Metabolism plasma protein binding

The recommended dose of pemetrexed is 500 mg/m2 administered as an intravenous infusion over 10 min on Day 1 of each 21-day cycle. Pemetrexed is not metabolized to an appreciable extent and is primarily eliminated in the urine, with 70-90% of the dose recovered unchanged within the first 24 h following administration. Pemetrexed has a steady-state volume of distribution of 16.1 L. Pemetrexed is highly bound (approximately 81%) to plasma proteins. Binding is not affected by the degree of renal impairment. Plasma... 

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

Above 5 Low solubility and poor oral bioavailability. Erratic absorption. High metabolic liability, although potency may still be high. Basic amines tend to show high to very high Vd (Volume of distribution = ratio of overall tissue binding to plasma protein binding)... 

A combination of various properties of antipyrine gives it an advantage over other microsomal enzyme metabolizing drugs. These include high oral availability useful for non-invasive oral administration, lack of plasma protein binding which prevents environmental clearance variability, and fast distribution... 

Phenylbutazone is metabolized by the liver at a rate of about 15-25% per day (B33), but plasma levels do not increase proportionately with increasing doses of the drug. The work of Burns et al. (B33) indicates that above a certain level plasma phenylbutazone concentrations plateau. The concentration at which this occurs varies among individuals and is probably a reflection of the level at which saturation of high-affinity plasma protein binding sites occurs. 

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. 

Pharmacokinetics The elimination half-lives of these drugs range from 4 to 8 hours. Elimination is primarily via hepatic metabolism. Plasma concentrations of alosetron are 30% to 50% lower and less variable in men compared with women given the same dose. Plasma protein binding is 82% for alosetron, 65% for granisetron and 70% to 76% for ondansetron. The terminal elimination half-life of alosetron is approximately 1.5 hours. 

Pharmacokinetics Entacapone is rapidly absorbed, with a T ax of approximately 1 hour. The absolute bioavailability following oral administration is 35%. The plasma protein binding of entacapone is 98%, mainly to serum albumin. Entacapone is almost completely metabolized prior to excretion, with only a small amount (0.2% of dose) excreted in the urine. 

The plasma protein binding of tacrolimus is approximately 99%. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein and has a high level of association with erythrocytes. It is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P450 system (CYP3A). The disposition of tacrolimus from whole blood was biphasic with a terminal elimination half-life of 11.7 hours in liver transplant patients. 

Abbreviations Sol, aqueous solubility F, bioavailability PPB, plasma protein binding Met, metabolism Tox, toxicity PA, passive absorption AP, apparent permeability. 

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. 

Data generated from metabolic clearance measurements using liver microsomes can lead to an overestimation of the tme in vivo clearance if the free versus bound fraction is not considered. A useful follow-up assay is therefore plasma protein binding measurement. The impact of cytochrome P-450 inhibition on metabolic clearance of the parent (and thus exposure) is more complicated and it remains rather difficult to make quantitative predictions from in vitro data alone. The reason is that there are generally multiple clearance pathways involved and genetic polymorphism needs to be considered as well. 

Christensen, H., Baker, M., Tucker, G.T. and Rostami-Hodjegan, A. (2006) Prediction of plasma protein binding displacement and its implications for quantitative assessment of metabolic drug-drug interactions from in vitro data. Journal of Pharmaceutical Sciences, 95, 2778-2787. 

Zidovudine was the first drug of the class. It is a dideoxythymidine analog. It has to be phos-phorylated to the active triphosphate. This triphosphate is a competitive inhibitor of HIV reverse transcriptase. By incorporation into viral DNA it also acts as a chain-terminator of DNA synthesis. Mutations in viral reverse transcriptase are responsible for rapidly occurring resistance. Zidovudine slows disease progression and the occurrence of complications in AIDS patients. It is readily absorbed. However, first pass metabolism reduces its oral bioavailability with some 40%. It readily crosses the blood-brain barrier. Plasma protein binding is about 30%. Zidovudine is glucuronidated in the liver to an inactive metabolite. Its elimination half-life is 1 hour. 

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