itself Active compounds are absorbed into the blood Metabolized by the liver to some degree Then migrate to the tissues Low blood serum levels may not indicate low bioactivity! Look at the curves—the second of two peaks might indicatethe start of elimination through urine and feces

CRM-LF consists of:CRM (6.17% w/w)—excipientGelucire 44/14 (16.46% w/w)—excipientLabrasol (5.76% w/w)—emulsifierVitamin E TPGS (3.29% w/w)--antioxidantPEG 400 (55.55% w/w)—solubility enhancerEthanol (8.23% w/w)—solventAnhydrous citric acid (2.88% w/w)preservativeHPMC E5 (1.64% w/w)—coatingPawar et al., 2012

From: Hussar, Merck Manual, Consumer version

Liver Enzymes & Drug Metabolism Most drugs, other chemicals that enterthe blood are metabolized by the liver Although metabolism typicallyinactivates drugs, some drugmetabolites are pharmacologicallyactive—sometimes even more so thanthe parent compound Drug (or active herbal compoundmetabolism) by the liver and body’scells—the goal is to make the drugeasier to excrete

Differences in Drug Metabolism—People PM means poor metabolizer EM means extensive metabolizer, which is thenormal or usual phenotype URM means ultra-rapid metabolizer Approximately 7% of the U.S. population has agenetic defect in CYP2D6 that results in a poormetabolizer phenotype people that have usual drug metabolizing ability(EM) can become phenotypic poor metabolizersif they are given a substance (drug or food aswe will see later) that inhibits the enzyme

Active constituent metabolism—elderly With aging, the liver’scapacity for metabolismthrough the CYP450enzyme system isreduced by 30% Drugs reach higherlevels and haveprolonged half-lives inthe elderlyLe--Overview of Pharmacokinetics

Food-Drug Interactions (grapefruit) affectingBioavailability serum drug levels– furanocoumarins from grapefruit juice such as bergamottin can causeirreversible inhibition of the cytochrome P450 enzyme, CYP3A4– resulting in an increase in systemic exposure, leading to adverse drugreactions and toxicity– flavonoids in grapefruit juice, naringin and hesperidin, reducebioavailability of some drugs (Dolton et al. 2012).– Inhibition of CYP3A4 is irreversible and it can last for longer than 3days after ingestion of grape fruit juice until new enzyme has beensynthesized in the gut wall (Pirmohamed 2013)

Herbs are not Drugs Animals co-evolved withplants for millions of years! A drug’s action is affected bythe quantity of drug that reachesthe receptor and the degree ofattraction (affinity) between itand its receptor on the cell’ssurface. Herbs have many weakerchemicals that bind toreceptor sites on and in cells They usually are not astightly-binding as drugs thatare specifically designed tobind and have a dramaticeffect

Herbal inhibitors—Cytochrome P450 EnzymesSource: Foti & Wahlstrom, 2008. role of dietary supplements in cytochrome P450-mediated drug interactions

Herbs Affecting P450 EnzymesSource: rs

St. John’s Wort Induces CYP3A CYP3A is responsible for metabolizing thegreatest number of marketed drugs Inhibitors of CYP3A– Grapefruit juice– Some pharmaceutical drugs (antifungals,erythromycin) Inducers of CYP3A– St. John’s wort– Mean plasma concentration time course of indinavirin 8 healthy volunteers with indinavir alone or aftertaking indinavir with St. John’s wort.1 (57% reductionin AUC)

St. John’s wortSt. John’s wort has effects on the cytochromeP450 system (induction of CYP 3A4 and 2C9)as well as the major drug transport protein – PglycoproteinEffect of SJW on drug metabolism of Xanax (14-dayadministration (JAMA. 2003. 290:1500-1504.

Kava—Hepatotoxicity?Source: Henderson et al., 1999. Phytomedicine 11(4):285.

Traditional Herbal Formulas—Absorption Traditional herbal formulas in traditional Chinese medicine(for instance) often includes 3-12 different herbs– Some are used to enhance the bioactivity of major actives– Also to act on different aspects of a disease process or symptom For instance, URI—antiviral, enhance host immunity, relieve symtpoms– Some are added for flavor and taste (“harmonize”)– Other herbs can reduce toxicity– Others are added to enhance bioavailability of actives Studies show that in the presence of anthocyanins, other compounds, themajor actives are better absorbed!

Examples of traditional formulas thatinclude bioavailability enhancers Fu gan feng (contains active hepatoprotective compoundsthat are better absorbed within the context of the formula San huang xie xin tang (rhubarb and coptis tea pills)– Rhein, known active bowel-enhancer is better absorbed—in therhubarb herb, but even more from the formula

Pharmacokinetics, Pharmacodynamics of majorcompounds from Fugan Fang (tx hepatic diseases) Fugan Fang (FGF) is an effectivetraditional Chinese medicine (TCM)prescribed for the clinical treatmentof hepatic diseases Pharmacokinetic parameters of–calycosin-7-O-β-D-glu (isoflavone) Hormone modulator, phytoestrogen– ononin (isoflavone) Hormone modulator, phytoestrogen– gentiopicroside (iridoid glycosides) Bitter, digestive enzyme activator, immune– Sweroside (iridoid) Bitter, digestive enzyme activator, immune– ferulic acid (phenolic acid) Abundant in fruits, veggies, mint familyPotent antioxidant, antiinflammatory– p-coumaric acid (phenolic acid) Immunomodudlator, antiinflammatory

Pharmacokinetics of Rhubarb Actives Cofactors increase absorption of rhein San-Huang-Xie-Xin-Tang (SHXXT) Coptis and rhubarb tea pills Contains coptis stem, rhubarb root,scute Root (Scutellaria baicalensis) Chinese patent for treating constipation Conclusion: “the herbal formulae(SHXXT) are more efficient than thesingle herb (rhubarb) or the purecompound (rhein) in rhein absorption”Hou et al., 2014

Pharmacokinetics of CurcuminPawar et al., 2012

Products

Commercial Products--Issues FDA does have regulatory controlover dietary supplements Claims and quality are mainconcerns Still, some unproven ingredients aremarketed No licensure required, like Canada,most European countries Products should meet GNPs,identity, purity, potency, consistency Still some problems withsubstitution, reduced actives, testing,purity, but many improvements made

Tinctures vs. powdered extractsMaltodextrin and other “Carriers” Tinctures vs. powdered extracts– Tinctures Cold process, increasedabsorption, good shelf life Some “farm to bottle” - Contains alcohol, highly diluted– Powdered extracts Up to 25x more concentrated -Extraction can hide poor quality,filth Fillers have to be tested for Carriers are often necessary,but they can also be “fillers” They become fillers when inexcess for the purpose ofhelping the ingredient to “flow”and to help avoid cakingbecause ingredients are toohydroscopic

Selecting the Best Preparation–AbsorptionPreparation Extractionof activesTeasgoodexcellentTinctures excellentBioavailability Potencyof activesgood-excellent good, depends onextraction timeexcellentFair (1:5 extract)TabletsgoodexcellentgoodCapsules should 3 years good, sizecontain extracts, notof tablet,powders (4:1, 5:1)coatingmoreconcentratedthan capsulesSyrupsgoodgoodfair-goodmay containalcohol, oodgood-excellent Capsules shouldcontain extracts, notpowders (4:1, 5:1)Shelf-life Compliance Notes2-4 daysin 'fridgeca. 3years 1 year 1 year 2 od 2 years good,dependson tasteshortgoodSelf-made, takestimecontains alcoholexternalexternalcheck extractionratio andstandardizationmake a strongtea, add to bath

Quality—a course in itself GIGO (herb quality)– cultivated, “wild”– Parts collected (barks, roots)– How processed, dried, stored Fumigation, other chemicals Storage of herbs (years?) Extraction (solvents?) Standardization Manufacturing process Spiking, purity Maltodextrin levels Micro

Standardization Plants vary considerably in types and levels of actives Identify known actives Doesn’t lead necessarily to purification and isolation ofactive constituents Insure sufficient and consistent levels based on studies Stability Recommended dose should follow clinical trials “pixie dust” effect

StandardizationQuality Assurance of Phytopharmaceuticals Growing methods Harvesting, processing Identification Determination ofactive compounds Purity considerations Product manufacture Efficacy, safety testing

Current Problems with Quality, Efficacy Farm to medicine chest? Dose—not enough actives– Tinctures (1:5), dry-weight basis Powdered extracts– 5:1, but often cut with maltodextrin Identification– Species ID DNA vs. chromatography Microscopic, organoleptic

Dose and Dosage Dose depends onconcentration of the herbsin the product–––––level of active constituentsTinctures from fresh herbs from dried herbsDried herbs in capsulesPowdered extracts usingwater, alcohol, othersolvents (acetone, hexane) TCM, average dose– Single herb in a blend 5-20 g– 3-15 herbs in a blend (5-10 typical)– Typically in decoction, or waterextracted tea pills– Some alcoholic extracts, typicalysingle herbs Western herbs– Dose and dosage varies widely

Dose and Dosage Regimen Adjust for body weight, age Adjust for patient vitality,sensitivity, age Consider level of purification andconcentration Most constituents are usually atactive levels in serum between0.75-6 hours Usually take herb capsules, tabletswith meals, b.i.d., morning andevening (compliance) Curcumin pharmacokinetics—rapidglucoronidation by liverAnand et al., 2007

Storage of chemicals in Cell

Cell Compartments

Four Major Chemical PathwaysFatty AcidsTerpenesPhenylPropanoidsAlkaloidsCinnamic acidPhenolic sLignin

Shikimic Acid Pathway—Phenolics, AlkaloidsSalicylatesSerotonin, insFlavonoidsAnthocyaninsTannins

Terpenes, Mevalonic PathwayEssential Oils Complex mixtures of monoterpenes (middle notes,moderately volatile), esters (high notes, very volatile),sesquiterpenes (low notes, not too volatile Some essential oils contain several hundred identifiedcompounds Families commonly containing essential oils include theparsley family (Apiaceae), mint family (Lamiaceae), laurelfamily (Lauraceae), and the eucalyptus family Essential oils penetrate the skin, are used topically asantiinflammatory and antimicrobial agents, internally asmild sedatives (lemon balm, chamomile), antiinflammatoryand antispasmodics (chamomile, yarrow) and flavoringredients

Further Reading Best book:– Pharmacognosy—the study of herbal “drugs”– Fundamentals of Pharmacognosy and Phytotherapy, Barnes et al, 2012 ( 40, Kindle edition, 50)Potter’s Herbal has a concise review of major constituents found in most medicinal plants:– Bruneton J. Pharmacognosy, Phytochemistry, Medicinal Plants. 2 nd ed. Paris, France: Technique &Documentation-Lavoisier, 2005, 487–9. (Order from www.herbalgram.org) Pricy, but great! ( 122)Potter’s New Cyclopaedia of Botanical Drugs and Preparations. Williamson, E.M., Evans, F.J.London: C.W. Daniel Company Ltd. tgeog/utvatlas/index.html (online flora forUtah)

Pharmacokinetics—Practical Aspects Absorption co-factors– Phenolic compounds– Spicy foods Black pepper Ginger Cinnamon– Glycoside form? Sugars attached, higher water-solubility

Herbal Bioenhancers Black pepper extract (Piperidine) Phospholipid (Phosphatidylcholine) Quercetin (onion) Ginger Cumin Licorice Naringin (grapefruit only)(Dudhatra et al., 2012)

Herbal Liposomal FormulationsSource: Kesarwani & Gupta, 2013

Microspheres—between 0.1 and 100 μm in sizeSource: Kesarwani & Gupta, 2013

Nanoparticles—between 1 and 100 nm (under 0.1 μm)Source: Kesarwani & Gupta, 2013

Transferosomes—Lipophilic vesicles containing a hydrophilic drug as a delivery system Transferosomes are a special type of liposomes, consisting ofphosphatidylcholine and an edge activator. They are softmalleable vesicles tailored for enhanced delivery of activeagents. The reason for using vesicles in transdermal drug delivery isbased on the fact that they act as drug carriers to deliverentrapped drug molecules across the skin, as well as penetrationenhancers because of their composition. Avoid liver metabolismSource: Kesarwani & Gupta, 2013

Lipid-based herbal formulations (with a phospholipid)Source: Kesarwani & Gupta, 2013

Examples—How to increase blood levels Phytosomes, liposomes Black pepper extract (piperine) Liver metabolism modulators Micro-, nanoencapsulation––––GinkgoCurcuminMilk thistleGreen tea (ECGC)

Phytosome vs. Liposome

Pharmacokinetics of Gingko-Phytosome Ginkgolide A, GinkgolideB and Bilobalide 12 healthy volunteers Oral, 60 mg standardized Taking with mealsincreases Tmax, but notAUC quantitatively(Fourtillan et al., 1995)Mauri P, et al. 2001. Liquidchromatography/atmospheric pressurechemical ionization mass spectrometry ofterpene lactones in plasma of volunteersdosed with Ginkgo biloba L. extracts, RapidCommun. Mass Spectrom. 15, 929-934. Elimination half-lives varyin the 3 compounds (4.5,10.57, 3.21 h)

PharmacokineticsGreen tea EGCG and Milk Thistle, PhytosomesHealthy volunteersTime course of epigallocatechingallate (EGCG) after ingestionof Greenselect andGreenselect Phytosome (Pietta et al., 1998)Patients withcirrhosisSchreiber et al.,2008.

Curcumin from Turmeric Curcumin is very poorly absorbedorally, and the liver metabolizeswhat is absorbed rapidly to a moreinactive form Products aim to increase absorptionand slow liver metabolism– Phospholipid complexes– Microencapsulation, nanoencapsulation– Complex with black pepper extract(piperidine)

Curcumin blood levels with nanoemulsion

Curcumin micelles--absorptionHsieh et al., 2014. Oral intake of curcumin.

Curcumin and BioperineCurcumin bloodconcentration (in humanswith oral administration)Anand et al., 2007

Chitosan coated curcumin nanocrystalsfor the treatment of sepsis chitosan coated curcuminnanocrystals (Chi-CUR-NC-4b) parenteral therapeutic approachagainst endotoxemia-induced sepsis curcumin-bearing nano-formulationcould serve as a valuable option forthe therapeutic intervention of sepsisand associated hyper-inflammatorydisorders.(Shukla et al., 2015)

Solubility of curcumin powdervs. nanocrystals Free curcumin (a) Curcumin nanoparticles (b)Ravichandran, 2013

Traditional delivery systems Traditional way to useturmeric and enhanceabsorption Curry! Stir-fry veggies, meat, andspicesJim Duke:“I’d rather enjoy my medicine!” Heat, bio-enhancers(pepper, ginger), oil

Blood levels of 4 related compoundsfrom TCM Formula Lonicera japonicaIsatis indigoticaRheum palmatumPhellodendron chinenseScutellaria baicalensis Significant pharmacokineticdifferences were observedbetween the Africa

Pharmacokinetics & Pharmacodynamics of Herbal Active Constituents 1. First, the active constituents need to be identified, characerized 2. First, the active constituents have to be absorbed 3. Second, the ingredients in supplements or herbs need to have active constituents 4. The product has to have enough of the ingredients that have

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