Pharmacokinetics compartmental

Fig. 1. Schematic compartmental pharmacokinetic representation of different classes of contrast agents a. nonspecific agent (NSA e.g. iobitridol) b. low-diffusion agent (LDA) c. rapid-clearance blood-pool agent (RCBPA e.g. P743) d. slow-clearance blood-pool agent (SCBPA, e.g. P840). From Id e et al. (2001) Invest Radiol 26 41,with permission ( Lippincott Williams Wilkins)...

Rates of hydroquinone glucuronidation in human liver microsomes showed a two- to three-fold variation between individual liver samples they were somewhat higher than in the rat, and lower than in the mouse liver (Seaton et al., 1995). A compartmental pharmacokinetic model was derived to describe the pharmacokinetics of hydroquinone in vivo in humans, rats and mice, incorporating hydroquinone glucuronidation rates sulfation of hydroquinone was not included in this model. NAD(P)H quinone acceptor oxidoreductases protect against reactive quinones by reducing them to the hydroquinone this enzyme seems to be absent in some individuals, which will lead to loss of such protection and make them more sensitive to hydroquinone toxicity (Ross, 1996). 

A simple compartmental pharmacokinetic model was proposed by Seaton et al. (1995) to describe the phannacokinetics of hydroquinone in mice, rats and humans. The model did not include hydroquinone sulfation, which does occur in rats and possibly in mice, although glucuronidation is the major reaction. Phenol and hydroquinone may mutually inhibit their sulfation if both are present simultaneously in the rat (Legathe etal., 1994). 

A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed [33] and validated for the determination of donepezil in human plasma samples. Diphenhydramine was used as the IS. The collision-induced transition m/z 380 > 91 was used to analyze donepezil in selected reaction monitoring mode. The signal intensity of the m/z 380 —> 91 transition was found to relate linearly with donepezil concentrations in plasma from 0.1 to 20.0 ng/ml. The lower limit of quantification of the LC/MS/MS method was 0.1 ng/ml. The intra- and inter-day precisions were below 10.2% and the accuracy was between 2.3% and +2.8%. The validated LC/MS/MS method was applied to a pharmacokinetic study in which healthy Chinese volunteers each received a single oral dose of 5 mg donepezil hydrochloride. The non-compartmental pharmacokinetic model was used to fit the donepezil plasma concentration-time curve. Maximum plasma concentration was... 

When the dose of a drug is administered as an intravenous bolus, the volume of distribution at steady-state (Vd(ss)) can be calculated. This parameter represents the volume in which a drug would appear to be distributed during steady-state if the drug existed throughout that volume at the same concentration as in the measured fluid (plasma or blood). The volume of distribution at steady-state is generally calculated by a non-compartmental method, which is based on the use of areas (Benet Galeazzi, 1979) and does not require the application of a compartmental pharmacokinetic model or mathematical description of the disposition curve ... 

When the drug is administered as an intravenous bolus dose, the total areas under the curves can be calculated from the coefficients and exponents of the equation describing the disposition curve and obtained by compartmental pharmacokinetic analysis of the plasma concentration-time data. 

The advantages of using non-compartmental methods for calculating pharmacokinetic parameters, such as systemic clearance (CZg), volume of distribution (Vd(area))/ systemic availability (F) and mean residence time (MRT), are that they can be applied to any route of administration and do not entail the selection of a compartmental pharmacokinetic model. The important assumption made, however, is that the absorption and disposition processes for the drug being studied obey first-order (linear) pharmacokinetic behaviour. The first-order elimination rate constant (and half-life) of the drug can be calculated by regression analysis of the terminal four to six measured plasma... 

Fig. 3.2 Analogue computer-generated curves showing the levels (as fraction of the intravenous dose) of benzylpenicillin in the central (serum) and peripheral (tissue) compartments of the two-compartment pharmacokinetic model and the cumulative amount excreted unchanged in the urine as a function of time. The curves are based on the first-order rate constants (k12, k21, kel) associated with the compartmental pharmacokinetic model. Note...

Figure 24.3 Compartmental pharmacokinetic model linking skin absorption determined in an in vitro model to a systemic model to predict plasma concentration time profiles in vivo.

A pharmacokinetic study is composed of three phases, namely the in-life phase, bioanalysis, and data analysis. The in-life phase includes administering the compound to animals or humans and collecting samples from the appropriate matrix of interest such as blood or urine at predetermined time intervals for bioanalysis. The bioanalytical phase involves analysis of a drug and/ or its metabolite (s) concentration in blood, plasma, serum, or urine. This analysis typically involves sample extraction and detection of analytes using sensitive methods like LC/MS/MS. The third phase is data analysis using noncompartmental or compartmental pharmacokinetic computational methods. 

Non-Compartmental Pharmacokinetic Parameters of ATRA after i.v. Administration of Sodium ATRA or ATRA Microemulsion, Equivalent to 4mg/kg as ATRA, to Rats (n = 5)... 

Groll, A.H. Miokiene, D. Petraitis, V. Petraitiene, R. Ibrahim, K.H. Piscitelli, S.C. Bekersky, I. Walsh, T.J. Compartmental pharmacokinetics and tissue distribution of the antifungal echinocandin lipopeptide micafungin (FK463) in rabbits, Antimicrob.Agents Chemother., 2001, 45, 3322-3327. 

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