Humans clearance

The size of the fibrous particles that appear to induce disease in the animal models is compatible with the measured respiratory range in humans (Lipp-man, 1977). Most particulate deposition takes place not in the upper or conducting portion of the airways but in the alveolar region of the pulmonary tree (the respiratory unit). Some surface deposition may occur at bifurcations in the bronchial tree, but the actual amount at each location is influenced by anatomy, specific to the species—probably to an individual—as well as the variety of fiber. A large proportion of airborne particulates are rejected as part of the normal clearance mechanisms in animals, but in humans clearance mechanisms may be compromised by smoking, for example. We are unaware of any experiments on fiber toxicity using smoking rats ... 

The incorporation of in vitro metaboHsm data into allometric seating of compounds cleared by hepatic metabolism has been extensively evaluated [18] and shown to accurately predict human clearance. In this review it is suggested that the utility of such methods are most appropriately applied in drug candidate selection, to confirm early estimates and to support early clinical studies. 

In a first step the scaling of intrinsic clearances determined in rat hepatocytes was compared to in vivo clearance. When taking account of non-linearity, the estimated hepatic metabolic clearance values were in reasonable agreement with observed total clearances, which ranged from 7 to 35 mL/min/kg, and it was considered reasonable to estimate the expected clearances in human by a similar scaling of human hepatocyte data. The error around the mean predicted human clearance was based on the variability seen in different batches of human hepatocytes. 

Obach RS. The prediction of human clearance from hepatic microsomal metabolism data. Curr Opin Drug Discov Devel. 2001 4 36-44. 

There are limited data on the distribution of aluminum in humans. Clearance of26Al from the blood was assessed in 2 male volunteers orally exposed to 100 mg aluminum as aluminum chloride (Hohl et al. 

Obach RS. Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data an examination of in vitro half-life approach and nonspecific binding to microsomes. Drug Metab Dispos 1999 27 1350-1359. 

Mahmood I. The correction factors do help in improving the prediction of human clearance from animal data. J Pharm Sci 2005 94(5) 940-5 author reply 946-7. 

Toxicokinetics TCA is readily absorbed from the gastrointestinal tract in experimental animals and humans and its clearance from blood is relatively slow relative to other HAAs. Approximately half of the administered dose was eliminated unchanged. There are substantial differences in the clearance by different species. Clearance is much faster in mice than in rats and human clearance is very slow. The half-life is 5.8 h in mice, 9.3 h in rats, 50 h in humans and approximately 200 h in dogs. TCA produces same metabolites as DCA with or without being converted to DCA. 

Galetin, A., Brown, C., Hallifax, D., Ito, K. and Houston, J.B. (2004) Utility of recombinant enzyme kinetics in prediction of human clearance impact of variability, CYP3A5, and CYP2C19 on CYP3A4 probe substrates. Drug Metabolism and Disposition The Biological Fate of Chemicals, 32, 1411-1420. 

At this point, the standard equation for hepatic clearance (see Equations 9.9 and 9.12) is used to convert CLillt to in vivo human clearance (CLH(Caic)) ... 

Wong H, Lewin-Koh SC, Theil FP, Hop CE. 2012b. Influence of the compound selection process on the performance of human clearance prediction methods. 7 Plrarm Sci 101 509-515. 

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