Tissue residence time

The major difference in pharmacokinetics between PS oligodeoxynucleotides and 2 -MOE partially modified ASOs is that 2 -MOE partially modified ASOs have improved metabolic stability to nucleases [28]. Therefore, tissue residence time for the 2 -MOE partially modified ASOs is much longer compared to the first-genera-... 

Until recently, nonparenteral routes have failed to deliver sufficient quantities of ASO to be systemically therapeutic. The recent advent of novel oral delivery technologies, coupled with the increased tissue residence time for second-generation ASOs, allows oral delivery to achieve therapeutic levels for select systemic indications. This chapter will initially outline certain more conventional aspects of parenteral dosage forms, and then focus on formulation technologies that more specifically address local treatment. For the oral route, we will pass to the biopharmaceutic considerations for both local delivery to the gut and systemic delivery via absorption from solid dosage forms. Incumbent with the discussion on formulations is the need initially to overview the physico-chemical properties of ASOs, which in large part determine their biopharmaceutic characteristics. 

One of the potential advantages of radiometals as protein labels is their enhanced in vivo stability and tissue residence times, however unlike iodine, a direct attachment of the metal to the antibody cannot be easily achieved. 

The most important VD value for dictating the dosing regimen is the steady-state volume of distribution (VDSS). This volume represents the extent of distribution when the rate of transit to and from the tissues is equal. It is more representative of a time-averaged volume of distribution and its value will reside somewhere in between VDC and VDp. The steady-state VD is calculated from the mean-residence time (MRT). 

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. 

Following a single oral dose of 2,000 mg/kg of di-/ -ocLylphthalatc in rats, mono- -octylphthalate was detected in blood with peak levels observed at 3 hours and in the testes with peak levels observed at 6 hours (Oishi 1990). The biological half-life and mean residence time of mono-w-octylphthalate in blood were 3.3 and 5.4 hours, respectively. After 13 weeks of oral exposure of rats to di-w-octylphthalate in the diet at concentrations up to 5,000 ppm (350 and 403 mg/kg/day in males and females, respectively), the livers contained di -/ -oc1y lphthalate residues that were either below or just slightly above the detection limit (<3 ppm) (Poon et al. 1995). The adipose tissue of rats fed 5,000 ppm showed di-/ -octylphthalate residue levels of 15 ppm (males) and 25 ppm (females). This study is limited in that it did not analyze tissues for the presence of metabolites. 

Figure 8. Calcium values in vertebrate bone and soft tissue samples versus 6 Ca in dietary source (Skulan and DePaolo 1999). Bone values are systematically about 1.3%o lower than source values. Soft tissue values are more variable. All of the values are hypothesized to reflect the balance between Ca dietary intake and exchange with bone calcium (Fig. 9). The soft tissue values are variable largely because the residence time of Ca in the tissues is short. The high value of the egg white reflects Rayleigh-type distillation the egg white loses light Ca to the shell as the shell forms. The small amount of Ca left in the egg white is highly fractionated. The low 6 Ca value of the seal muscle is interpreted as a sign of distress the seal may have had a dietary Ca deficiency for several days or longer before it died, and hence was deriving most of its Ca from bone dissolution.

Each of these reactor systems can be described by a residence time or time constants for example, Tdigestion is the time for food to pass through the digestive system, and Tcircuiation is the time for blood to circulate. Consumption and metabolism of medicines and alcohol are described by the transient response of the concentration in the bloodstream or in tissues. 

Answer Bupivacaine use for local anesthesia of this type is very safe and commonly done. However, SOMETIMES inadvertent vascular injection results in a large amount of anesthetic in the systemic circulation. Because the heart is beating, the excitable tissue in the heart is being depolarized repetitively. Local anesthetics bind to rapidly depolarizing tissues more than tissues at rest (frequency-dependent block). Also, bupivacaine has a long duration of action because of its long residence time at receptors (sodium channel). Thus, this combination of factors contributed to the catastrophic outcome of this case. Had the same case involved lidocaine, the resuscitation would have likely been successful. 

Not only must we optimize the expression and yield of purified recombinant proteins, we must ensure that the protein is stable, has a high degree of potency and a low degree of toxicity, and has suitable pharmaceutical properties. Pharmaceutical properties encompass distribution and residence time in target tissues, and frequency of dosing, and may have an impact on efficacy and safety. 

IgG molecules found outside the extravascular space can accumulate and penetrate into a tumor mass within a tissue by several mechanisms. The rate of IgG accumulation in tissue and subsequent penetration into the tumor mass depends on the affinity and avidity of the antibody for a tumor-associated antigen. According to one model, based on computer simulations, penetration of the tumor mass is influenced by diffusion and convection, while binding affinity determines residence time of the antibody molecule bound to antigen expressed on tumor cells [23-25]. 

Tire means by which chemicals enter the body are inhalation (breadiing), ingestion (swallowing), and absorption (skin or living tissue contact). Once in the system these chemicals may produce such symptoms as tissue irritation, rash, dizziness, anxiety, narcosis, headaches, pain, fever, tremors, shortness of breath, birth defects, paralysis, cancer, and death, to mention a few. The amount of chemical diat enters the body is called the "dose." The relationship that defines the body response to the dose given is called the "dose-response curve." The lowest dose causing a detectable response is the "threshold limit." The "limit" is dependent on factors such as particle size of contaminant, solubility, breathing rate, residence time in the system, and human susceptibility. 

Each situation requires an evaluation of the hypotheses to be tested before the personal monitor can be designed and the identification of the types and duration of exposure that may occur. Once inhaled, the compound may be rapidly metabolized in the body short-term measurements would be appropriate for such processes. The compound may instead have a long residence time at a specific site in the lung or may be stored in an organ or tissue. Thus, the inhaled compound or one or more of its adducts or metabolites could eventually deliver a biologically effective dose to a target organ or cell (13). The monitor must be developed with consideration of the... 

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