Elimination and Excretion

As discussed in Section 4.2.3, the elimination of 2 -MOE partially modified AS Os is attributed to slow (but continuous) nuclease-mediated metabolism in tissue, followed by ultimate excretion of these shortened metabolites in the urine. This major elimination pathway for 2 -MOE partially modified AS Os is shown graphically in Fig. 4.9, where approximately 75% of the total radiolabeled dose is excreted in the urine by 90 days after a single dose (5 mg/kg) of [3H]-ISIS 104838 to rats [26]. Another example of the ultimate elimination of this class of compound via slow metabolism in tissues, followed by the urinary excretion of metabolites, is the mass-balance study with [3H]-labeled ISIS 113715. Here, between 8% and 37 % of administered dose was excreted within the first 24 h, followed by a daily ur- 

Sequence Dose Route Dose excreted as parent drug [%] Dose excreted as total oligo [%] 

Therefore, this review of pharmacokinetic/pharmacodynamics (PK/PD) correlation will include investigations between the effective concentrations at the target sites of antisense oligonucleotides with each of the pharmacological effects discussed above. Moreover, an establishment of the correlation between plasma equilibrium concentrations with concentrations at the target sites is pertinent, enabling plasma concentrations to be used as a surrogate in clinical studies to establish relationships between pharmacodynamics and pharmacokinetics. 

Although the mechanisms of action for antisense oligodeoxynucleotide and 2 -MOE partially modified ASOs are the same, the 2 -MOE modifications provide increased affinity to the target mRNA while maintaining favorable RNase H activity and, therefore, enhanced potency and specificity over the first-generation ASOs [28, 40, 44, 45]. The pharmacodynamic section of this chapter will, once again, focus on 2 -MOE partially modified ASOs. 

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The realization of sensitive bioanalytical methods for measuring dmg and metaboUte concentrations in plasma and other biological fluids (see Automatic INSTRUMENTATION BlosENSORs) and the development of biocompatible polymers that can be tailor made with a wide range of predictable physical properties (see Prosthetic and biomedical devices) have revolutionized the development of pharmaceuticals (qv). Such bioanalytical techniques permit the characterization of pharmacokinetics, ie, the fate of a dmg in the plasma and body as a function of time. The pharmacokinetics of a dmg encompass absorption from the physiological site, distribution to the various compartments of the body, metaboHsm (if any), and excretion from the body (ADME). Clearance is the rate of removal of a dmg from the body and is the sum of all rates of clearance including metaboHsm, elimination, and excretion. 

No studies were located regarding elimination and excretion in humans or animals after inhalation exposure to mineral oil hydraulic fluids, organophosphate ester hydraulic fluids, or to polyalphaolefm hydraulic fluids. 

C02 and in the Okoh (1983) study, about 4% of the radioactivity was expired, mostly as carbon dioxide. See Section 2.3.4 for information on studies examining elimination and excretion. 

There is no information regarding tire elimination and excretion of 3,3 -diehlorobenzidine or metabolites in children following any route of exposure. 

Polybrominated Diphenyl Ethers. A limited amount of data is available on the toxicokinetics of PBDEs. There are data gaps in a number of areas, particularly for octaBDE and pentaBDE mixtures and the tetia and hexa congeners that are most prevalent in the environment. Quantitative absorption studies could corroborate the conclusions on oral uptake in animals that are based on elimination and excretion data. Metabolism studies would help to characterize the enzymes involved as well as the transformation of some congeners to biologically active hydroxylated BDEs and the debromination of decaBDE to lower brominated BDEs. 

A biological matrix such as serum provides a good example. Nature generally tends to make metabolites more polar than the original compound. These polars exist to aid in elimination and excretion as well as serving as building blocks and reaction components. At the same time, nonpolar molecules are present in transport and structural roles and end up in the circulating blood. 

The optimal administration of drugs in clinical practice is facilitated by effective application of the principles of clinical pharmacokinetics (PK) and pharmacodynamics (PD). Relationships between drug levels in the systemic circulation and various body compartments (e.g., tissues and biophase) following drug administration depend on factors governing drug absorption, distribution, elimination, and excretion (ADME). Collectively, the study of the factors that govern the ADME processes is termed pharmacokinetics. 

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