Plasma clearance values

A substance that fulfills these criteria is para-aminohippuric acid (PAH). All of the PAH not filtered at the glomerulus is secreted by the proximal tubule. The net effect is that all of the plasma flowing through the nephrons is completely cleared of PAH. It is important to note that about 10 to 15% of the total renal plasma flow supplies regions of the kidneys that are not involved with filtration or secretion. Consequently, this plasma cannot be cleared of PAH. Therefore, the plasma clearance of PAH provides a measurement of the effective renal plasma flow, that is, the volume of plasma that actually flows through the nephrons. The ERPF is normally about 625 ml/ min. (This value is based on a renal blood flow of about 1.1 1/min and a hematocrit of about 42.)... 

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. 

If the apparent plasma clearance (dose/area under the plasma concentration-time curve, equivalent to true clearance/fraction of dose absorbed) gives an implausibly high value of clearance (e.g., greater than hepatic and renal plasma flow), it is likely the bioavailability is low. However, this could be due to presystemic metabolism in addition to low absorption. 

The clearance of a drug is usually defined as the rate of elimination of a compound in the urine relative to its concentration in the blood. In practice, the clearance value of a drug is usually determined for the kidney, liver, blood or any other tissue, and the total systemic clearance calculated from the sum of the clearance values for the individual tissues. For most drugs clearance is constant over the therapeutic range, so that the rate of drug elimination is directly proportional to the blood concentration. Some drugs, for example phenytoin, exhibit saturable or dose-dependent elimination so that the clearance will not be directly related to the plasma concentration in all cases. 

Plasma clearance (Cl), blood-brain barrier permeability surface area product (PS) and accumulation as % injected dose detected in brain tissue (%ID tissue) at 1 h after administration. Results show free [ H]-daunomycin (Daunomycin), [ H]-daunomycin encapsulated in conventional liposomes (Liposomes), sterically stabilized liposomes (PEG-liposomes), immunoliposomes (29 0X26, where 29 designates the number of 0X26 mAb conjugated per liposome) and control immunoliposomes where the 0X26 mAb was replaced by a non-specific isotype control antibody (IgG2a). Values are means SEM of n = 3 experiments. 

Abbreviations include t elimination half-life Cl, total plasma clearance and Clj-enab renal clearance. Data expressed as mean values (from James et al., 1998). 

Animal studies Pharmacokinetics of hyperforin after administration of an ethanolic SJW extract (WS 5572, Dr. Willmar Schwabe, Karlsruhe, Germany) to rats were investigated by Biber et al. (72). Maximum plasma levels of approximately 370ng/mL (approximately 690 nM) were reached after three hours. Estimated half-life and clearance values were six hours and 70mL/min/kg, respectively. 

In an attempt to further simplify the caffeine phenotyping test, a trait measure based on the plasma or salivary paraxanthine caffeine concentration ratio between three hours and seven hours after administration of the probe has been suggested (56). High linear correlations (>0.89) have been observed between this trait value and caffeine s oral clearance, and if necessary, a predicted caffeine clearance value may be calculated from the ratio (56). Currently, this phenotyping approach appears to be the simplest and most noninvasive means of readily assessing CYP1A2 activity using caffeine as a probe in addition, the method is reproducible and appears to be robust (56), despite the theoretical dependency of the trait value on the urine flow rate (51). 

A strong inhibitor is one that causes a >fivefold increase in the plasma AUC values or more than 80% decrease in clearance of CYP substrates (not limited to sensitive CYP substrate) in clinical evaluations... 

In the ferret, aprepitant (1) shows a plasma half-life of 9.7 h after a 0.5 mg/kg i.v. dose. The volume of distribution is 1.3 L/kg, giving a clearance value of 1.5 mL/min/kg, and confirming the slow clearance of the compound and long duration of action seen in the in vivo studies reported above. After a 1 mg/kg p.o. dose, Tmax is reached in 3.3 h, and the oral bioavailability is 45%. 1 Brain penetration was assessed in this study using C-14-labeled aprepitant, which showed a brain to plasma ratio of about 0.8 after an oral dose of 3 mg/kg. Although several metabolites of aprepitant were detected, the study concluded that the activity of aprepitant was due to the parent drug. 

The binding to plasma or subcellular liver fraction can be taken into account for the prediction of human pharmacokinetic parameters either from preclinical and/or in vitro metabolism data (Obach et al. 1997 Mahmood 2000). Obach (1999) showed by comparison the in vivo investigated clearance values and clearance values projected from in vitro intrinsic clearance data of 29 drugs that the inclusion of blood and liver microsomes binding values gave the best agreement. 

IFOSFAMIDE CISPLATIN t risk of neurotoxicity, haematotoxicity and tubular nephrotoxicity of ifosfamide due to t plasma concentrations of ifosfamide Cisplatin tends to cause renal damage, which results in impaired clearance of ifosfamide Do renal function tests before initiating therapy and during concurrent therapy, and adjust dosage based on creatinine clearance values. Advise patients to drink plenty of water -vigorous hydration - and consider mesna therapy for renal protection... 

We can use these recovery clearances to examine the effective flow of plasma (Qeff) that is needed if Equation 6.2 is to yield an estimate of dialysis clearance that is consistent with the corresponding recovery clearance value. Since CLb = Qb / it follows from Equation 6.4 that ... 

Since UFR cannot exceed blood flow through the hemofilter/ that establishes the theoretical upper limit for CLuf- The major determinants of SC are molecular size and the unbound fraction of a compound in plasma water. Values of SC may range from 0/ for macromolecules that do not pass through the pores of the hemofilter membrane/ to 1, for small-molecule drugs that are not protein bound. Although less information has been accumulated about the ultrafiltration clearance of drugs than about their dialysis clearance/ in many cases the unbound fraction of drug in plasma water can be used to approximate SC. 

What is the underlying cause for these interspecies differences For equal doses, differences in plasma AUC values simply indicate differences in total body clearance. Renal and metabolic elimination processes are the major contributors to total body clearance. When allometric scaling is used as described in Chapter 30, renal clearance tends to exhibit only small differences across species, whereas there are many examples of interspecies differences in metabolism. Further, across many drug categories, metabolism is quantitatively more important than is renal elimination. Therefore, more emphasis on inter species differences in drug metabolism could improve Phase I studies. The next two sections provide specific examples of the impact of monitoring metabolism during early human studies. 

Antipyrine is oxidized through biotransformation, independently of perfusion, predominantly in the micro-somes, and is excreted after hydroxylation and conjugation. After oral administration (15 or 18 mg/kg BW, respectively), the metabolic clearance ability of the liver (metabolic capacity of the microsomal monooxygenase system) can be assessed by computation of the concentration curve and the plasma half-life (after 3 and 24 hours). The serum half-life and plasma clearance are significantly enhanced/decreased, depending on the reduction in liver function. There is a close correlation with the galactose elimination capacity as well as with Quick s value. (58-60, 74, 88)... 

---