Drug distribution half-life

The half-life (fi/2) of a drug is a function of two variables clearance and volume of distribution. Half-life is directly related to volume of distribution (VD) and inversely related to clearance (CL) ... 

Also included in in vivo data is a set of human (90% of drugs) and animal pharmacokinetic (30% of drugs) data. While the in vitro data are generated in-house (Cerep), pharmacokinetic data are gathered from the literature. A variety of different parameters are covered including absolute bioavailability, oral absorption, clearance, volume of distribution, half-life, protein binding and excretion information. 

In this example, the increased unbound phenytoin concentration resulted in a larger volume of distribution (more free drug distributed to the tissues), increased clearance (more free drug available for metabolism), but no change in the drug s half-life. The paradox in this case is that the increased clearance caused the total phenytoin blood concentration to go down, while the free concentration was elevated and led to clinical toxicity. Moreover, the unchanged half-life would not have clarified the cause of the subther-apeutic phenytoin level. 

Because BZs are redistributed until over 95% of the drug is outside the blood circulation and the brain, it is the distribution half-life that is most important in determining the duration of action of each BZ. Unfortunately, it is the elimination half-life that is most studied and best known (see Table 27.1 Chouinard et ah, 1999). 

Category Drug Name TTade Name Dosage Form and Dose Route of Administration Clearance Volume of Distribution Half-life Effective Dose Toxic Dose Major Route of Elimination... 

Cl plasma concentration at time zero fi/2a, distribution half-life f1/2jg, elimination half-life Kej, elimination rate constant from central compartment Ki2/.K2i, transfer rate constant between peripheral and central compartments AUC(o ), total area under plasma drug concentration time curve Vd(area> apparent volume of distribution GB, total body clearance. 

In the clinic, esmolol s distribution half-life is 2 min and its elimination half-life is 9 min. Esmolol hydrochloride is rapidly metabolized by hydrolysis of the ester linkage, chiefly by esterases in the cytosol of red blood cells and not by plasma cholinesterases or red cell membrane acetylcholinesterase [22]. Its volume of distribution is 3.4 L kg-1, and its total clearance is 285 mL kg-1 min-1, "... which is greater than cardiac output thus the metabolism ofesmolol is not limited by the rate of blood flow to metabolizing tissues such as the liver or affected by hepatic or renal blood flout [22]. As expected from such a "... high rate of blood-based metabolism, less than 2% of the drug is excreted unchanged in the wind [22]. Within 24 h after infusion, approximately... 

The phenothiazines have a long duration of effect compared with many of the other sedative-tranquillizers used in horses. The onset of effect is relatively slow after i.v. administration and the maximum clinical effect occurs 20-30 min after i.v. administration. Peak plasma drug levels occur 30 min after the i.m. injection of acepromazine (Chou et al 1998). Acepromazine has a biphasic concentration decay pattern after i.v. administration (Marroum et al 1994). The distribution half-life is 3-5 min (Ballard et al 1982, Marroum et al 1994) and the elimination half-life is 2-3 h. The terminal half-life of acepromazine after oral administration is approximately 6h. Acepromazine is highly protein bound in the plasma (>99%) with a large apparent volume of distribution (Vj, 6.61/kg) (Ballard et al 1982). 

Because lidocaine undergoes nearly complete first-pass hepatic metabolism by CyP 3 A4 and 2D6 when administered orally, it is administered only as an intravenous or intramuscular injection. Once in the blood, it is 50% bound to protein, mainly to AAG and albumin. Clearance of lidocaine is very rapid. The distribution half-life is -0.5 hour, and the elimination half-life is 1 to 1.5 hours. Reduced hepatic function impairs clearance and causes prolonged elimination and accumulation of the drug. This is due both to reduced blood flow to the liver (seen in heart failure) and to decreased metabofism of lidocaine. The end effect is lidocaine intoxication if the dose is not adjusted to account for this decreased metabolic rate. 

Pharmacokinetics After Oral and Intravenous Administration. For proper characterization of an inhalation drug, information on the systemic pharmacokinetic properties needs to be provided. One of the major challenges for such studies is to provide a suitable formulation for injection, especially because new drug candidates are often very lipophilic. The resulting parameters of such studies (systemic clearance, volume of distribution, half-life, mean residence time) can then easily be extracted from concentration-time profiles after IV administration and subsequent standard pharmacokinetic analysis by noncompartmental approaches. In addition, a detailed compartmental analysis based on concentration-time profiles will be useful in evaluating the systemic distribution processes in sufficient detail. This will be especially important if deconvolution procedures (see later) are included for the assessment of the pulmonary absorption profiles. 

Question Drag B has a total clearance of 3 L/hour and a volume of distribution of 25 L 10% is excreted unchanged. Assuming liver blood flow is normal (90 L/ hour), what is this drug s half life, what is its likely dosing schedule per day, and how long will it take to get this drug s level to a steady state ... 

In vivo PK and tissue distribution (e.g., clearance, volume of distribution, half-life, mean residence time, fraction drug bound). 

It should be noted that as in absorption, first-order distribution represents linear kinetics, as the net rate of distribution is a linear function of the amount of drug remaining in compartment 1 (Ai) and the amount of drug remaining in compartment 2( 2). Also as in the absorption case, a half-life of distrihution tvz,dist) be defined in terms of the distrihution rate constants. However, because distribution occurs in more than one direction, and due to other model complications that will be explained later, the distribution half-life cannot be written as a simple function of ki2 and 1. It turns out that the distribution half-life is defined in terms of a hybrid rate constant (/Ij) by the equation... 

The drug is redistributed within 15 minutes (the distribution half-life), but is metabolized and eliminated from the body in approximately 3 hours (terminal half-life). 

The first polymer-drug conjugate to be tested in humans for anticancer therapy is doxorubicin coupled with iV-(2-hydroxypropyl)methacrylamide copolymer via a linker that is degraded in lysosomes, thereby releasing the drug [29]. In contrast to the free drug doxorubicin, which has a distribution half-life of 0.08 h and an elimination half-Ufe of 30 h (see Table 8.6), the doxorubicin conjugate has a distribution half-life of 1.8 h and an elimination half-life of 90 h. 

A patient is admitted to the emergency room 2 hours after taking an overdose of phenobarbital. The plasma level of the drug at time of admission is 100 mg/L, and the apparent volume of distribution, half-life, and clearance of phenobarbital are 35 L, 4 days, and 6.1 L/d, respectively. The ingested dose was approximately... 

The plasma clearance of the drug is found to be triexponential having a distribution half-life of nearly 45 minutes whereas, a second-phase of approximately extending upto 3.5 hours. It has an elimination half-life of 6 to 69 hours. The renal tubular seeretion is responsible for nearly 80% of the elimination. 

Only the unbound fraction of hydrocortisone and the synthetic corticosteroids are biologically active. Generally, the amount of transcortin in the plasma determines the distribution of glucocorticoids between free and bound forms, and free glucocorticoid concentrations determine the drug s half-life. Glucocorticoids cross the placenta and may be distributed into milk. 

Clinically, half this loading dose is administered intravenously or orally. The remaining dose is divided equally and administered at 6-h intervals (e.g., 1/2 dose, 1/4 dose, 1/4 dose at 6-h intervals). This is necessary to account for the slow distribution half-life of the drug. 

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