Renal excretion, model

PK modeling can take the form of relatively simple models that treat the body as one or two compartments. The compartments have no precise physiologic meaning but provide sites into which a chemical can be distributed and from which a chemical can be excreted. Transport rates into (absorption and redistribution) and out of (excretion) these compartments can simulate the buildup of chemical concentration, achievement of a steady state (uptake and elimination rates are balanced), and washout of a chemical from tissues. The one- and two-compartment models typically use first-order linear rate constants for chemical disposition. That means that such processes as absorption, hepatic metabolism, and renal excretion are assumed to be directly related to chemical concentration without the possibility of saturation. Such models constitute the classical approach to PK analysis of therapeutic drugs (Dvorchik and Vesell 1976) and have also been used in selected cases for environmental chemicals (such as hydrazine, dioxins and methyl mercury) (Stem 1997 Lorber and Phillips 2002). As described below, these models can be used to relate biomonitoring results to exposure dose under some circumstances. 

Because of the kidney s involvement in the excretion of hydrophilic compounds and because most of the substrates of P-gp are hydrophobic compounds that are likely to be cleared mainly by biliary excretion or intestinal secretion, comparably fewer studies have been performed with the isolated perfused kidney. The isolated perfused rat kidney model was used to demonstrate that digoxin is actively secreted by P-gp located on the luminal membrane of renal tubular epithelial cells and that clinically important interactions with qui-nidine and verapamil are caused by the inhibition of P-gp activity in the kidney (332). These results provide an excellent example of how the isolated perfused kidney model can be used to definitively conclude that P-gp-mediated efflux is involved in the renal excretion of a compound and also to elucidate possible DDIs that might arise in the kidney following coadministration of P-gp sub strates/inhibitors. 

Most substances intermix rapidly within their distribution spaces, and the rate-limiting step in their removal from the system is biochemical transformation or renal excretion. Substances of this nature are best described by compartmental models and exponential functions. 

Most species have low plasma levels and low renal excretion of uric acid and thus are poor models for the human. There are two exceptions, however the Dalmatian dog and the Cebus monkey. 

To evaluate the pattern and the rate of excretion, the residual concentration of the drug in the body one week after administration and the estimation of the absorption in case of a relevant renal excretion. The kind of study is obligatory for the registration as a drug when the rat is chosen as rodent model (in toxicology). 

Over the years, research efforts in biomedical sciences from academia, industry, and government institutions have underpinned a wealth of detailed knowledge regarding metabolism and physiology in humans and vertebrates, and many TK models have been developed. A critical aspect for the development of such models is the identification of the specific enzymes involved in the metabolism of a particular compound. For vertebrates these enzymes are well characterized, at least in terms of structure, if not also in terms of function, but such detailed knowledge is not available for invertebrates. In humans, metabolic routes can be split into phase I, phase II, and renal excretion. However, the relatively recent characterization of transporters such as P-glycoprotein has introduced them in the system as phase 0 or phase III because they can transport the parent compound or the metabolite. Major metabolic routes include phase I enzymes responsible for initial oxidation, reduction, and hydrolysis... 

For renal excretion, we used the model shown in Figure 3. Here, the rate constant for the decrease in the concentration of drug in the blood by glomerular ultrafiltration is ku for the tubular reabsorption process is k2, and for the movement of drug from tubule to bladder is fc3-We assume that k2 is much larger than and that concentration of the... 

Poola et al studied the renal excretion of pentamidine in the isolated perfused rat kidney, which is an established model to study the renal disposition of drugs and that correlates with in vivo disposition. The data showed that a combination of filtration, active secretion and passive reabsortion are involved in the renal disposition of pentamidine [150]. 

DC Mays, KF Dixon, A Balboa, LJ Pawluk, MR Bauer, S Nawoot, N Gerber. A nonprimate animal model applicable to zidovudine pharmacokinetics in humans Inhibition of glucuronidation and renal excretion of zidovudine by probenecid in rats. J Pharm Exp Ther 259 1261, 1991. 

In this model, CIh.it is defined as the ability of the organ to remove drug in the absence of flow and binding restrictions. In terms of renal excretion, deseribes tubular secretion. 

Papich and Riviere report marked variability in aminoglycoside pharmacokinetics (distribution, clearance, and half-life) with altered physiologic or pathologic states, including pregnancy, obesity, dehydration, immaturity, sepsis, endotoxemia, and renal disease. The latter influence is predictable from the fact that body clearance is dependent almost entirely on renal excretion. Martin-Jimenez and Riviere concluded that aminoglycoside pharmacokinetics can be predicted across species by population pharmacokinetic modeling. ... 

In recent years, in vitro models to predict biliary excretion have been introduced. Prior to that, most models involved animals whose bile ducts were cannulated or ligated. Note that renal excretion, not otherwise discussed herein, although not part of the first pass effect, is a very important clearance mechanism for small, polar molecules, in many ways acting as a counterpart to biliary excretion. 

Transporters are involved in biliary and renal excretions that are the two common routes of drug elimination. In the liver, a drug is first taken up into hepatocytes, then either secreted back to the systemic circulation or excreted to the bile in an intact form or as metabolites via Phase I and/or Phase II enzymes. Given the involvement of transporters in both uptake at the sinusoidal membrane and efflux at the sinusoidal and canulicular membranes (Fig. 6.1c), the hepatic clearance can be expressed based on well-stirred model as the following equation (Shitara et al., 2005 Yamazaki et al., 1996) ... 

Figure 3.18 Scheme of one-compartment intravenous bolus model of drug eliminated by both urinary excretion and metabolism. X,mass (amount) of drug in the blood/body at time, t X , mass of unchanged drug in the urine at time t Xm, mass of metabolite in the blood/body at time f X u, mass of metabolite in the urine at time t ff , first-order renal excretion rate constant (time ) K , first-order metabolite formation rate constant (time ) Kmu, first-order metabolite excretion rate constant (time ). 

On the basis of nickel concentrations in the air, plasma, and urine of four nickel platers, Tossavainen et al. [29] calculated biological half-lives in plasma of 20-34 hr and in urine of 17-39 hr referring to a one-compartment-model. Raithel et al. [30] estimated the half-life of renal excretion on the basis of nickel concentrations in urine firom an electroplating worker to 30-50 hr. 

Renal Anthracyclines have minimal renal excretion, being mainly eliminated in bile, and although they are nephrotoxic in some animal models, do not induce major renal toxicity in humans [63 ]. However, PLD induces a high incidence of chronic kidney disease (CKD) and hypertension in women treated long term for recurrence of ovarian cancer. Of 56 patients with recurrent ovarian cancer that were treated with PLD for at least six cycles, 13 developed stage three or higher CKD. Prior exposure to platinum compounds appears to be involved in this toxicity [64 ]. 

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