Drug elimination pathways

Most drug elimination pathways will become saturated if the dose is high enough. When blood flow to an organ does not limit elimination (see below), the relation between elimination rate and concentration (C) is expressed mathematically in equation... 

ADME study compounds in humans and animals Elucidate drug elimination pathways in humans Elucidate metabolite structures per person or animal). Usually collection of plasma up to 48 h and urine and feces up to 2 weeks. subjects/animals or time detection NMR disposition in humans and animals Support design of clinical studies Support regulatory submissions for approval... 

Brown, H.S., Ito, K., Galetin, A. and Houston, J.B. (2005) Prediction of in vivo drug—drug interactions from in vitro data impact of incorporating parallel pathways of drug elimination and inhibitor absorption rate constant British Journal of Clinical Pharmacology, 60 (5), 508-518. 

What makes prediction of drug elimination complex are the multiple possible pathways involved which explain why there is no simple in vitro clearance assay which predicts in vivo clearance. Because oxidative metabolism plays a major role in drug elimination, microsomal clearance assays are often used as a first line screen with the assumption that if clearance is high in this in vitro assay it is likely to be high in vivo. This assumption is often, but not always true because, for example, plasma protein binding can limit the rate of in vivo metabolism. However, compounds which have a low clearance in hepatic microsomes can be cleared in vivo via other mechanisms (phase II metabolism, plasmatic errzymes). Occasionally, elimination is limited by hepatic blood flow, and other processes like biliary excretion are then involved. The conclusion is that the value of in vitro assays needs to be established for each chemical series before it can be used for compound optimization. 

Oxybutynin has a relatively low oral bioavailability (6%) due to an extensive first-past presystemic metabolism after administration [194], Indeed, the absence of intact oxybutynin in urine suggests that the major elimination pathway of this drug is hepatic metabolism [195]. The compound is readily converted to its stable toxic metabolite, iV-desethyloxybutynin by cytochrome P450-mediated oxidation [196], Following oral administration of oxybutynin, peak plasma concentrations are reached within 1 h. The short half-life of this drug (less than 2 h), when administered as a conventional oral formulation, necessitates multiple 5 mg daily dosing [197],... 

Oral administration is the most complicated method of administration covered in this text. Modeling the plasma concentration of an orally administered drug combines both elimination pathways and absorption of a drug after it has been ingested. 

The distribution and metabolism of protein-based biotech drugs, for example, generally follows the mechanisms of endogenous and nutritional proteins. This includes, for example, unspecific proteolysis as a major elimination pathway for proteins rather than oxidative hepatic metabolism typical for the majority of small-molecule drugs. As a consequence, drug interactions studies focused on cytochrome P-450 enzymes do not usually need to be performed for protein-based biotech drugs [17]. 

Target-mediated drug disposition is often associated with nonlinearity in the pharmacokinetics of the affected drug, as the elimination pathway mediated via... 

For most traditional small-molecule drugs, allometric scaling is often imprecise, especially if hepatic metabolism is a major elimination pathway and/or if there are interspecies differences in metabolism. For peptides and proteins, however, allometric scaling has frequently proven to be much more precise and reliable,... 

The neutrophil-mediated clearance was expressed as a Michaelis-Menten function, because G-CSF receptor binding is subject to saturation. The product of kcat and the ratio of ANC and ANC at baseline is the maximum velocity of drug elimination from this pathway, km is the Michaelis constant, and C is the pegfilgrastim concentration. CL2 denotes the linear clearance pathway. 

Since both l]/2 and /cei are constant for elimination processes following first order kinetics, Cl will also be constant. Flowever, should the order of the elimination change due to a change in the biological situation, such as the drug concentration increasing to the point where it saturates the metabolic elimination pathways, then clearance may not be constant. 

Figure 11 Relationship between the inhibitor index Ri and the degree of inhibition of a metabolic pathway for various values of the fraction of the drug eliminated by that pathway in the absence of the inhibitor, /m.

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