By A. Sancho. Denver Seminary.

Sometimes it is also dependent of the plant culture conditions and the season of harvest quality 10 mg torsemide blood pressure zetia. In the drug industry order 10mg torsemide arrhythmia and palpitation, especially, the extract must be concentrated and the active material isolated by selective precipitation, chromatography, electrophore- sis, etc. Solvents have to be carefully chosen, not only for their extraction proper- ties, but also for their compatibility with the final formulation and their harm- lessness. Selective Extracts Special extraction processes or the use of specific solvents will lead to the obten- tion of a specific class of molecules. The fragrance industry has for centuries obtained essential oils or floral water by water vapor extraction or ‘‘enfleurage’’—a process by which the plant flowers are put in contact with solid fats and terpens and sesquiterpens migrate into the oil phase. The use of vegetable oils as solvent allows for the extraction of oil-soluble vitamins or lipids. Purification Extract purification to separate specific molecules from others are done following classic physicochemical processes—cryoprecipitation, column chromatography, electrophoresis, use of selective solvents and salts, etc. Biotechnology Extracts Biotechnology can be used to obtain, purify, or transform extracts. One can find different enzymes to be used for very specific reactions in certain conditions. They could become an alternative to chemical reactions as they provide stereospecificity or eliminate the risk of solvent residues. Today, protein hydrolysates obtained by enzymatic 100 Khaiat reaction are free of the chlorine residues formed when acid hydrolysis is used. In addition, the use of exo-, endo-, or amino-acid-specific proteases allows for a better control of the end result. Enzymes will allow for better yields by transforming or releasing specific molecules (use of pectinases, β-glucosidase, β-glucanase, lipases, transferases, esterases, etc. Amino acids, polyols, esters of fatty acids, polyol organic acids, more stable liposoluble vitamin esters with slow release properties, and new molecules (5) can be obtained. Usage Extracts or purified botanical molecules can be incorporated directly into solu- tions, emulsions, or vectors or can be used to form a vector (liposomes, phyto- somes, phytospheres) (6). They can be topically applied, ingested, or injected, depending on the intended use and provided absence of toxicity has been shown. For example, lilium bulb oil extract use for sunburns has been reported since ancient Greece, while the water extract has been shown to be toxic. Natural ingredients have been shown to have a broad spectrum of activity, including hallucinogenic mushrooms and cardiotonic belladona. Scientific research conducted on plant extracts described in traditional pharmacopeas (7,8) has led to a broader range of potential applications. Furthermore, research conducted during the last 10 years on skin biology allows us to better understand the biological mechanisms involved in dehydra- tion, aging, etc. This, in turn, leads to the search for extracts with specific activi- ties for targeted applications. Antioxidants Free radicals have been shown to play a major role in sun damage as well as in aging or in pollution (tobacco, stress). Free radical actions can be blocked by the following Vegetable oils rich in tocopherols and tocotrienols. Wheat germ oil and palm oil are particularly rich in tocopherols and α-, β-, γ-tocotrienols. Carotenoids, such as β-carotene, found in plants or in part of plants ex- posed to the sun. However, under extreme conditions (high salinity, low pH, high sunlight, lack of nitrogen or phosphorus), they protect themselves by multiplying their β-carotene concentration by 10. The ponds become red, and the β-carotene concentration can reach 14% of their dry weight. As first shown by Kligman (10), the action of retinoids and carotenoids (11) on sun damage has led to numerous works.

Nevertheless cheap 20 mg torsemide with visa blood pressure 3060, studies in Asia of women who eat whole and fermented soy show reduced symptoms of low estrogen purchase torsemide 20 mg amex hypertension obesity, such as fewer hot flashes, and lower rates of breast cancer and osteoporosis. Perhaps, like me, you’re wondering why the paradox: why do Japanese women, whose diets compared with American women seem to favor lower estradiol levels, demonstrate fewer symptoms of low estrogen? Scientists hypothesize that the paradox relates to the higher consumption of whole soy. Soy is structurally similar to estrogen, so it makes sense that it acts like a weak estrogen in the body. One large meta-analysis, in which several studies are combined to address a particular question, showed that consuming soy brought no change in estradiol levels in premenopause and a small increase in estradiol after menopause. At present there’s insufficient support that dietary soy and extracts improve hot flashes or night sweats. Perhaps there are significant differences in how the various soy products and extracts show up in the body, or perhaps different ethnic groups are genetically programmed to handle soy differently, or perhaps all of the above. Try adding fresh organic tofu to your salad or stir-fry; sauté it in olive oil with fresh herbs and garlic for a light side dish. Flaxseeds contain lignans, one of the major classes of phytoestrogens, which are estrogenlike chemicals that also serve as antioxidants. One study showed that eating 2 tablespoons of flaxseeds twice per day (approximately 30 grams total) for six weeks reduced hot flashes—a key symptom of low estrogen— by half, and diminished the intensity by 57 percent. Because flax also offers a good dose of fiber (at about 8 grams of fiber in 4 tablespoons), I believe, despite the need for more data, that flaxseeds are a healthful addition to your diet if you’re low in estradiol. Female orgasm and sexual stimulation raise estradiol levels in women who are premenopausal. Orgasm raises oxytocin, which works with estrogen in the female body to buffer stress and lower cortisol, and help women feel more connected and loving. One practice that I prescribe is Orgasmic Meditation, a combination of Buddhist practice and orgasm. Anecdotally, women who practice Orgasmic Meditation have fewer symptoms of low estrogen after menopause than women who do not. Women who are overweight can actually increase their vasomotor symptoms—such as hot flashes and night sweats—if they do too hard a workout. If you are overweight or prone to injury, it’s better to walk briskly than to run; to jog one mile three times a week instead of six miles four times a week; to spin or bicycle at a moderate speed. Acupuncture has been shown to raise estradiol levels, although not sufficiently to help with vaginal dryness or bladder infections. It does reduce hot flashes, and it may be as effective as hormone therapy when acupuncture is combined with the Chinese herbal medicine Kun Boa Wan. Some women in menopause swear by pomegranate in one form or another for the treatment of symptoms of low estrogen. One trial showed that pomegranate seed oil at a dose of 30 mg twice per day for twelve weeks reduced hot flashes significantly, although the placebo treatment did as well. However, twelve weeks after treatment was completed, hot flashes were significantly improved in the pomegranate group but not the placebo group, suggesting a real effect. The oldest remedy in the book for certain symptoms of low estrogen, including hot flashes, vaginal dryness, and mood swings, is vitamin E. According to one study, supplementing with vitamin E was shown to increase blood supply to the vaginal wall and improve menopausal symptoms. Among breast cancer patients, magnesium was shown to reduce hot flashes, fatigue, and distress, all common symptoms of low estrogen. Higher doses can cause loose bowels, though, so check with your doctor before going beyond 400 mg per day. The magical herb maca (Lepidum meyenii) has consistently been shown to increase estradiol in menopausal women, and helps with insomnia, depression, memory, concentration, energy, hot flashes, and vaginal dryness, as well as improved body mass index and bone density. Maca has a malty taste that I prefer to mask with 1 to 2 tablespoons of raw cocoa powder in my smoothies for breakfast.

Moldy foods (pasta) and lunch meats (benzopyrenes) were the source of liver toxicity safe torsemide 20 mg hypertension 2014 guidelines. Each new Salmonella attack immediately invaded the liver so a vicious cycle was set up discount torsemide 20 mg fast delivery arteria3d mayan city pack. Perhaps in two years the liver will have recovered enough to kill Salmonella that enter it, but she is not taking any chances till then. Although Kristen was eating food polluted with both Sal- monellas and Shigellas she only “picked up” Salmonella, never Shigella! It is caused by fluke parasites reaching the brain or spinal cord and attempting to multiply there. All meats are a source of fluke parasite stages unless canned or very well cooked. Pets and family members are undoubtedly carriers of the same flukes, although they do not show the same symptoms. The most important question you must be able to answer is why did these parasites enter your brain and spinal cord? Evidently these solvents accumulate first in the motor and sensory regions of the brain, inviting the parasites to these locations. Your brain is trying desperately to heal these lesions, only to be assailed by a fresh batch of solvent and Shigellas and another generation of parasites and pathogens. The mercury that is constantly released in the mouth does not all get excreted by the kidneys or eliminated by the bowels. You will be able to eliminate and excrete more mercury by doing a kidney and liver cleanse. For this reason mercury removal should be done extra thoroughly to be sure no thallium has been left behind. Or pur- chase pork brains at the grocery store and snip out a portion of the sensory lobe and cerebellum. Also test for parasites, bacteria (especially Nocardia and Shigella) and other pollutants such as arsenic and pesticides. If the disease (tremor and lack of sensation) has not progressed too far, you can cure it. In all cases you can stop it from progressing further by cleaning up dentalware, the environment and diet. Our tests showed her brain was full of scandium (tooth metal alloy) and fluoride (toothpaste). She had several bacteria growing in her jaw bone: Strep G (sore throat bacteria), Staphylococcus aureus (this was raising her pulse to over 100), Clostridium tetani (causes great stiffness), and Shigella (produces nerve toxins). She was put on the parasite program plus thioctic acid (2 a day) and histidine (500 mg, one a day to keep nickel levels down)and advised to cook and eat with non metal. A half year later she was walking and working normally, doing liver cleanses and keeping up her vigilance against parasites and pollutants. She went to a chelating doctor and this cleared up her temporary ischemic attacks (T. But she had lost her balance, eyesight was getting worse, her feet and hands stung. These are dental alloys, al- though barium could come from bus exhaust (she wore no lip- stick). She stated she was afraid to stop her new health program, though, and this was good policy. She had intestinal flukes and stages, human liver flukes and Trichinella in the brain. She also had propane and asbestos in her brain from leaky pipes and a worn washing machine belt. They eagerly removed the platform, found the oil on the water surface, cleaned everything up carefully, until no benzene could be found which put her on the road to recovery. Norma Luellen, a young mother, had tingling, numbness and weakness on the entire left side of her body. She had intestinal flukes and their stages, not in the intestine or liver or thymus, but in her brain!

Anatomical evidence can also be presented to support the concept of presynaptic inhibition and examples of one axon terminal in contact with another are well documented buy generic torsemide 20 mg line prehypertension la gi. The electromyograph from the anterior nuclear complex of the adult rat thalamus shows two terminals 1 and 2 establishing synaptic contact on the same dendrite generic 10 mg torsemide with mastercard blood pressure zero gravity. Asymmetric synapses are 1±2 mm long with a 30 nm (300 A) wide cleft and very pronounced postsynaptic density. Symmetric synapses are shorter (1 mm) with a narrower cleft (10±20 nm, 200 A) and although the postsynaptic density is less marked it is matched by a similar presynaptic one. The presynaptic vesicles are more disk-like (10±30 nm diameter) the shape of the presynaptic vesicle is of particular interest because even if the net result of activating this synapse is inhibition, the initial event is depolarisation (excitation) of the axonal membrane. In the lateral superior olive, antibody studies have shown four types of axon terminal with characteristic vesicles (Helfert et al. In smooth muscle the noradrenergic fibres ramify among and along the muscle fibres apparently releasing noradrenaline from swellings (varicosities) along their length rather than just at distinct terminals. In the brain many aminergic terminals also originate from en passant fibres but it seems that not all of them form classical synaptic junctions. The fact that vesicular and neuronal uptake transporters for the monoamines can be detected outside a synapse along with appropriate postsynaptic receptors does suggest, however, that some monoamine effects can occur distant from the synaptic junction (see Pickel, Nirenberg and Milner 1996, and Chapter 6). For further details on the concept of synaptic transmission and the morphology of synapses see Shepherd and Erulkar (1997) and Peters and Palay (1996) respectively. The system is fitted for the induction of the rapid short postsynaptic event of skeletal muscle fibre contraction and while the study of this synapse has been of immense value in elucidating some basic concepts of neurochemical transmission it would be unwise to use it as a universal template of synaptic transmission since it is atypical in many respects. There are also positive and negative feedback circuits as well as presynaptic influences all designed to effect changes in excitability and frequency of neuronal firing, i. Such axons have a restricted influence often only synapsing on one or a few distal neurons. The axons, especially the very long ones, show little divergence and have a relatively precise localisation, i. Distinct axo-dendritic type I asymmetric synapses utilising glutamate acting on receptors (ionotropic) directly linked to the opening of N‡ channels are common and a these systems form the basic framework for the precise control of movement and monitoring of sensation. Such pathways are well researched and understood by neuro- anatomists and physiologists, but their localised organisation makes them, perhaps fortunately, somewhat resistant to drug action. Since these interneurons exert a background control of the level of excitability in a given area or system their manipulation by drugs is of great interest (e. Although intrinsic neurons can only have a localised action they may be influenced by long-axon inputs to them and so incorporated into long pathway effects (Fig. The tonic background influence of these systems and their role in behaviour have instigated the development and study of many drugs to manipulate their function. It also seems that the cholinergic input into the cortex from subcortical nuclei can also be included in this category (see Chapter 5). Of course, while the identification of these distinct systems may be useful there are many neural pathways that would not fit easily into one of them. The dopamine pathway from the substantia nigra to striatum may start from a small nucleus but unlike other monoamine pathways it shows little ramification beyond its influence on the striatum. The object of the above classification is not to fit all neural pathways and mechanisms into a restricted number of functional categories but again to demonstrate that there are different forms of neurotransmission. It could unfold a whole new requirement and dimension to our understanding of synaptic physiology and pharmacology and the use of drugs. On the other hand, it may be of little significance in some cases for although cholinergic-mediated nicotinic and muscarinic responses as well as dopamine and peptide effects are observed in sym- pathetic ganglia, it is only nicotinic antagonists that actually reduce transmission, acutely anyway. All are required for a perfect picture but some are obviously more important than others. While the mechanism of their release may be similar (Chapter 4) their turnover varies. Such processes are ideally suited to the fast transmission effected by the amino acids and acetylcholine in some cases (nicotinic), and complements the anatomical features of their neurons and the recepter mechanisms they activate. By contrast, the peptides are not even synthesised in the terminal but are split from a larger precurser protein in the cell body or during transit down the axon. They are consequently only found in low concentrations (100 pmol/g) and after acting are broken down by peptidases into fragments that cannot be re-used.

Molecular modeling of cytochrome P450 2B1: mode of membrane insertion and substrate specificity buy torsemide 10mg visa hypertension jokes. Probing the active site of cytochrome P450 2B1: metabolism of 7-alkoxycoumarins by the wild type and five site-directed mutants torsemide 20 mg low cost arrhythmia heart disease. Reassessment of cytochrome P450 2B2: catalytic specificity and identification of four active site residues. Site-directed mutagenesis as a tool for molecular modeling of cytochrome P450 2B1. Structure-function analysis of human cytochrome P-4502B6 using a novel substrate, site-directed mutagenesis, and molecular modeling. Metabolism of sirolimus and its derivative everolimus by cytochrome P450 3A4: insights from docking, molecular dynamics, and quantum chemical calculations. Direct interaction between substrates and endogenous steroids in the active site may change the activity of cytochrome P450 3A4. Structure-function relationships of human aromatase cytochrome P-450 using molecular modeling and site-directed mutagenesis. Construction of a model of the Candida albicans lanosterol 14-alpha-demethylase active site using the homology modelling technique. Membrane-protein interactions contribute to efficient 27-hydroxylation of cholesterol by mitochondrial cytochrome P450 27A1. X-ray structure of nitric oxide reductase (cytochrome P450nor) at atomic resolution. Improvements in protein secondary structure prediction by an enhanced neural network. A new method for building protein conformations from sequence alignments with homologues of known structure. Deviations from standard atomic volumes as a quality measure for protein crystal structures. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. A general and fast scoring function for protein-ligand interactions: a simplified potential approach. Further development and validation of empirical scoring functions for structure-based binding affinity prediction. Background The gastrointestinal mucosa represents a major physical and metabolic barrier to the systemic availability of orally ingested drug molecules. A critical component of that barrier is a collection of drug-metabolizing enzymes localized primarily at the apical aspect of the intestinal epithelium. The liver is generally considered to be the dominant site of drug metabolism, but it is now clear that for a number of drug molecules (e. Indeed, some prodrugs have been developed that take advantage of the enzy- matic activity of the intestinal mucosa (e. It has also been suggested that a functional interaction occurs between P-gp and meta- bolic enzymes at the apical interface of the mucosa that increases the resi- dence time of a drug molecule and results in enhanced first-pass metabolism at the intestine. It stands to reason that modulation of intestinal drug-metabolizing enzyme and efflux transporter function could constitute a mechanism of drug-drug interaction. In this chapter, we review the expression and localization of intes- tinal enzymes and transporters that have been implicated in metabolically based drug-drug interactions and the pharmacokinetic characteristics of those interaction events. Pharmacokinetic Principles If a metabolically based drug-drug interaction is to have clinical significance, the affected process of drug metabolism must represent an appreciable part of the overall drug elimination scheme. In the case of intestinal metabolism, it is the fraction of a dose metabolized by the gut mucosa on first pass (Egm) that is most relevant. In general, intestinal mucosal enzymes that contribute significantly to the first-pass metabolism of a drug have a much lower contribution to the sys- temic clearance of the same molecule because of the relatively low blood flow to enterocytes that express drug-metabolizing enzymes (1,2). Thus, important drug interactions involving gut metabolism will generally be associated with drugs that have an appreciable first-pass intestinal extraction. In the context of first-pass metabolism after oral administration, it is important to define in what region of the gastro- intestinal tract the majority of the drug dose will be absorbed when assigning 474 Thummel et al. Figure 1 Physiological model for sequential intestinal and hepatic first-pass metabolism. Blood flow to the small intestine is functionally divided into mucosal (Qgm) and serosal (Qgs) blood flow.

Particle size: wet/dry sieve analysis; optical microscopy; laser diffraction; sedimentation buy 10mg torsemide mastercard pulse pressure vs stroke volume. A pearlescent material should have a smooth surface to allow specular reflection and be nontoxic cheap 20mg torsemide otc arrhythmia medication. Generally, the most transparent formulation of pearlescent pigments should be used and grinding or milling the pearl pigments should be avoided, and pearls that comple- ment one another should be blended. Organic Pearls These pearls produce a bright silver effect and can be obtained from fish scales as platelets or needles that are highly reflective. The materials responsible for the pearl effect are crystals of a purine called guanine. Bismuth oxychloride produces a silvery–gray pearles- cent effect and is synthesized as tetragonal crystals. Crystal sizes vary from ap- proximately 8 µm, which gives a soft, opaque, smooth luster and 20 µm, which give a more brilliant sparkling effect. Its major disadvantage in use is poor light stability that may cause darkening after prolonged exposure. Inorganic pigments may 288 Schlossman be bonded to BioCl and then deposited on mica. They exist in several different forms: (1) Silver–titanium dioxide uniformly coats platelets of mica: rutile crystals give a brilliant pearl effect because of a higher refractive index than the anatase grade. At a certain thickness, interference of light can take place so that some wavelengths of the incident light are reflected and others transmitted. As the layers become thicker, the reflec- tion goes from silvery white, to yellow–gold, red, blue, and green. Additionally, colorants such as iron oxides can be laminated with this interference film provid- ing a two-color effect. Pigment Pearls Colored pearls are produced by laminating a layer of iron oxides on titanium dioxides–coated mica producing a color and luster effect. Specialty Pigments In addition to BioCl and the titanium dioxide–coated mica systems, polyester foil cut into regular shapes which have been epoxy coated with light-fast pigments have been used for nail enamels and body makeup. Finally, aluminum powder and copper/bronze powder have been used as reflective pigments, especially in eye shadows. For cosmetic use, as in aluminum powder, 100% of the particles must pass through a 200 mesh screen; 95% must pass through a 325 mesh (44 millimicron) screen. The benefits of using these treat- ments may be divided into two categories: those evident in the finished cosmetic product, and the benefits derived from process improvements. Consumer benefits include hydrophobicity yielding greater wear, improved skin adhesion, smoother product feel, improved optical appearance, moisturization, and ease of applica- tion. Processing benefits include ease of dispersion, pressability, less oil and moisture absorption, and uniformity. The following surface treatments are commercially available: Amino acids: N-Lauroyl Lysine, acyl amino acid (11): natural; good skin adhesion; pH balanced; heat-sensitive. Decorative Products 289 Fluorochemical: perfluoropolymethylisopropyl ether perfluoroalkyl phos- phate: hydrophobic and lipophobic greatly enhance wear; heat and shear resistance. Lecithin (12): natural; exceptionally smooth, silky skin feel, particularly in pressed products; heat-sensitive, slightly soluble in water. Natural wax: natural; moisturizing skin feel; good skin adhesion; heat- sensitive (low m. Polyacrylate: enhanced wetting in aqueous systems; feel is not very good, but is usually used in dispersion. Polyethylene: hydrophobic; waxy, smooth skin feel; enhanced compress- ibility; heat sensitive. Silicone (polymethylhydrogensiloxane): methicone will be chemically bonded and cannot be removed later; hydrophobic; achieves full color development; main use is to improve wetting. Other silicones: no potential for hydrogen evolution; dimethiconol; ab- sorbed dimethicone; silicone/lecithin. Titanate ester: isopropyl triisostearyl titanate (13): enhances wetting in oil; smooth skin feel; high pigment loading; lowers oil absorption of pig- ments. With microfine pigments, formulations for darker skin tones can be formulated which avoid the ‘‘ashy’’ or ‘‘made-up’’ appearance caused by conventional opaque pigments. Purpose: improve appearance; impart color; even out skin tones; hide im- perfections; protection. Powder The term powdered cosmetics are generally used to describe face powders, eye- shadows, and blushers.

In vitro stimulation of warfarin metabolism by quinidine: increases in the formation of 4 -0 and 10-hydroxywarfarin order 20mg torsemide amex prehypertension 135. Activation of human cytochrome P-450 3A4-catalyzed meloxicam 5 -methylhydroxylation by quinidine and hydroquinidine0 in vitro buy torsemide 10mg without prescription blood pressure varies. Inhibitory monoclonal antibodies to human cytochrome P450 enzymes: a new avenue for drug discovery. Role of a potent inhibitory monoclonal antibody to cytochrome P-450 3A4 in assessment of human drug metabolism. Effect of albumin on the estimation, in vitro, of phenytoin Vmax and Km values: implications for clinical correlation. Effect of albumin on phenytoin and tolbuta- mide metabolism in human liver microsomes: an impact more than protein binding. Purification of two isozymes of rat liver microsomal cytochrome P450 with testosterone 7 alpha-hydroxylase activity. Expression and characterization of func- tional dog flavin-containing monooxygenase 1. Extrahepatic metabolism of carbamate and organophosphate thioether compounds by the flavin-containing monooxygenase and cytochrome P450 systems. In vitro drug interaction between diflunisal and indomethacin via glucuronidation in humans. Rifampin induces alterations in myco- phenolic acid glucuronidation and elimination: implications for drug exposure in renal allograft recipients. In vitro-in vivo correlation for drugs and other compounds eliminated by glucuronidation in humans: pitfalls and promises. Glucuronidation of thyroid hormone in rat liver: effects of in vivo treatment with microsomal enzyme inducers and in vitro assay conditions. In vitro glucuronidation using human liver microsomes and the pore-forming peptide alamethicin. Species differences in the urinary excretion of the novel primary amine conjugate: tocainide carbamoyl O-beta-D-glucuronide. Characterization of a carbamic acid ester glucuronide of the secondary amine sertraline. Metabolism and disposition of novel des- fluoro quinolone garenoxacin in experimental animals and an interspecies scaling of pharmacokinetic parameters. Metabolite profile of sibutramine in human urine: a liquid chromatography-electrospray ionization mass spectrometric study. Metabolism and disposition of varenicline, a selective alpha4beta2 acetylcholine receptor partial agonist, in vivo and in vitro. Sertraline is metabolized by multiple cyto- chrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study. Thakker The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U. Certainly one major reason that transporters have become a key area of research that continues to grow involves the efflux pump, P-glycoprotein (P-gp). The ‘‘P’’ in P-gp stands for permeability, as this efflux transporter was found to reduce the permeability of a wide variety of chemically unrelated cell per- meable substrates. Subsequent to the recognition of P-gp’s role in cancer, P-gp was found to be expressed in many normal tissues, namely, epithelial and endothelial barrier tissues (3,4). In this capacity, P-gp provides a biochemical mechanism to modulate the trafficking of endogenous compounds and drugs across these barriers, and this activity has been shown to influence the disposition of these compounds. Since the recognition of its role in limiting the oral absorption of certain drugs (5–10), P-gp has emerged as an important determinant of the oral bioavailability of drug molecules. For certain substrates, P-gp has been shown to be a determinant of elimination, playing a role in renal and biliary excretion (13,14). Recently, it has been shown that P-gp efflux activity can have a profound influence on the extent of metabolism (15–18).