Clearance, drugs

Maintenance doses widely vary among patients (e.g., from 1 to 20 mg/day for warfarin), and are influenced by diet (variable vitamin K intake) and medications that affect coumarin metabolism (decreased drug clearance e.g., cotrimoxazole, amiodarone, erythromycin increased clearance e.g., barbiturates, carbamaze-pine, rifampin). Thus, regular monitoring is needed... 

The glucan synthase inhibitor caspofungin (intravenous formulation) is new on the market for the treatment of invasive aspergillosis in patients whose disease is refractory to, or who are intolerant of, other therapies. During the clinical trials fever, infused vein complications, nausea, vomiting and in combination with cyclosporin mild transient hepatic side effects were observed. Interaction with tacrolismius and with potential inducer or mixed inducer/inhibitors of drug clearance was also seen. 

A special case for reduced bioavailabilty results from first-pass extraction that sometimes might be subjected to saturable Michaelis-Menten absorption kinetics. The lower the hepatic drug clearance is (Clhep) in relation to liver blood flow (Ql), or the faster the drug absorption rate constant (Ka), and the higher the dose (D) are, the more bioavailable is the drug (F). 

Total drug clearance is the sum of nonrenal clearance and renal clearance (Clren). According to the MDRD-2 formula, the estimated GFR (eGFR) is a function of serum creatinine (SCr in mg/dl) and age (Age in years). It has the unit ml/min per 1.73 mA2. 

The renal clearance can be under estimated in the case of renal drug metabolism. The total drug clearance depends on bioavailability. Therefore, the most reliable estimate for the fraction eliminated by the renal route (fren) is given by the normal clearance (Clnorm) and drug clearance in case of acute and/ or chronic renal failure (Clfail), or from half-lives (Tl/2norm) and (Tl/2fail). 

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. 

Ito K and Houston JB. Prediction of human drug clearance from in vitro and preclinical data using physiologically based and empirical approaches. Pharm Res 2005 22 103-12. 

Yap, C. W U, Z. R Chen, Y. Z. Quantitative strucmre-pharmacokinetic relationships for drug clearance by using statistical learning methods. /. Mol. Graph. Model. 2006, 24, 383-395. 

Pharmacodynamics Duration 1-4 weeks Absorption IM slow Time to peak serum levels 12-24 hours Duration 15-24 hours Absorption IM slow Distribution Poor blood-brain barrier penetration, enters breast milk Metabolism =30% hepatic inactivation Protein binding 65% Time to peak serum levels 1-4 hours Excretion Urine (60-90% as unchanged drug) Clearance Renal... 

KS Pang, M Rowland. Hepatic clearance of drugs. I. Theoretical considerations of a well-stirred model and a parallel tube model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance. J Pharmacokin Biopharm 5/6 625-653, 1977. 

Renal elimination of unchanged drug accounts for 66% of drug clearance, and the dose should be adjusted for impaired renal function. The role of therapeutic drag monitoring is unknown. It has linear pharmacokinetics and is metabolized in blood by nonhepatic enzymatic hydrolysis. 

Drug therapy optimization in ARF is a challenge. Confounding variables include residual drug clearance, fluid accumulation, and use of RRTs. 

The mode of CRRT determines the rate of drug removal, further complicating individualization of drug therapy. The rates of ultrafiltration, blood flow, and dialysate flow influence drug clearance during CRRT. 

Shitara, Y., Horie, T. and Sugiyama, Y. (2006) Transporters as a determinant of drug clearance and tissue distribution. European Journal of Pharmaceutical Sciences, 27, 425-446. 

The reference formulation is used to correct for differences in drug clearance between study populations when data from more than one study are combined. The reference formulation is chosen so that when it is used in deconvolution with the ER formulation, the in vivo drug release or absorption from the ER formulation is obtained. Appropriate reference formula-... 

When drugs are received by routes other than intravenous injection, input is not "instantaneous" or a short-order zero, and the function must often be represented as a mixed-order, primarily a first-order, process, which must then be taken into account in simulating drug concentration. Drug clearance, however, is not always a constant parameter, especially when an organ such as the liver is involved in the removal of the drug from the body ... 

A typical drug clearance curve is shown in Fig. 5.9. The curve in Fig. 5.9 is a first-order curve that is, the elimination rate is proportional to the amount of drug in the bloodstream. As the amount of drug in the blood is reduced, the elimination rate is also reduced. Another term often used is half-fife. This is the time taken to clear half (50%) of the remaining drug in the body. Mathematically, it is given by... 

Limited data are available on the pharmacokinetics of arecoline. Intravenously administered arecoline in subjects with Alzheimer s disease shows variation in the optimal dose (between 4 and 16 mg/day) due to differing plasma kinetics (Asthana et al. 1996). The mean plasma half-lives for these doses were 0.95 0.54 and 9.3 4.5 minutes, respectively. However, the mean plasma concentrations that optimized cognitive effects were 0.31 0.14 ng/ml. Drug clearance was 13.6 5.8 L/min and the volume of distribution was 205 170 L. 

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