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Upon react- ing this with a primary amine purchase metoclopramide 10mg mastercard, in particular isopropylamine buy metoclopramide 10 mg mastercard, the hydrogen atom in the imine region of the molecule is formally replaced with an alkyl group of the introduced amino group (in this case with an isopropyl group) discount metoclopramide 10 mg amex, forming the desired drug—clofazimine [54–56]. Clofazimine exhibits a bactericidal effect between that of dapsone and rifampicin. Therefore, antibac- terial antibiotics are, as a rule, ineffective against pathogenic fungi. However, that statement may be untrue for a few geographical regions that are favorable for the existence and growth of specific fungal pathogens. A few fungal infections can spread to the surface of the body and cause local disturbances, while others can be systemic and life threatening. Some of these organisms (for example, Candida) can spread from a superficial location to internal organs, leading to systemic diseases with serious complications. Fungal (mycotic) infections cause a lot of discomfort, and as a rule, are difficult to cure. Fungal infections are conventionally divided into three categories: dermatophylic, mucocutaneous, and systemic. The most widespread are dermatophytic fungal infections, which include skin, hair, and nails. Most infections can be cured by using topical drugs, such as tolnaftate, undecylenic acid, haloprogin, clotrimazole, and miconazole. Griseofulvin is used orally for deep infec- tions, in particular for infections of the nail bed. Mucocutaneous infections caused primarily by the fungus Candida albicans occur in regions of moist skin and mucous membranes (i. Amphotericin B, miconazole, clotrimazole, and nystatin are used topi- cally to treat such infections. Systemic fungal infections are very rare, although they do present a serious problem since they are naturally chronic and difficult to diagnose and treat. So, antifungal drugs are medications used to treat fungal infections such as athlete’s foot, ringworm, and candidia- sis (thrush) as well as serious systemic infections like cryptococcal meningitis. Antifungals work by exploiting differences between mammalian and fungal cells to kill the fungal organism and without significantly harming the host. From the chemical point of view, antifungal drugs can be divided into polyenes, imida- zole and triazole derivatives, allylamines, and others. The polyenes (nystatin, amphotericin B, natamycin) bind with sterols in the fungal cell wall, principally ergosterol. Human (and other animal) cells contain cholesterol rather than ergosterol so are much less susceptible. The imidazole and triazole groups of antifungal drugs (imidazoles: miconazole, ketoconazole, clotrimazole, econazole, mebendazole, butoconazole, fluconazole) inhibit the enzyme cytochrome P450 535 536 35. This enzyme converts lanosterol to ergosterol, and is required in fungal cell-wall synthesis. Allylamines (naftifine, terbinalfine, butenafine, amorolfine) inhibit the enzyme squalene epoxidase, another enzyme required for ergosterol synthesis. Others: Griseofulvin binds to polymerized microtubules and inhibits fungal mitosis. From the medical point of view, antifungal drugs are con- sidered dermatophytic, mucocutaneous, and systemic. Amphotericin B: Amphotericin B, [1R(1R∗,3S∗,5R∗,6R∗,9R∗,11R∗,15S∗,16R∗,17R∗, 18S∗,19E∗,21E∗,23∗,25E∗,27E∗,29E∗,31E∗,33R∗,35S∗,36R∗,37S∗)]-33-[3-amino-3,6- dideoxy-β-D-mannopyranosyl)-oxy]-1,3,5,6,9,11,17,37-octahydroxy-15,16,18-trimethyl- 13-oxo-14,39-dioxabicyclo [33. The antifungal activity of amphotericin B is exhibited because it binds with sterols, in particular with ergosterol in the cellular membrane of sensitive fungi. This reaction makes pores in the membrane and increases the perme- ability of the membrane to small molecules, thus reducing the function of the membrane as an osmotic barrier and making the cells more sensitive to being destroyed. However, this compound is not highly selective and reacts with host mammalian cells. Despite the many side effects, amphotericin B remains the primary drug for treating severe, acute systemic fungal infections. It is used for generalized fungal infections, such as can- didomycosis, aspergillosis, histoplasmosis, cryptococcosis, coccidioidomycosis, blasto- mycosis, and pulmonary mycoses. The mechanism of antifungal activity is similar to the mechanism of action of ampho- tericin B. It is used for preventing and treating candida infections of the skin and mucous membranes. In terms of preventative action, it is used for preventing the development of candidomycosis during prolonged treatment with penicillin drugs and antibiotics of other group, especially during oral use of tetracycline antibiotics, levomecytin, and others. Synonyms of this drug are biofanal, moronal, nicporil, fazigin, candex, and others. Natamycin: Natamycin, a mixture of stereoisomeric 22-[(3-amino-3,6-dideoxy-β-D- mannopyranosyl)oxy]-1,3,26-trihydroxy-12-methyl-10-oxo-6,11,28-trioxatricy- clo[22. It exhibits especially pronounced activity against a few strains of Fusarium and Cefalosporium. Natamycin is a drug for treating superficial fun- gal infections, and it is used only for ophthalmologic purposes. They are ketoconazole, miconazole, clotrimazole, econazole, butoconazole, and others. Antifungal Drugs The antifungal activity of imidazole derivatives is currently explained by their ability to selectively raise the permeability of the membrane of fungal cells by interfering with the biosynthesis of sterins, in particular ergosterin, by inhibiting its synthesis and by changing the lipid content of the membrane.

Ellingwood’s American Materia Medica cheap 10mg metoclopramide, Therapeutics and Pharmacognosy - Page 420 This agent is especially applicable to hysterical females with nervous weakness from persistent uterine disorder discount 10 mg metoclopramide with amex. In hysteria the agent is given in small doses where the following specific conditions are present: Dragging pains in pelvis metoclopramide 10 mg with amex, dysmenorrhea with uterine colic, sexual apathy, congestive headache, burning on the soles of the feet, reduced general strength. In nervous depression, from whatever cause, Ignatia in small closes frequently repeated and persisted in will be found an important remedy. Physiological Action—Nux Vomica and its alkaloid, strychnine, act on the spinal cord and the medulla oblongata, a non-poisonous dose stimulating, and a toxic dose paralyzing them. There is contraction of the arterioles, while the heart is stimulated by a moderate dose. A poisonous dose causes spasm of the muscles of the chest and prevents the respiratory act, with resulting asphyxia. According to the quantity taken, there may be weariness, stiffness in the muscles, soreness and heaviness in the limbs, stiffness of joints and the muscles of the chest and of the lower jaw. A larger dose causes violent tetanic convulsions, with brief intermissions, acute sensibility, and death may result in five minutes and usually within six hours. There is contraction of the Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 421 muscles, resembling trismus, with constriction in the throat, headache, dizziness, with symptoms of asphyxia. There is a leaden color of the skin; breathing is laborious; the pulse is rapid and fluttering, pupils dilated, while the face has a staring expression, with an appearance of fright. In some cases there is pain—a neuralgia of the spinal nerves—when an attack is accompanied with shrieks of pain, or with dizziness, insensibility and convulsions. Small doses in the corpulent may cause slight creeping sensations in the skin like electric shocks, with involuntary contraction of muscles, with headache, a disagreeable sensation in the head and dizziness. In some particulars it resembles the action of electricity in its effect upon the nervous system. There is often a sensation of tingling, a temporary stimulation, a sensation of increased nerve force, a renewed energy imparted to both voluntary and involuntary muscles. Specific Symptomatology—The indications for nux vomica are sallow skin, a sallow circle around the mouth, yellowness of the conjunctivae. A thick yellow, pasty coat on the tongue, fullness, soreness or pain in the region of the liver, suggest the use of nux vomica in medicinal doses. It is also suggested by colic due to atonicity characterized by abdominal fullness, sharp pain at the umbilicus and a general torpor of the system. These symptoms are more quickly relieved by small doses of specific nux vomica than by powerful anodynes, and the relief by this agent is a cure. The indications are directly in the line of its physiological influence in small doses, especially when there is an impairment of tone of the gastro- intestinal apparatus, a general or local atonicity of the digestive organs or organs concerned in these processes. Therapy—This condition is sometimes induced by reflex influence, apparent in the persistent vomiting of pregnancy, the vomiting or regurgitation of food present in hysteria, and in the vomiting of phthisis pulmonalis, especially occurring in these latter cases after coughing. Perry advises nux vomica, ten drops in four ounces of port wine, giving a teaspoonful every three or four hours when sea-sickness threatens, or Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 422 when it may be anticipated. A small quantity of the mixture may be taken on the tongue every few minutes, sometimes with better results. The same atonic condition is present with infantile diarrhea of hot weather, in cholera infantum, in cholera morbus and in cholera. In the vomiting of these conditions small doses of nux vomica frequently repeated are specific. In atonic congestion of the spleen or of the liver, existing from malarial influences, with whatever disease manifested, this agent is directly indicated. It is one of the very best, if indeed it is not the best, of our restorative tonics. In all debilitated conditions, in convalescence from exhausting disease and protracted fevers, wherever there has been depression or exhaustion of nerve force, it is the remedy. In chronic stomach disorder, with deficient digestive power and general malnutrition, this agent arouses the nervous system and increases the functional activity of the digestive and assimilative apparatus more satisfactorily than any other known agent. Cases of vomiting in pregnancy have been controlled by frequently repeated doses of the tincture of nux vomica, and the weakness of the stomach in dipsomaniacs with vomiting and anorexia are controlled with the agent, which is often rendered more efficient by combination with capsicum. Description—This most important of the alkaloids of nux vomica occurs in the form of colorless prismatic crystals, or as a white crystalline powder. It is permanent in the air, very sparingly soluble in water, soluble in one hundred and ten parts of alcohol and in seven parts of chloroform. Its salts, named below, are in more common use than the uncombined alkaloid, largely because of its insolubility, but it may be given in doses of from one-eightieth to the one-twentieth of a grain. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 423 Strychnine Sulphate. In the prostration following any inflammatory disease of a severe and protracted character this combination is specific, but it seems to be particularly beneficial in the prostration of beginning convalescence after pneumonia, especially if there has been abscess or other exhausting complications. Often in these cases there is a tendency to sub-normal temperature and slow pulse; when this is the case there are but few remedies that will act as strychnine, and none will excel it. Therapy—In impotence due to exhaustion, to relaxation or atony of the erectile tissue of the sexual apparatus, strychnine in small doses persistently used is an advantageous remedy. The extract of nux vomica may be given, but will not work as promptly as the alkaloid. In the incontinence of urine of the feeble and aged, and in nocturnal enuresis in childhood from atonicity without local irritation, minute doses of strychnia sulphate will often cure after repeated failure with other remedies. These facts are especially true in plethoric and relaxed cases and in inactive patients. In uterine inertia from exhaustion or lack of nerve force, this agent excels all others.

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There are also no reports of an association of adverse fetal effects with the use of castor oil during pregnancy buy 10 mg metoclopramide visa. It has been a commonly held belief that this agent would stimulate labor and it is often utilized for this purpose in women close to term buy metoclopramide 10 mg mastercard. However 10mg metoclopramide fast delivery, little scientific data support the use of this agent as a potent stimulant of labor. Antidiarrheal agents Unlike constipation, diarrhea is an uncommon complaint of pregnancy and is usually secondary to medications (especially antibiotics), infections (bacterial, viral, and para- 234 Nutritional and dietary supplementation during pregnancy Box 12. Fortunately, most cases of acute diar- rhea are self-limited and require no specific therapy. Antidiarrheals can generally be divided into three major categories – bulk- forming agents, absorbents, and opiates (Box 12. There are no epidemiological studies regarding the use of this agent in pregnant women. However, since very little, if any, of it is absorbed from the gastrointestinal tract, it seems very unlikely that this antidiarrheal poses a significant risk to either mother or fetus. The addition of belladonna and opioid agents results in decreased gastrointestinal mobility. There is little available information regarding the use of opium-containing agents in pregnant women. There were only 36 women with early pregnancy exposure included in the Collaborative Perinatal Project database, but there was no evidence of a significant increase in the frequency of congenital anomalies (Heinonen et al. Almost 100 women were exposed to paregoric in early preg- nancy with no significant increase in frequency of congenital anomalies (Aselton et al. There is, however, the possibility of addiction and withdrawal syndrome in neonates whose mothers use this agent on a chronic basis. Another commonly used antidiarrheal is the combination of diphenoxylate and atropine (Lomotil and others). Diphenoxylate is a compound similar to meperidine and acts primarily to reduce intestinal motility. Of interest is the fact that atropine is included in this preparation in an effort to prevent abuse. Although there is a case report of an infant born with congenital heart disease whose mother used this agent during pregnancy (Ho et al. Moreover, there were less than 10 patients who utilized this agent in early pregnancy included in the Collaborative Perinatal Project (Heinonen et al. According to its manufacturer, loperamide was not ter- atogenic in rats and rabbits. Nausea and vomiting All pregnant women probably experience nausea to some degree in early pregnancy. Nausea and vomiting or ‘morning sickness’ are common symptoms of pregnancy during the first trimester, but most pregnant women do not require antiemetic therapy. Frequent small meals may prove a beneficial way to manage nausea without medical intervention. Fortunately, hyperemesis gravidarum, the most severe form of pregnancy-associated nau- sea and vomiting occurs in only a small percentage of gravidas. Women with hypereme- sis gravidarum may require hospitalization and intravenous hydration, and antiemetic therapy. One of the most effective antiemetic agents for nausea and vomiting associated with pregnancy was doxylamine plus pyridoxine (Bendectin). When antiemetics are indicated, promet- hazine suppositories (or occasionally orally) in doses of 25 mg should be used. Other agents which may prove useful for hyperemesis gravidarum are described in Box 12. Such agents as prochlorperazine, promethazine, chlorpromazine, and thiethylperazine may be associated with extrapyramidal side effects manifested by dystonia, torticollis, and oculogyric crisis. If it occurs, this unusual syndrome of adverse effects can be treated with diphenhydramine (Benadryl). Importantly, chlorpromazine may be associated with significant hypotension when given intravenously. In severe cases of hyperemesis gravidarum in which other agents are largely ineffec- tive, ondansetron (Zofran) 32 mg intravenously as a single dose may be effective. It is also available in oral form (8 mg twice a day), but this is much less likely to be effective in cases of hyperemesis gravidarum where almost everything taken orally is vomited. Reflux esophagitis Reflux esophagitis resulting in heartburn or pyrosis is very common in pregnancy and is thought to be secondary to decreased gastroesophageal sphincter tone with resultant 236 Nutritional and dietary supplementation during pregnancy Table 12. Therapy consists primarily of one of the antacid preparations dis- cussed in the previous section. Frequent small feedings and elevation of the head of the bed at night may be beneficial. An H -receptor antagonist or omeprazole, as well as2 metoclopramide, may also prove useful for severe forms of reflux. Esomeperazole and omeprazole are the most popular treatments for reflux esophagitis, and omeprazole is well studied during pregnancy. Peptic ulcer disease Peptic ulcer disease is not common during pregnancy and active ulcer disease may actu- ally improve during pregnancy. The mainstay of therapy in patients with ulcer disease is reduction of gastric acid production. It is not generally recommended that pregnant women with inactive or asymptomatic disease be treated with ‘prophylactic’ antacids. The H -receptor antagonists cimetidine and ranitidine inhibit gastric acid secretion and2 may be used to treat peptic ulcer disease in pregnant women.

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Additional information Common and serious Immediate: Anaphylaxis and other hypersensitivity reactions have been undesirable effects reported 10 mg metoclopramide free shipping. Injection/infusion-related: Local: Injection-site reaction purchase metoclopramide 10mg visa, pain purchase 10mg metoclopramide with visa, oedema, phlebitis. Other: Dizziness, nausea, vomiting, diarrhoea, abdominal pain, dyspepsia, anorexia, pruritus, rash, headache, acute pancreatitis. Counselling May be associated with permanent tooth discoloration if used during tooth development (therefore not recommended children under 8 years of age). This assessment is based on the full range of preparation and administration options described in the monograph. Pre-treatment checks * Avoid in acute bacterial endocarditis, major bleeding or high risk of uncontrolled haemorrhage including recent haemorrhagic stroke. Prevention of extracorporeal thrombus formation during haemodialysis: see product literature. Tinzaparin sodium | 823 Dose in renal impairment: adjusted according to creatinine clearance:1 * CrCl >20--50mL/minute: dose as in normal renal function. For treatment doses either monitor anti-Factor Xa levels or use unfractionated heparin. For treatment doses either monitor anti-Factor Xa levels or use unfractionated heparin. Dose in hepatic impairment: the manufacturer advises avoid in severe hepatic impairment. Pinch up a skin fold on the abdominal wall between the thumb and forefinger and hold through- out the injection. Technical information Incompatible with Not relevant Compatible with Flush: NaCl 0. Monitoring Measure Frequency Rationale Platelets Alternate days from * Thrombocytopenia can occur in this period of day 5 to day 21 therapy. Serum K After 7 days * Heparins inhibit the secretion of aldosterone and so may cause "K (especially in chronic kidney disease). Anti-Xa activity If indicated * Not required routinely but may be considered in patients during haemodialysis (one hour after dosing should be within the range 0. Additional information Common and serious Immediate: Anaphylaxis has been reported rarely. Other: Risk of bleeding with organic lesions, invasive procedures, asymptomatic thrombocytopenia during the first days of therapy, clinically significant "K in patients with diabetes or chronic renal failure. This assessment is based on the full range of preparation and administration options described in the monograph. Infusion should ideally be started within 12 hours of the last anginal episode and continued for at least 48 hours. Tirofiban | 827 Dose in renal impairment: adjusted according to creatinine clearance: * CrCl >30--50mL/minute: dose as in normal renal function. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Remove the plastic protector from the outlet port at the bottom of the container and attach the giving set. Usingthe250micrograms/mLstrength, withdraw 50mL tirofiban from the50-mL vial andadd to the prepared infusion bag. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Stability after From amicrobiologicalpoint ofview,shouldbe usedimmediately;however,prepared preparation infusions may be stored at 2--8 C and infused (at room temperature) within 24 hours. Platelet count * If the platelet count falls below 90000/mm3, further platelet counts should be carried out to rule out pseudo thrombocytopenia. Additional information Common and serious Immediate: Anaphylaxis has been reported rarely. Significant * The following may "risk of haemorrhage with tirofiban: interactions anticoagulants, heparins, antiplatelet agents, e. Stop administration and give supportive therapy as appropriate including fresh frozen plasma or fresh blood if necessary. This assessment is based on the full range of preparation and administration options described in the monograph. Tirofiban | 829 Table T3 Loading and maintenance infusion rates using a 50 micrograms/mL solution Patient weight Patients with Renal impairment (kg) CrCl >30mL/minute CrCl <30mL/minute 30-minute Maintenance 30-minute Maintenance loading infusion loading infusion infusion (mL/hour) infusion (mL/hour) (mL/hour) (mL/hour) 30--37 16 4 8 2 38--45 20 5 10 3 46--54 24 6 12 3 55--62 28 7 14 4 63--70 32 8 16 4 71--79 36 9 18 5 8 8 9 1 1 1 1 1 1 830 | Tobramycin Tobram ycin 40mg/mL solution in 1-mL, 2-mL and 6-mL ampoules * Tobramycin sulfate is an aminoglycoside antibiotic. Whichever method is employed, it is important to check these criteria to avoid overdosing, e. Either the dose interval can be adjusted (Table T4) or a reduced dose may be given every 8 hours (Table T5). If this is not possible then flush the line thoroughly with a compatible solution between drugs. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. If this is not possible then flush the line thoroughly with a compatible solution between drugs. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Technical information Incompatible with Administer at different sites and times from penicillins and cephalosporins.

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However metoclopramide 10 mg generic, this complexity can be a strength to the role P-gp plays in concert with other key factors that influence absorption and can be studied in parallel 10mg metoclopramide fast delivery. It is possible that results will differ for intestinal region and also due to the presence of Peyer’s patches that have different physiological roles from enterocytes (414 best 10mg metoclopramide,416). Furthermore, these studies suffer from an interspecies variability (rats are typically the test subjects). Despite certain disadvantages, if these studies are con- ducted with appropriate controls involving known P-gp substrates, it can provide valuable insights on how to correlate the effectofP-gpobservedincellulartransport studies to that expressed in the absorption of drugs in vivo. By measuring the intestinal absorption from small intestine of rat in situ, Saitoh et al. Compared with prednisolone and hydrocortisone, meth- ylprednisolone absorption was significantly retarded in jejunum and ileum by an intestinal efflux system. In the presence of verapamil and quinidine, the attenua- tion in the absorption of methylprednisolone was reversed, suggesting that P-gp is responsible for the unique features of methylprednisolone absorption. This study provides a good example of the usefulness of an intestinal perfusion experiment in further determining the regional differences in intestinal drug absorption modu- lated by P-gp that would otherwise be difficult to deduce in experiments per- formed with cell culture models or performed with whole animal systems. The isolated perfused rat liver has been extensively used because of the minimal surgical manipulation needed due to its size and because the organ is less than 25 g, the perfusate used can be hemoglobin-free while ensuring ade- quate oxygen delivery at the flow rates used in these experiments (425). The isolated perfused liver system provides an excellent model for studying the hep- atobiliary disposition of compounds without confounding influences that may be seen in vivo, such as influences on hepatic metabolism and additional metabolism or excretion by other organs of clearance (270,425). The isolated perfused rat liver can be used to study biochemical regulation of hepatic metabolism, synthetic function of liver, and mechanism of bile formation and secretion (270). In a similar study on the hepatic elimination of other P-gp substrates, including vincristine and daunorubicin, it was reported that canalicular P-gp plays a significant role in the biliary secretion of these com- pounds (428,429). Because of the kidney’s involvement in the excretion of hydrophilic compounds and because most of the substrates of P-gp are hydrophobic com- pounds that are likely to be cleared mainly by biliary excretion or intestinal secretion, comparably fewer studies have been performed with the isolated perfused kidney. The isolated perfused rat kidney model was used to demonstrate that digoxin is actively secreted by P-gp located on the luminal membrane of renal tubular epithelial cells and that clinically important interactions with qui- nidine and verapamil are caused by the inhibition of P-gp activity in the kidney (332). One major advantage this technique has over an in vivo experiment involves the perfusion fluid used in the experiment. The composition of the solution can be controlled with respect to test compounds, plasma proteins, nutrients, and met- abolic cofactors (432). However, the use of a perfusate solution can also be a disadvantage as it may not be possible to provide all the necessary nutrients or metabolic cofactors that would be present in vivo and, thus, may lead to incorrect conclusions (430). The major disadvantages of the model with respect to in vitro models include the lack of control of the extracellular fluid concentration for studies of drug efflux from the brain and a greater complexity that the brain matrix provides. As with other perfusion systems, this technique requires anes- thesia and thereby may act to confound results. These in situ techniques can be powerful tools to gauge the actual extent of P-gp efflux that can be expected in vivo. There are confounding factors that must be addressed when interpreting data obtained from these studies, and as with all biological models, the appropriate controls must be used to ensure that the observed effect appears to be due to P-gp-mediated efflux activity. In Vivo Models The major advantages to in vivo models are that they provide a method to understand relevance on an organism level and that these models have been used successfully to predict outcomes in humans. The obvious disadvantages of these models are their limitations with regards to study designs and sampling, reduced ability to deconvolute complex processes, and the need for animal experimenta- tion. For that reason, the in vivo model is a tool more suitable for aiding the understanding of the ramifications of P-gp efflux liability for gross disposition processes. A great deal of understanding around how P-gp affects disposition has come from in vivo models. Both gene products are expressed in the kidney, heart, lung, thymus, and spleen (12,444). The relative sequence identity of the human P-gp with the mouse mdr1a P-gp is 82% (227,446,447). The proteins show the least homology in the first extracellular loop, the connecting region between the homologous halves, and at both terminal ends (31,227,448). It was concluded that mdr1 P-gp has no essential physiological function, since no gross disturbance in corticosteroid metabolismduringpregnancyandinbileformationwasobservedinmdr1a (À/À) mice. However, lack of mdr1 P-gp significantly altered the disposition profile of P-gp substrates. In P-gp gene knockout mice, the absorption was increased, the elimination was decreased, and the concentration of certain substrates in key organs, such as the brain, testes, and heart, was increased dramatically (12). However, this and other transgenic models have not been widely employed in the evaluation of the effects of P-gp on drug pharmacokinetics. In Vivo/In Vitro Correlations In vitro models have provided invaluable information about properties of com- pounds that affect their in vivo transport and absorption. Regardless of how closely in vitro systems model in vivo conditions, they cannot completely rep- resent what may be seen in vivo by virtue of their reduced nature. For that reason, it is important to consider that a focused endpoint generated using an in vitro model will only correlate to a much more complex parameter like absorption when that endpoint is a major determinant of the complex parameter. The lack of in vitro/in vivo correlation does not necessarily implicate a failure of the model, but rather that the endpoint may not be sufficient to describe the in vivo process. Furthermore, the in vivo data used for these correlations are rarely The Role of P-Glycoprotein in Drug Disposition 405 precise or granular enough to gauge differences that may be related to P-gp efflux. For any number of reasons above, attempts to elucidate a quan- titative in vivo/in vitro correlation for P-gp efflux have been difficult and have had limited success. However, recent efforts to generate qualitative under- standings have shown some utility. Despite our inability to predict quantitatively the influence P-gp may have on the in vivo transport of substrates in normal tissues with respect to other processes, in vitro experiments remain the best means of demonstrating that a compound is a substrate for polarized efflux. Nearly all experiments designed to study the extent of P-gp efflux of test compounds in vivo require adequate in vitro data to support the hypothesis (48,217,226,454).

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