Clearance in vivo

Benmansour, S., Owens, W.A., Cecchi, M., Morilak, D.A., and Frazer, A., Serotonin clearance in vivo is altered to a greater extent by antidepressant-induced downregulation of the serotonin transporter than by acute blockade of this transporter, J. Neurosci. 22(15), 6766-6772, 2002. 

Serum protein binding is an important contributor to distribution and clearance in vivo. In addition, results from in vitro tests of compounds with high serum protein binding are expected to be sensitive to the presence of serum or other proteins in assay incubations. 

Taylor M, Le Goff L, Harris A, Malone E, Allen JE, Maizels RM Removal of regulatory T cell activity reverses hyporesponsiveness and leads to filarial parasite clearance in vivo. J Immunol 2005 174 4924-4933. 

Artemisinin-based regimens are often regarded as safe and effective drugs in the recent years however, clinically relevant artemisinin resistance has been reported both from laboratory and field studies. Some of these studies have shown that P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. This resistance was characterized by a slow parasite clearance in vivo, without corresponding reductions on conventional in vitro susceptibility testing.Although this resistance to artemisinin is still very mild and limited, its emergence would be disastrous because of the lack of alternative treatments. 

Gabizon, A., and Papahadjopoulos,D. (1992),The role of surface charge and hydrophihc groups on liposome clearance in vivo, Biochim. Biophys. Acta, 1103, 94-100. 

Partida-Sanchez, S., Cockayne, D. A., Monard, S., Jacobson, E. L., Oppenheimer, N., Garvy, B., Kusser, K., Goodrich, S., Howard, M., Harmsen, A., Randall, T. D., and Lund, F. E. (2001). Cyclic ADP-ribose production by CD38 regulates intracellular calcium release, extracellular calcium influx and chemotaxis in neutrophils and is required for bacterial clearance in vivo. Nat. Med. 7, 1209-1216. 

FIGURE 30.10 Intrinsic clearance in vivo versus hepatic microsomal clearance of 19 drugs metabolized by cytochromes P450 in the rat. The line represents the predicted correlation. In vitro clearance lA as measured either by substrate loss ( ) or metabolite formation ( ). Intrinsic clearance lA as normalized to a standard rat weight (SRW) of 250 grams. (Reproduced with permission from Houston JB. Biochem Pharmacol 1994 47 1469-79.)... 

He P, Court M H, Greenblatt D J, et al. (2005). Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo. Clin. Pharmacol. Ther. 71 313-318. 

Profiling of elevated plasma coneentrations of bile acids provides evidence of functional inhibition of bile salt clearance in vivo. This has been observed in rats exposed to a variety of drugs that inhibit BSEP activity in vitro, and in some instances also in humans (Fattinger et al., 2001), which snggests that evalnation of plasma (or serum) bile acids could provide a useful noninvasive biomarker of in vivo BSEP inhibition. However, since uptake carriers on the basolateral plasma membrane domain mediate hepatic nptake of bile acids and therefore also play important roles in bile acid clearance (Kullak-Ublick et al., 2004), potential interactions involving these transporters need to be considered when interpreting effects of compounds on plasma bile acid concentrations. In addition, elevated bile acid concentrations have been observed in plasma and urine from rats treated in vivo with a variety of hepatotoxic drugs, some of which do not inhibit BSEP (e.g., acetaminophen, carbam-azepine Yamazaki et al., 2013). Therefore while elevated total plasma bile acid levels can provide a nseful indirect index of impaired in vivo BSEP-mediated bile salt clearance, they may also arise due to other mechanisms and so cannot be considered a specific in vivo BSEP inhibition biomarker. 

Soars MG, Grime K, Sproston JL, Webbom PJ, Riley RJ. Use of hepatocytes to assess the contribution of hepatic uptake to clearance in vivo. Drug Metab Dispos 2007a 35 (6) 859-865. 

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