Uptake, tissue

Control of secretion of anterior pituitary hormones also includes inhibition by hormones produced by target organs. For example, CRH stimulates the anterior pituitary to secrete ACTH, which in turn stimulates the adrenal cortex to secrete corticosteroids. Corticosteroids then feed back to inhibit the secretion of ACTH. Feedback mechanisms are important for the control of most hormones. For example, insulin (qv) secretion from the pancreas increases in response to increased blood glucose resulting from ingestion of a meal. Insulin increases tissue uptake and metaboHsm of glucose, which lowers blood glucose and in turn reduces insulin secretion. 

Tissue Uptake and Storage. Cell surface receptors take up the transcobalamin II—cobalamin complex, which is internalized into endosomes. The complex is dissociated and the transcobalamin II released. The mechanism by which cobalamin leaves the endosome is uncertain. 

The study of diisopropyl methylphosphonate distribution in a lactating Jersey cow was the only study that used multiple doses of diisopropyl methylphosphonate (Ivie 1980). In this single cow, radioactivity was detected in the blood 2 hours after dosing with [14C]-radiolabeled compound but not in the tissues. The animal had received diisopropyl methylphosphonate in one gelatin capsule for 5 days before the radiolabeled dose was administered. If tissue uptake in the cow was similar to that in dogs, measurements made 2 hours after dosing may not have provided an opportunity to measure tissue uptake of label. After 24 hours, 0.1% of the administered label was found in the cow s milk (Ivie 1980). 

Yamaoka T, Tabata Y, Ikada Y (1994) Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J Pharm Sci 83 601-606... 

Adequate data were available for development of the three AEGL classifications. Inadequate data were available for determination of the relationship between concentration and time for a fixed effect. Based on the observations that (1) blood concentrations in humans rapidly approach equilibrium with negligible metabolism and tissue uptake and (2) the end point of cardiac sensitization is a blood-concentration related threshold phenomenon, the same concentration was used across all AEGL time periods for the respective AEGL classifications. 

Blood-tissue uptake rates (l< ) can often be approximated from data at early (t < 10 minutes) time points in IV studies, provided the blood has been washed from the organ (e.g., liver) or the contribution from blood to the tissue residue is subtracted (fat). High accuracy is not usually required since these parameters can be optimized to fit the data when they are used in more complex models. Tissue-blood recycling rates (A y) and residence times can be computed from partition coefficients if estimates of uptake rates are available. 

Johnson BM, Charman WN, Porter CJH (2003) Application of compartmental modelling to an examination of in vitro intestinal permeability data Assessing the impact of tissue uptake, P-glycoprotein, and CYP3A. Drug Metab Dispos 31 1151-1160. 

Panyam, J., Sahoo, S.K., Prabha, S., Bargar, T., Labhasetwar, V., Fluorescence and electron microscopy probes for cellular and tissue uptake of poly(D,L-lactide-co-glycolide) nanoparticles. Int J Pharm 262, 1-11 (2003). 

Blood-bome fuels are glucose, which is derived from liver glycogen, and fatty acids derived from adipose tissue. Uptake depends on the flow of blood through the muscle, the concentration of the fuel in the blood and the demand for ATP within the muscle. During sustained exercise the flow of blood to the muscle can increase up to 50-fold and the rate of utilisation of the fuel can increase to a similar extent, yet the concentration of the fuels in blood remains remarkably constant (Table 13.5). 

Figure 5.3. (a) Structure and (b) tissue uptake clearance of alkylglycoside-derivatized AVP. Position of H-label. Adapted from reference [23]. 

The rates of onset and cessation of action vary widely between different inhalational anesthetics and also depend on the degree of lipophilicity. In the case of N2O, there is rapid elimination from the body when the patient is ventilated with normal air. Due to the high partial pressure in blood, the driving force for transfer of the drug into expired air is large and, since tissue uptake is minor, the body can be quickly cleared of N2O. 

In contrast, with halothane, partial pressure in blood is low and tissue uptake is high, resulting in a much slower elimination. 

Pharmacokinetic Long time for tissue uptake Plasma digoxin only correlates with... 

Payan JP, Fabry JP, Beydon D, et al. 1991. Biliary excretion of hexachloro-1,3-butadiene and its relevance to tissue uptake and renal excretion in male rats. J AppI Toxicol 11 437-442. 

Y. Seimbille, F. Benard, J. Rousseau, E. Pepin, A. Aliaga, G. Tessier, J.E. van Lier, Impact on estrogen receptor binding and target tissue uptake of [F-18]fluorine substitution at the 16-alpha-position of fulvestrant, Nucl. Med. Biol. 31 (2004) 691-698. 

Pfiarmacokineticsx Readily absorbed from the GI tract (high-fat meals delay absorption). Protein binding 85%. Widely distributed. Crosses the blood-brain barrier. Extensive intracellular tissue uptake. Metabolized in the liver to active metabolite. Excreted in urine eliminated in feces. Unknown if removed by hemodialysis. Half-life 16-69 hr. 

The DPDP ligand was synthesized in order to lower the toxicity of the man-ganese(II) ion and to provide selective tissue uptake [40]. The LD50 of an i.v. dose of Mn-DPDP is between 1.9-5.4 mmol kg1 in mice [18, 41]. No mortalities occurred in dogs injected i.v. with 1.8 mmol kg-1 [41]. With the recommended clinical dose of 0.005 mmol kg1, the safety factor for Mn-DPDP is at least 360 [41]. In the European phase III clinical trials adverse events were reported for 46 of 624 patients (7%) [42]. In comparison, 123 of 546 patients (23%) in the U.S. clinical trials reported at least one adverse event [43]. In both trials the most common complaints were headache, vomiting and nausea. In addition, 377 of 546 patients (69%) in the U.S. trials and 26 of 624 patients (4%) in the European trials reported discomfort at the site of injection. The difference between the two trials is likely due to the method of administration and formulation of the Mn-DPDP solution. In the European trials, a 0.010 mM solution of the agent was slowly infused while in the U. S. trials Mn-DPDP was administered as a bolus injection of a 0.050 mM solution. Experiments have demonstrated a lower incidence of adverse events with infusion of the agent [44]. 

Figure 19.1 Physiological pharmacokinetic model for evaluating in vivo disposition of a macromolecular drug. (A) A multi-compartment model in which every tissue compartment is connected with the plasma pool by blood flow. (B) Tissue uptake of a drug from vascular space to tissue parenchyma.

After systemic administration, a drug is generally delivered to tissues in the body through blood circulation. Therefore, the concentration of drug in plasma defines the rate of tissue uptake. 

Tissue uptake clearance is a useful parameter to characterize the in vivo distribution properties of a drag since it is independent of the drag concentration in plasma. However, when the tissue uptake process depends on the drag concentration in plasma and follows non-linear kinetics, the calculated CZapp i represents an average value of its time-dependent clearance for the overall experimental period (Nishikawa et al., 1992). 

When CLmL1 is much larger than Q, CZapp comes close to Q and this value (plasma flow rate to a tissue) is the upper limit of r/.app whatever specific and rapid uptake mechanism is involved in the tissue uptake. 

Since CZtola is the sum of tissue uptake clearances and urinary excretion clearance, CLtotal is also expressed as ... 

We examined the biodistribution of cationic liposomes/pDNA complex following intravenous injection in mice and pharmacokinetically analyzed the data based on the clearance concept (Mahato etal., 1995a, 1997). These analyses showed that the pharmacokinetics of 32P-pDNA complexes depend on their mixing (charge) ratio, the type of cationic and helper lipids (Mahato et al., 1998). When analyzed using radioactivity counting following the injection of the complex prepared with 32P-pDNA, the tissue uptake clearance per g... 

Nicolazzo et al. [52] considered the use of the lipophilic skin penetration enhancers, octisalate and padimate (both used in sunscreens), in comparison to Azone on the buccal absorption of various drugs in vitro. They were found to have limited effect in enhancing the permeation of triamcinolone acetonide (although some increase in tissue uptake was proposed in some cases) relative to Azone, while reducing the penetration of estradiol and caffeine. One interesting report is that of the effect of capsaicin from capsicum, a commonly used food ingredient, which has been reported to enhance the permeability of sulfathiazole in human volunteers [53] presumably by a direct irritation effect on the mucosa. This raised an interesting issue of the effect of diet on oral mucosal permeability. 

The biologic half-lives of ACTHi 39 and ACTHi 24 are under 20 minutes. Tissue uptake occurs in the liver and kidneys. ACTHi 39 is transformed into a biologically inactive substance, probably by modification of a side chain. ACTH is not excreted in the urine in significant amounts. The effects of long-acting repository forms of porcine corticotropin persist for up to 18 hours with a gelatin complex of the peptide and up to several days with a zinc hydroxide complex. 

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