Hepatic clearance plasma protein binding

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. 

Buprenorphine is metabolized by the liver mediated by cytochrome P450 3A4, and its clearance is related to hepatic blood flow. Plasma protein binding is about 96%. The mean elimination half-life from plasma is 37 hours. 

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. 

For enantiomeric drugs with low organ clearance, differences in renal or hepatic clearance between stereoisomers may reflect their free fraction in the plasma and not real stereoselectivity of the ability of the organ to remove the free enantiomers (intrinsic clearance) from the plasma. Clearance differences between stereoisomers of verapamil and disopyramide may be a function of plasma protein binding differences. In addition, volumes of distribution as well as concentration ratios of stereoisomers in body fluids to total plasma and blood are influenced by plasma protein binding. For example, the larger volume of distribution and greater total body clearance of R-disopyramide compared to the S isomer may be explained by the lower... 

Numerous metabolic pathways involving mixed-fimction oxidases, esterases, transferases, and hydroxylases exhibit selectivity toward stereoisomeric substrates. Of all disposition differences that stereoisomers may display, the greatest stereoselectivity is expected in biotransformation, because of the specificity of metabolic enzymes and isoenzymes. The overall differences in hepatic clearance of stereoisomers reflect not only differences in intrinsic clearance (activity of drug metabolizing enzymes) for the isomers but also the steric effects of plasma protein binding and hepatic blood flow. 

Nicotine has low plasma protein binding (<5%) and a large volume of distribution (2-3 L/kg). It is eliminated mainly by hepatic metabolism, although some metabolism occurs in the lungs and kidneys. The main metabolites are cotinine (15% of the dose) and trans-3-hy-droxycotinine (45% of the dose). Only 10% of the absorbed dose is excreted unchanged in urine. In healthy adult smokers, nicotine has an apparent elimination half-life of 1-2 h and the average plasma clearance is 1.2 h (93). 

Protein Binding Measure Plasma Protein binding through dialysis Gauge potential for sequestration from renal and hepatic clearance... 

The relationship between chemical structure, lipophilicity, and its disposition in vivo has been extensively studied. These include solubility, absorption potential, membrane permeability, plasma protein binding, volume of distribution, and renal and hepatic clearance. Activities used in quantitative structure-activity relationships (QSAR) include chemical measurements and biological assays. QSAR currently are applied in many disciplines, with many pertaining to drug design and environmental risk assessment. 

The volume of distribution for ribavirin is large (-10 Ukg) owing to its cellular uptake. Plasma protein binding is negligible. The plasma t, increases to 200-300 hours at steady state, partly because erythrocytes concentrate ribavirin triphosphate and then release it with a of -40 days. Hepatic metabolism and rerml excretion of ribavirin and its metabolites are the principal routes of elimination. Hepatic metabolism involves deribosylation and hydrolysis to a triazole carboxamide. Ribavirin should be used cautiously in patients with creatinine clearances of <50 mUmin. 

After intravenous administration of I—1.3 mg/rrf of bortezomib in patients without renal or hepatic impairment, there is a rapid distribution phase (<10 minutes), followed by a longer elimination phase of 5—15 hours. Plasma protein binding averaged 83%. The mean terminal elimination in preclinical studies was 5.4 hours, with an average clearance of 66 Uh. Peak pharmacodynamic activity (proteasome inhibition) occurred at I hour with a mean of 61% inhibition and a tyi of 24 hours. Inhibition of the 20S subunit was 10—30% at 96 hours. Proteasome inhibition is highly concentration dependent. 

Warfarin enantiomers are extensively metabolized by liver, possess a low hepatic extraction ratio, and are extensively bound (> 99%) to plasma proteins (Table 3). Therefore any change in the protein binding of warfarin enantiomers may alter the clearance and plasma concentrations of R- and S-warfarin [54]. Yacobi and Levy [54] studied the plasma protein binding of racemic and individual enantiomers of warfarin in human blood. The free fraction of R-warfarin was significantly (32%) larger than that of S-warfarin (Table 3). The authors concluded that the difference in the potency of warfarin enantiomers could not be solely explained by the observed differences in the protein binding of the individual enantiomers but rather by the intrinsic ability of R- and S-warfarin for interactions with extravascular receptors. 

We next need to consider clearance parameters that are unaffected by hepatic blood flow and/or drug plasma protein binding. These parameters reflect the inherent ability of the hepatocytes to metabolize either total or unbound drug once it is presented to the liver. 

---