Clearance hepatic

Tirona RG, Schwab AJ, Geng W, Pang KS. Hepatic clearance models comparison of the dispersion and Goresky models in outflow profiles from multiple indicator dilution rat liver studies. Drug Metab Dispos 1998 26 465-75. Bassingthwaighte JB, Sparks HV. Indicator dilution estimation of capillary endothelial transport. Anna Rev Physiol 1986 48 321-34. 

Houston JB, Carlile DJ. Prediction of hepatic clearance from microsomes, hepa-tocytes, and liver slices. Drug Metab Rev 1997 Nov 29(4) 891-922. 

Thus, if the hepatic clearance for a drug is largely relative to the hepatic blood flow, the extent of availability for this drug will be low when it is given by a route that yields first-pass effects. The decrease in availability is a function of only the anatomical site... 

KS Pang, M Rowland. Hepatic clearance of drugs. I. Theoretical considerations of a well-stirred model and a parallel tube model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance. J Pharmacokin Biopharm 5/6 625-653, 1977. 

As described above, it will be normal to assume that the dose interval is 24 hours, i.e., once-a-day dosing. Absorption can be estimated with good confidence from absorption in the rat (see Section 6.1). Clearance is the sum of the predicted hepatic, renal, biliary and extrahepatic clearance. Hepatic clearance can be derived from in vitro studies with the appropriate human system, using either microsomes or hepatocytes. We prefer to use an approach based on that described by Houston and Carlile [83], Renal clearance can be predicted allometrically (see section 6.8.1). The other two potential methods of clearance are difficult to predict. To minimize the risks, animal studies can be used to select compounds that show little or no potential for clearance by these routes. As volume can be predicted from that measured in the dog, after correction for human and dog plasma protein binding (see Section 6.2), it is possible to make predictions for all of the important parameters necessary. 

Peripheral Compartment Third Compartment A Renal and other extra-hepatic clearances... 

It was determined that 9.5% of an oral 80-mg dose of verapamil was absorbed in a 70-kg test subject. However, because of extensive bio transformation during its first pass through the portal circulation, the bio availability of verapamil was only 25%. Assuming a liver blood flow of 1500 mLAmin, the hepatic clearance of verapamil in this situation was... 

Incomplete (N-linked) glycosylation prompts decreased in vivo activity due to more rapid hepatic clearance of the EPO molecule. Enzymatic removal of terminal sialic acid sugar residues from oligosaccharides exposes otherwise hidden galactose residues. These residues are then free to bind specific hepatic lectins, which promote EPO removal from the plasma. The reported plasma tm value for native EPO is 4-6 h. The tm for desialated EPO is 2 min. Comparison of native human EPO with its recombinant form produced in CHO cells reveals very similar glycosylation patterns. 

Excessive dietary intake of cholesterol and saturated fatty acids leads to decreased hepatic clearance of LDL and deposition of LDL and oxidized LDL in peripheral tissues. 

An important DMPK property of a NCE is oral bioavailability (F) of the compound in various pre-clinical species.3 The oral bioavailability of a compound is dependent on several factors including intestinal permeability (estimated by the Caco-2 assay) and hepatic clearance (estimated with an in vitro metabolic stability assay).3 30 The metabolic stability assay is typically performed by incubating test compounds in liver microsomes or hepatocytes. The results can provide estimates of in vivo stability in terms of metabolic liabilities.3 8 59 62 Several authors described this assay as an important tool for the rapid assessment of the DMPK properties of NCEs.3 6 8111819 26 44 59 62-65... 

Lau, Y.Y. et al. 2002. Development of a novel in vitro model to predict hepatic clearance using fresh, cryopreserved, and sandwich-cultured hepatocytes. Drug Met. Disp. 30 1446. 

The species differences in biotransformation pathways, rates of elimination, and intrinsic hepatic clearance of esfenvalerate and deltamethrin using rat and human liver microsomes were examined [33]. Esfenvalerate was eliminated primarily via NADPH-dependent oxidative metabolism in both rat and human liver microsomes. The CLint of esfenvalerate was estimated to be threefold greater in rodents than in humans on a per kg body weight basis. Deltamethrin was also eliminated primarily via NADPH-dependent oxidative metabolism in rat liver microsomes however, in human liver microsomes, deltamethrin was eliminated almost entirely via... 

The volume of biological fluid totally cleared of xenobiotic per unit time and usually includes hepatic clearance and renal clearance. 

S. Suzuki, A. Kagayama, A. et ah Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans. Drug Metab Dispos 2001, 29, 1316-1324. 

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