Half-life volume of distribution

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. 

Receptor ligand complex Receptor occupancy Substrate concentration time after drug administration Dosing interval Flimination half-life Volume of distribution... 

Ratio of binding proteins in extracellular fluid (except plasma) to binding proteins in plasma Correlation coefficient Elimination half-life Volume of distribution Volume of extracellular fluid Volume of plasma Volume of remaining fluid... 

Total clearance Elimination half-life Volume of distribution ... 

Basic ADME characteristics (absorption, C, plasma half-life, area under the curve, terminal half-life, volume of distribution, protein binding, clearance)... 

The pharmacokinetics of pentazocine have been investigated in humans (11,76,86). Table 13 shows values for half-life, volume of distribution, bioavailability and clearance calculated by various authors. The plasma half-life values obtained range from 2 to 5.7 hours. The possibility that... 

The clinical development stage comprises three distinct components or phases (I, II, and III), and culminates in the filing of the NDA/MAA. Each phase involves process scale-up, pharmacokinetics, drug delivery, and drug safety activities. During phase I clinical development, the compound s safety and pharmacokinetic profile is defined. The determination of maximum concentration at steady state (Cmax), area under the plasma concentration time curve (AUC), elimination half-life, volume of distribution, clearance and excretion, and potential for drug accumulation is made in addition to studies that provide estimates of efficacious doses. Dose levels typically... 

The focus before IND is on Tmax, Cmax and AUCs, while the complexity of pharmacokinetic characterization (like oral bioavailability, plasma half life, volume of distribution, mean residence time, absorption, solubility and concentration) is built up during clinical trials and on the basis of comparable human data. 

Many of the drug monographs contain a new section entitled Disposition in the Body. This section details die absorption, distribution, and excretion of the drug, notes the major metabolites and therapeutic and toxic plasma concentrations, and gives values for pharmacokinetic parameters such as half-life, volume of distribution, clearance, and protein binding. In addition, abstracts from published clinical studies and case histories are included. 

Table 6.5 provides the pharmacokinetic parameters noted for the listed anticonvulsants, which include, where possible, peak plasma levels, half-life, volume of distribution, and plasma protein binding. Additional explanations as noted in the table are provided as follows. 

Answer D. Back to basic principles Recall that the relationship between half-life, volume of distribution, and clearance is given by ... 

Drug information resources will not provide data on the elimination half-life of ethanol because, in the case of this drug, it is not constant. The elimination of ethanol follows zero-order kinetics because the drug is metabolized at a constant rate irrespective of its concentration in the blood (see Chapter 3). The pharmacokinetic relationship between elimination half-life, volume of distribution, and clearance, given by... 

Factor Synthesis site Biologica I half-life, h Volume of distribution, MPV" Hemostasis concentratio 0/ n, % Per population Inheritanc d e pattern Chromoso me... 

The apparent volume of distribution (Vd) slightly increases depending on plasma volume (Fp), tissue volume (Ft), and free tissue fraction (ft) whereas the half-life slightly decreases with significantly increasing free plasma fraction. 

Figure 15.5 Sammon map with SVM classification of drugs based on their volume of distribution (a) and plasma half-life (b) [95].

Plasma volume of distribution Initial plasma concentration Half-life time ... 

Plasma volume of distribution Half-life time of absorption Transfer constant of absorption Half-life time of elimination Transfer constant of elimination Area under the curve ... 

The pharmacokinetic profile of (16) and its two analogues were investigated in Sprague-Dawley rats. Removal of the metabolically labile tert-butyl group on the aryl moiety slowed metabolism and the rate of clearance. However, the overall half-life of (17a) was unaffected because of a lower volume of distribution. On the other hand, (17b) showed an increased half-life (ca. 3h versus 1 h) compared to (16) and (17a). While the oral bioavailability of (16) was negligible, (17a) and (17b) were better absorbed, with bioavailability values of 39% and 17%, respectively. While undoubtedly improved in terms of pharmacokinetics compared to (16), the bioactivity of (17a) and (17b) awaits validation in vivo. 

The area under the PCP concentration-time curve (AUC) from the time of antibody administration to the last measured concentration (Cn) was determined by the trapezoidal rule. The remaining area from Cn to time infinity was calculated by dividing Cn by the terminal elimination rate constant. By using dose, AUC, and the terminal elimination rate constant, we were able to calculate the terminal elimination half-life, systemic clearance, and the volume of distribution. Renal clearance was determined from the total amount of PCP appearing in the urine, divided by AUC. Unbound clearances were calculated based on unbound concentrations of PCP. The control values are from studies performed in our laboratory on dogs administered similar radioactive doses (i.e., 2.4 to 6.5 pg of PCP) (Woodworth et al., in press). Only one of the dogs (dog C) was used in both studies. 

Clearance is a critical parameter because of its role in determining a drug s dose size and frequency. First-pass clearance in combination with absorption determines a compound s bioavailability. Clearance and absorption in combination with potency determine dose size. Clearance and volume of distribution determine half-life, and thus dosing frequency. 

Gabapentin Modulate calcium channels and enhance GABA activity Loading dose Not recommended due to short half-life Maintenance dose 900-3600 mg/day in 3-4 divided doses (doses up to 1 0,000 mg/day have been tolerated) Half-life Not established 5-7 hours (proportional to creatinine clearance) Apparent volume of distribution 0.6-0.8 L/kg Protein binding less than 10% Primary elimination route Renal Drowsiness, sedation Peripheral edema, weight gain... 

Lamotrigine Modulate sodium channels Loading dose Not recommended due to increased risk of rash Maintenance dose 1 50-800 mg/day in 2-3 divided doses. Doses should be initiated and titrated according to the manufacturer s recommendations to reduce the risk of rash Half-life Not established Monotherapy 24 hours Concurrent enzyme inducers 12-15 hours Concurrent enzyme inhibitors 55-60 hours Apparent volume of distribution 1.1 L/kg Protein binding 55% Primary elimination route Hepatic Ataxia, drowsiness, headache, insomnia, sedation Rash... 

Levetiracetam Unknown Loading dose Not recommended due to excessive adverse effects Maintenance dose 1 000-3000 mg/day. Start at 1 000 mg/day and titrate upward as indicated by response Half-life Not established 6-8 hours Apparent volume of distribution 0.5-0.7 L/kg Protein binding less than 10% Primary elimination route 70% renal 30% hepatic Somnolence, dizziness Depression... 

The pharmacokinetics of bevacizumab demonstrate a terminal half-life of 21 days, with a volume of distribution consistent with limited extravascular distribution.34 Bevacizumab has shown clinical activity in the treatment of colorectal, kidney, lung, breast, and head and neck cancer. Patients may develop hypertension requiring chronic medication during therapy. Impaired wound healing, thrombolembolic events, proteinuria, bleeding, and perforation are serious side effects. 

Cetuximab is a human/mouse antibody that binds to the epidermal growth factor receptor to block its stimulation. The pharmacokinetics of cetuximab demonstrate a volume of distribution that approximates the vascular space and a terminal half-life of 70 to 100 hours. Cetuximab has shown clinical activity in the treatment of colorectal cancer. An acnelike rash may appear on the face and upper torso 1 to 3 weeks after the start of therapy. Other side effects include hypersensitivity reactions, interstitial lung disease, fever, malaise, diarrhea, abdominal pain, and nausea and vomiting. 

Half-life increases as the dose and serum concentration increases Volume of distribution Adults 0.7 L/kg Children 0.8 L/kg Neonates 1.2 L/kg Protein binding Adults, children 88-92% Neonates 65% Primary elimination route Hepatic (4-8 pmol/L) unbound concentration osteoporosis, rash... 

Half-life Monotherapy 7-9 hours Concurrent enzyme inducers 2.5-4.5 hours Apparent volume of distribution 0.6-0.8 L/kg Protein binding 96% Primary elimination Not established Dizziness, somnolence, irritability, slowed thinking ... 

Example. The biological half-life of procaine in a patient was 35 minutes, and its volume of distribution was estimated to be 58 L. Calculate the TCR of procaine. 

Example. Sulfadiazine in a normal volunteer had a biological half-life of 16 hours and a volume of distribution of 20 L. Sixty percent of the dose was recovered as unchanged drug in urine. Calculate TCR, RCR, and MCR for sulfadiazine in this person. 

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