Half-life clearance

The use of SOD in therapy is limited by its short plasma half-life (clearance by the kidney) and inability to penetrate cell membranes... 

Figure 4 Log-log plot of clearance versus volume of distribution of various drugs in humans illustrating that for a given half-life, clearance and volume of distribution can vary widely. Source Adapted from Ref. 8.

Studies on humans and dogs show that sulfur dioxide is excreted primarily in the urine as sulfate (Savic et al. 1987 Yokoyama et al. 1971). Yokoyama et al. (1971) exposed dogs via inhalation to 35S02 and determined that 35S was excreted primarily in the urine as sulfate. An average of 84.4% of the urinary radioactivity was exhibited as inorganic sulfate 92.4% was total sulfate. In humans it is estimated that 12-15% of sulfur dioxide absorbed to mucous membranes is desorbed and exhaled (Speizer and Frank 1966). Plasma S-sulfonates are relatively long-lived in the body, with half-life clearance of 4.1 d in rabbits exposed to 10 ppm sulfur dioxide (Gunnison and Palmes 1974). 

Longer elimination half-life clearance is reduced... 

The half-life of a drug is a major contributor to the dosing regimen, and it is a function of the clearance and apparent volume of distribution (VD), each of which can be predicted and combined to predict the half life. Drugs with short half-lives are more likely to be required to be administered more frequently than those with long half-lives. Much attention has been focused on the prediction of human half-life. Good success is attained if the two major components of half-life, clearance and VD, are predicted separately and combined to generate a half-life prediction. 

For an ideal, so-called one-compartment drug (i.e., one that is in rapid equilibrium with all tissues), the parameters half-life, clearance, and volume of distribution are interrelated by Equation 6 (1, p. 24). Because half-life and clearance can be determined independently, it is possible to calculate V. Equation 6 shows that two drugs that have the same volume of distribution but different clearances will have different half-lives, which means that one drug will maintain plasma concentrations longer than the other and may need less frequent dosing. 

The oxicam NSAID isoxicam has a shorter half-life (30 hours) than piroxicam. However, there are large variations in half-life, clearance, and mean steady-state plasma concentrations. Except for edema, the incidence of adverse effects is unrelated to age (1). 

Test Items. As a rule, the pharmacokinetic parameters of test substances such as maximum concentration (Cmax) and time to reach maximum concentration (Tmax), area under curve (AUC), elimination half-life, clearance, distribution volume, bioavailability, etc., and pharmacokinetic nonlinearity are studied. The pharmacokinetics of metabolites of the test substance should be examined if necessary. 

In a placebo-controlled study in 12 healthy subjects, intravenous pantoprazole 240 mg for 7 days did not change the half-life, clearance and AUC of a 100-microgram/kg intravenous bolus dose of diazepam."... 

Key PK parameters such as bioavailability, plasma elimination half-life, clearance, and volume of... 

Drug Administration Dose (Pg/kg) Plasma level (pg/ml) Volume of distribution Elimination half-life Clearance Recommended administration... 

Structural Physicochemical Biochemical Pharmacokinetic Molecular weight, ionization, polarity, lipophilicity/hydrophilicity, shape, reactivity, polar surface area, H-bonding Solubility, dissolution rate, permeability, chemical stability Protein/tissue/cell binding, metabolism, receptor mediated transport (influx and efflux) Bioavailability, half-life, clearance, drug-drug interactions, toxicity, maximum concentrations in plasma... 

The principal organs involved in the peripheral clearance of hGH from the plasma are the kidney and fiver. hGH is cleared via glomerular filtration at the kidney and by a receptor-mediated mechanism at the fiver (58,59). In animal models, derivatives of hGH such as the 20,000 mol wt variant, oligomeric forms, and hGH complexed with GH-binding protein have been shown to be cleared from the semm at significandy lower rates than 22,000 mol wt hGH (60—62). The prolonged plasma half-life of these derivatives probably reflects a combination of decreased receptor affinity and size constraints on glomerular filtration. 

Lack of favorable ADME properties (absorption, distribution, metabolism, elimination) can preclude therapeutic use of an otherwise active molecule. The clinical pharmacokinetic parameters of clearance, half-life, volume of distribution, and bioavailability can be used to characterize ADME properties. 

Pharmacokinetics. Figure 1 Main pharmacokinetic processes and parameters Half-life (T1/2), volume (Vd), elimination rate constant (Ke), and clearance (Cl). 

The effect of hemofiltration on drug elimination can be estimated from serum creatinine (SCr), age, and the MDRD-2 formula to predict the combined effect of filtration rate (eGFR = GFRresidual + HFR) on drug clearance and drug half-life during hemofiltration. 

Positron emission tomography studies using "C-toluene in nonhuman primates and mice showed a rapid uptake of radioactivity into striatal and frontal brain regions (Gerasimov et al. 2002). Maximal uptake of the radiotracer by these structures occurred 1 minutes after intravenous administration. Subsequently, clearance of the radiotracer from the striatal and frontal areas occurred rapidly, with a clearance half-life from peak uptake of 10—20 minutes. Radiotracer clearance from white matter appears to be slower... 

Little is known regarding the pharmacokinetic properties of volatile nitrites in humans, particularly isobutyl nitrite and its primary metabolite, isobutyl alcohol. In rodents, after an intravenous infusion of isobutyl nitrite, blood concentrations peaked rapidly and then declined, with a half-life of 1.4 minutes and blood clearance rate of 2.9 L/min/kg (Kielbasa and Fung 2000). Approximately 98% of isobutyl nitrite is metabolized rapidly to isobutyl alcohol, concentrations of which also decline rapidly, with a half-life of 5.3 minutes. Bioavailability of inhaled isobutyl nitrite at a concentration of 300-900 ppm is estimated to be 43%. 

Toluene, volatile nitrites, and anesthetics, like other substances of abuse such as cocaine, nicotine, and heroin, are characterized by rapid absorption, rapid entry into the brain, high bioavailability, a short half-life, and a rapid rate of metabolism and clearance (Gerasimov et al. 2002 Pontieri et al. 1996, 1998). Because these pharmacokinetic parameters are associated with the ability of addictive substances to induce positive reinforcing effects, it appears that the pharmacokinetic features of inhalants contribute to their high abuse liability among susceptible individuals. 

The development of pegylated (peg) interferons that possess a sustained absorption, a slower rate of clearance, and a longer half life than unmodified interferons led to further improvement of sustained virologic response rates especially for patients infected with genotype 1 (Fig. 1) (Fried et al. 2002 Manns et al. 2001 Zeuzem et al. 2000). 

Figure 3). Except for the first two days following administration, the clearance of activity from the body followed apparent first order rate kinetics. The half-life for clearance, ti/2, was 17.4 dt 5.6 days. As previously indicated, it was assumed that the relatively large amount excreted during the first 2 days had not been absorbed therefore, these values were not used in calculating the clearance rate. 

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