By Z. Tom. New Brunswick Theological Seminary. 2019.

Less than 4% of a dose was recovered in the bile after 48 h in patients with biliary drainage tubes (Arbuck et al 30mg accutane visa. The faecal recovery of radiolabel after intravenous administration of [3H]etoposide (130– 290 mg/m2) was variable buy discount accutane 10 mg line, representing 0–16% of dose order accutane 30mg otc, but the collections were known to be incomplete because of faecal retention and other difficulties associated with the poor general condition of many of the patients (Creaven & Allen, 1975). In a study reported as an abstract in four patients with small-cell lung cancer given [14C-gluco- pyranoside]etoposide, 56% of the radiolabel was recovered in urine and 44% in faeces over five days, for a total recovery of 100 ± 6% (Joel et al. Studies in lung cancer patients have shown that the plasma concentrations asso- ciated with haematological toxicity are higher than those required for antitumour ac- tivity. The plasma concentration associated with antitumour activity may be different for different tumour types (Minami et al. The pharmacokinetics of etoposide is influenced by concurrent administration of a number of other drugs: clearance may be increased by phenytoin (Mross et al. Rhesus monkeys given [3H]etoposide showed biphasic elimination, with a distri- bution phase half-time of about 1. Biphasic elimi- nation was also observed in mice, with a distribution half-time of 1. The clearance rate was 17 mL/kg bw per min, and the distri- bution volume was 820 mL/kg bw (Colombo et al. The total plasma clearance rate (342–435 mL/min per m2) and the distribution volume (22–27 L/m2) were not dose-dependent. The peak plasma concentration occurred at the end of the infusion of etoposide phosphate, indi- cating rapid conversion of the pro-drug to etoposide (Igwemezie et al. Thirty minutes after intravenous administration of etoposide to rats, the highest concentrations were found in the liver, kidneys and small intestine. By 24 h after the dose, the tissue concentrations were negligible (Achterrath et al. In leukaemic cells, the uptake appeared to be linear up to 5 min and reached a steady state by 20–30 min (Allen, 1978; Colombo et al. After removal of the drug, an exponential efflux with a half-time of just 3 min was observed (Allen, 1978). At the same extracellular concentration, the intracellular concentrations of eto- poside were 15–20 times lower than those of the closely related drug teniposide (Allen, 1978; Colombo et al. In rat liver homogenates, liver microsomes and in rats in vivo, etoposide was exten- sively metabolized to only one major metabolite, which was not formally identified (van Maanen et al. In perfused isolated rat liver incubated with etoposide, the total recovery in bile was 60–85%, with roughly equal amounts of etoposide and two glucuronide metabolites (Colombo et al. After intravenous injection of [3H]etoposide to rabbits, the total urinary excretion of radiolabel was 30% after five days, with very little thereafter. A single glucuronide metabolite was identified in rabbit urine, which was present in larger amounts than etoposide. A number of authors have reported the peroxidase-mediated oxidation of etoposide to a phenoxy radical, with further oxidation to the ortho-quinone, semi-quinone and catechol derivatives (Broggini et al. Cytochrome P450-mediated demethylation directly to the catechol has also been reported (van Maanen et al. It remains unclear how much these reactive metabolites contribute to the cytotoxic or mutagenic activity of etoposide. The main, dose-limiting toxic effect is myelosuppression, manifest principally as leukopenia. After standard intravenous doses (375–500 mg/m2 total dose) of etoposide administered alone over three to five days, 20–50% of previously untreated patients experienced moderate to severe leukopenia or neutropenia, typically occurring around day 10–12, with recovery by day 21. Nausea and vomiting are gener- ally mild but may be more common after oral administration. Mucositis can occur at standard doses, when it is generally mild, but at high doses (< 3500 mg/m2), mucositis can become dose-limiting (Postmus et al. Hypersensitivity reactions to etoposide have been reported but are uncommon (O’ Dwyer & Weiss, 1984). In eight patients reported to the Investigational Drug Branch of the National Cancer Institute between January 1982 and May 1983, these reactions included flushing, respiratory problems, changes in blood pressure and abdominal pain, often occurring soon after the start of drug administration and generally resolving rapidly when the infusion was stopped. These reactions are less common with etoposide than with the related drug teniposide and have not been reported after oral administration, suggesting that other agents in the formulation may be at least partly responsible. The very low incidence of reported cases may reflect only serious hyper- sensitivity reactions (Weiss, 1992), as mild reactions were found in 51% of patients receiving etoposide as part of combination chemotherapy for Hodgkin disease (Hudson et al. Most patients can be successfully re-treated with etoposide after a premedication comprising antihistamine and/or corticosteroids (Hudson et al. Cardiotoxicity was reported in three of eight patients with pre-existing cardiac disease who received etoposide by infusion (Aisner et al. Four-week studies of toxicity were conducted in rats treated intraperitoneally at 0. At the highest doses, the main toxic effect was myelosuppression, with anaemia, leukopenia and thrombocytopenia, and some hepatotoxicity. Pathological changes were noted in the lung in rats, and mild enteritis was seen in dogs. After oral and intravenous administration at the same doses as in the previous studies, no additional toxicity was observed up to nine weeks (review of unpublished studies by Achterrath et al. No other effects were seen in the rats, while those in dogs included renal and hepatic impairment, electrocardiographic changes, decreased testis weight and disorders of spermatogenesis (review of unpublished studies by Achterrath et al. After intraperitoneal administration of a clinical formulation or intrapleural adminis- tration of etoposide dissolved in dimethyl sulfoxide and Tween 80 diluted in Hank’s buffer to rats and mice, delayed chronic pleuritis and peritonitis, with liver and spleen inflammation were reported. After intravenous infusion of a single dose of 461 mg/m2 etoposide phosphate to dogs over 5 min, all animals vomited, and leukopenia and thrombocytopenia were seen at this and lower doses (Igwemezie et al. Etoposide- and etoposide phosphate-induced sensory neuropathy has been reported in mice after single doses of 88 mg/kg bw and 100–150 mg/kg bw, respectively (Bregman et al. Six days later, she developed neutropenia and septicaemia and had a spontaneous vaginal delivery. The female infant developed profound leukopenia with neutropenia three days later (10 days after in-utero exposure), which had resolved by day 13. At 10 days of age, the infant started to lose her hair, which was growing again when she was discharged at 12 weeks. A woman was treated for acute leukaemia at 25 and 30 weeks of gestation with cytarabine, daunorubicin and etoposide (400 mg/m2 per day for three days). Her infant, delivered by caesarean section at 32 weeks because of fetal distress, had leukopenia with profound neutropenia, which was confirmed to be due to bone-marrow suppression by measurement of circulating haemopoietic progenitor cells. This condi- tion responded to transfusion of packed cells and subcutaneous injections of granulocyte colony-stimulating factor, and the infant was well at follow-up at one year (Murray et al.

The breakdown products of dietary proteins can compete with L-dopa for this active transport mechanism trusted 40 mg accutane, thereby reducing its oral bioavailability order accutane 10 mg with amex. Taking L-dopa at least 30 min before eating and controlling dietary protein has been shown to improve L-dopa treatment in Parkinson’s disease cheap 5 mg accutane mastercard. A further example is the avoidance of milk 2 h prior to taking preparations containing tetracyclines, as these drugs chelate calcium ions in milk, forming a poorly absorbable complex. Interestingly, the presence of food may favor drug absorption in other situations. The positive effect of food on the absorption of this drug was also observed with Eudragit S100 nanoparticles. The administration of a 150 mg diclofenac hydrogel-based capsule dose within 30 min following a standardized breakfast was shown to minimally affect the bioavailability of dicolfenac relative to administration under fasted conditions. The insoluble fraction forms 141 a semi-impermeant layer, which, in conjunction with bicarbonates (secreted by gastric cells at the surface and in gastric pits), protects underlying cells from damage by gastric acid. Studies have shown that gastrointestinal mucus presents a physical barrier to the diffusion of small molecules such as urea, benzoic acid, antipyrine, l-phenylalanine and warfarin as well as to large protein molecules. Similarly, the passive absorption of testosterone was shown to be doubled upon ridding the intestinal epithelial cells of the overlying mucus layer. However, the situation regarding the effect of mucus on oral bioavailability is a complex one; for example, it has been shown that drug binding to the mucosal surface is essential to the absorption of barbituric acid derivatives from the rat small intestine. Gender Gastric acid secretion is greater in men than in women, whereas gastric emptying time is slower in women. Enzyme expression is also different between men and women; for example, sex-related cytochrome P-450 isozymes and glucuronidation enzymes are more abundant in men. However, in general, gender differences are small and insufficient to warrant a modification in dosage regiments. Pregnancy results in reduced gastric acid secretion, increased intestinal motility, increased plasma volume, decreased plasma drug binding and also an additional pharmacokinetic compartment. These altered pharmacokinetic factors may require modifications in the dosage regimen for certain drugs. Race Racial differences in oral drug bioavailability are known to exist and may be due to environmental, dietary or genetic differences. These differences are becoming increasingly important in therapeutics, due to both the increasingly international nature of drug development and use, and also the multi-racial nature of the population of many countries. The hydroxylation defect for debrisoquine also applies to the oxidative metabolim of codeine, metoprolol, and perphenazine. The clinical conse-qunces of polymorphic oxidation have not been examined in great detail. Obviously, the small percentage of the population who are poor metabolizers may be at considerable risk of adverse effects from the usual doses of many drugs. Age Few pharmacokinetic studies are carried out beyond the range of 28–40 years and, consequently, there are few data on oral bioavailability for extremes of age. Gastric fluid is less acidic in newborns than in adults, which can affect the absorption of ionizable and acid-labile drugs. Decreased enzymatic activity, including hepatic first-pass metabolism, is associated with the elderly, which may result in an increased oral bioavailabiliy for drugs subject to the first- pass effect. The effect of the shunt is to increase the presistence of the drug in the body and, provided the concentrations of the drug at its sites of action are sufficiently high, to prolong its duration of action. It is important to remember that although a drug molecule may be predominantly absorbed via one particular route/mechanism, it is also likely that suboptimal transport will occur via alternative routes and mechanisms. Diffusion is driven by a concentration gradient and is inversely related to molecular weight. The junctional complexes begin immediately below the luminal surface and are made up of three components (Section 1. Thus only small hydrophilic molecules, such as, for example, mannitol, are capable of squeezing through the junctional complexes to be absorbed via the paracellular route. The rate of absorption is governed by Fick’s Law and is determined by the physicochemical properties of the drug as well as the concentration gradient across the cells (Section 1. Carrier-mediated transport Amino acid transporters, oligopeptide transporters, glucose transporters, lactic acid transporters, monocarboxylic acid transporters, phosphate transporters, bile acid transporters and other transporters present on the apical membrane of the epithelial cells serve as carriers to facilitate nutrient absorption by the intestine. Drug moieties possessing similar structures to nutrients that are absorbed by such carriers may also be absorbed in this manner. Endocytic processes Considerable evidence has accumulated indicating that macromolecules and microparticulates can be taken up by the intestinal enterocytes, generally via pinocytosis. For example, studies have shown that receptor-mediated endocytosis via enterocytes is a major pathway for the intemalization of certain antisense oligonucleotides. In contrast, endocytic uptake of macromolecules and microparticles is carried out extensively by the M cells of the 144 Peyer’s patches. Transcellular shuttling through the M cells to the underlying Peyer’s patch may involve an adsorptive and/or receptor-mediated process, with membrane-bound vacuoles or vacuoles already present in the apical cytoplasm of the cells (see below, Section 6. Therefore, they are ionized to a certain extent, determined by their pKa and the pH of the biological fluid in which they are dissolved; the extent of ionization can be quantified by the Henderson-Hasselbalch Equation (see Section 1. According to the pH-partition hypothesis, the nonionized form of a drug, with a more favorable oil/water partition coefficient (Ko/w) than the ionized form, is preferentially absorbed. For example, the absorption of salicylic acid, a weakly acidic drug, is approximately twice as high at pH 4 than at pH 7. By contrast, quinine, a weakly basic drug, is absorbed approximately four times higher at pH 7 than at pH 4 (Table 6. The numbers refer to 1, atenolol; 2, practolol; 3, pindolol; 4, metoprolol; 5, oxprenolol; and 6, alprenolol. Generally, the larger the partition coefficient, the more lipophilic is a compound, and the more readily would it partition into biological membranes. By contrast, hydrophilic atenolol, with the smallest partition coefficient, shows the lowest permeability. Some drugs exhibit a lower absorption than expected on the basis of their partition coefficient. This reduced absorption is thought, in some cases, to be due to the P-glycoprotein efflux effect (see above, Section 6. The results shown with the squares represent the relationship between intestinal absorption clearance (ka) observed from the in situ jejunum loop in the presence (■) and absence (□) of cyclosporin A in rats and octanol-buffer (pH 7. The numbers refer to 1, atenolol; 2, nadolol; 3, acetamide; 4, celiprolol; 5, acebutolol; 6, doxorubicin; 7, timolol; 8, sulfathiazole; 9, quinidine; 10, sulfamethoxazole; 11, digoxin; 12, cyclosporin A; 13, vinblastine; 14, b-estradiol; 15, verapamil. The ionized form of a drug displays a higher dissolution rate and greater solubility than the nonionized form (see Section 1.

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However discount accutane 5mg fast delivery, these polymers cannot be used for in vivo application due to their poor transfection efficiency and high cytotoxicity cheap accutane 40mg fast delivery. The effect of colloidal and surface characteristics of plasmid/ dendrimer complexes on gene transfer has been examined accutane 40 mg cheap. These complexes were monodisperse, with a mean hydrodynamic diameter of about 200 nm. The particle size, surface charge and gene transfer efficiency of plasmid/dendrimer complexes prepared with the 5th generation of dendrimers has been shown to be influenced by dendrimer concentration in the complexes. The colloidal and surface properties of plasmid/chitosan complexes have been shown to depend on the molecular weight of chitosan, the ratio of plasmid to chitosan and the preparation medium. Smaller nanoparticles have been observed with low molecular weight chitosan (2 kDa) as compared to high molecular weight chitosan (540 kDa). Interestingly, the transfection efficiency of the complexes was not affected by the presence of serum proteins, even though the presence of serum is known to adversely affect the transfection efficiency. The blood capillary walls are comprised of four layers, namely plasma-endothelial interface, endothelium, basal lamina, and adventia. Macromolecules can cross the endothelial barrier: • through the cytoplasm of endothelial cells themselves; • across the endothelial cell membrane vesicles; • through inter-endothelial cell junctions; • through endothelial cell fenestrae. Based on the morphology and continuity of the endothelial layer, capillary endothelium can be divided into three categories: continuous, fenestrated, and discontinuous endothelium (see Section 5. The continuous capillaries are found in skeletal, cardiac, and smooth muscles, as well as in lung, skin, subcutaneous and mucous membranes. The endothelial layer of brain microvasculature is the tightest endothelium, with no fenestrations. Capillaries with fenestrated endothelia and a continuous basement membrane are generally found in the kidney, small intestine and salivary glands. Most of these capillaries have diaphragmed fenestrae, which are circular openings of 40–60 nm in diameter. The discontinuous capillaries, also known as sinusoidal capillaries, are common in the liver, spleen, and bone marrow. These capillaries show large interendothelial junctions (fenestrations up to 150 nm). Highly phagocytic Kupffer cells line the sinusoids of the liver, and those of the bone marrow by flattened, phagocytic reticuloendothelial cells. In the spleen, the endothelial cells contain a large number of pinocytic vesicles (up to 100 nm in diameter). Due to their large molecular weight (> 1,000 kDa) and hydrodynamic diameter in aqueous suspension of 100 nm, plasmids extravasate poorly via continuous capillaries because of tight junctions between the cells. However, plasmids can easily extravasate to sinusoidal capillaries of liver and spleen. Formulating plasmids into unimeric particles of 20–40 nm in diameter may enhance extravasation of plasmids across continuous and fenestrated capillaries. The (patho)physiology and microanatomy of tumors is significantly different from normal tissues (see Section 5. A tumor contains vessels recruited from the pre-existing network and vessels resulting from angiogenic response induced by cancer cells. There is a considerable variation in the cellular composition, basement membranes and in the size of the interendothelial cell fenestrations. Tumor interstitium is characterized by large interstitial volume and high diffusion rate. Sven Frøkjaer, Lona Christrup and Povl Krogsgaard-Larsen; Munksgaard, Copenhagen, 1998, pp. Tumor accumulation of plasmid could result from the enhanced permeability of the tumor vasculature, combined with their reduced clearance from the tumor due to the absence of the lymphatic system. Pharmacokinetic analysis of in vivo disposition profiles of radiolabeled plasmid provides useful information on the overall distribution characteristics of systemically administered plasmids, with one critical limitation. The plasma half-life of plasmid is less than 10 min, and hence tissue distribution and pharmacokinetic parameters of plasmid calculated on the basis of total radioactivity are not valid at longer time points. Thus, polymerase chain reaction and Southern-blot analysis are required to establish the time at which the radiolabel is no longer an index of plasmid distribution. The deposition of plasmids after systemic administration is restricted to the intravascular space due to its low microvascular permeability in most organs with continuous capillary bed. Some organs with fenestrated capillaries, such as liver, spleen, and bone marrow, provide some opportunities for extravasation of plasmids. Intravenously injected plasmids initially perfuse the pulmonary vascular beds, maximizing the 347 Figure 14. Reproduced with permission from: Biodistribution and gene expression of plasmid/lipid complexes after systemic administeration, Mahato R. Southern-blot analysis of blood showed the rapid degradation of plasmid, with a half-life of less than 5 min for intact plasmid, and was no longer detectable at 1 hr postinjection. By Southern-blot analysis, there was no detectable plasmid in the brain, large intestine, small intestine, or gonads at the 1-hr timepoint. Southern blot analysis also demonstrated that plasmid remained in the liver, spleen, lung, marrow, and muscle, although at diminished levels, up to 24 hr postinjection. The plasma membrane is the next obstacle to be overcome in delivering genes into a cell. Gene delivery systems rely on binding to cell surface molecules, either specific, non- specific or both, prior to cellular internalization. The surface bound material usually gains entry into the cell either by endocytosis or membrane fusion. The schematic representation of the process of gene delivery and expression is shown in Figure 14. Gene delivery systems can distribute plasmids to the desired target cells, after which the plasmid is internalized into the cell by a number of mechanisms, such as adsorptive endocytosis, receptor-mediated endocytosis, micropinocytosis, caveolae-mediated endocytosis and phagocytosis (see Section 1. The intracellular fate of plasmids depends on the means by which they are internalized and translocated to the cytoplasms and then to the nucleus. Extacellular environment → tissue targetability → cellular uptake → intracellular trafficking → nuclear entry → gene expression The transition from coated vesicle to early endosome is accompanied by acidification of the vesicular lumen that continues into the late endosomal and lysosomal compartments, reaching a final pH in the perinuclear lysosome of approximately 4. Such acidification associated with endosome maturation provides the means by which certain viruses gain access to the cytosol.

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