Distribution volumes, apparent pharmacokinetics

Pharmacokinetics provides the scientific basis of dose selection, and the process of dose regimen design can be used to illustrate with a single-compartment model the basic concepts of apparent distribution volume (Vd), elimination half-life (b/2) and elimination clearance (CLg). A schematic diagram of this model is shown in Figure 2.4, along with the two primary pharmacokinetic parameters of distribution volume and elimination clearance that characterize it. 

Pharmacokinetics. Amiodarone is effective given orally its enormous apparent distribution volume (701/kg) indicates that little remains in the blood. It is stored in fat and many other tissues and the t) of 54 days after multiple dosing signifies slow release from these sites (and slow accumulation to steady state means that a loading dose is necessary, see Table 24.1). The drug is metabolised in the liver and eliminated through the biliary and intestinal tracts. 

Apparent volume of distribution The apparent volume of distribution (V ) is an important pharmacokinetic parameter that reflects the above determinants of drug distribution in the body. relates the amount of drug in the body to the concentration in the plasma. (See Chapter 3 and Table 1-2.)... 

Studies interested in the determination of macro pharmacokinetic parameters, such as total body clearance or the apparent volume of distribution, can be readily calculated from polyexponential equations such as Eq. (9) without assignment of a specific model structure. Parameters (i.e., Ah Xt) associated with such an equation are initially estimated by the method of residuals followed by nonlinear least squares regression analyses [30],... 

Figure 3.1 shows the appearance of dihydromethysticin in the acceptor well as a function of time [15], The solid curve is a least-squares fit of the data points to Eq. (1), with the parameters Pe = 32 x 10-6 cm s 1, R = 0.42, and t s = 35 min. The membrane retention, R, is often stated as a mole percentage (%R) of the sample (rather than a fraction). Its value can at times be very high - up to 90% for chlor-promazine and 70% for phenazopyridine, when 2% wt/vol DOPC in dodecane is used. Figure 3.2 shows a plot of log %R versus log Ka(7.4), the octanol/water apparent partition coefficient. It appears that retention is due to the lipophilicity of molecules this may be a good predictor of the pharmacokinetic volume of distribution or of protein binding. 

Mihaly et al. [127] examined the pharmacokinetics of primaquine in healthy volunteers who received single oral doses of 15, 30, and 45 mg of the drug, on separate occasions. Each subject received an intravenous tracer dose of 14C-prima-quine (7.5 pCi), simultaneously with 45 mg oral dose. Absorption of primaquine was virtually complete with a mean absorption bioavailability of 0.96. Elimination half-life, oral clearance, and apparent volume of distribution for both primaquine and the carboxylic acid metabolite were unaffected by either dose size or route of administration. 

The concentration (c) of a solution corresponds to the amount (D) of substance dissolved in a volume (V) thus, c = D/V. If the dose of drug (D) and its plasma concentration (c) are known, a volume of distribution (V) can be calculated from V = D/c. However, this represents an apparent volume of distribution (Vapp), because an even distribution in the body is assumed in its calculation. Homogeneous distribution will not occur if drugs are bound to cell membranes (5) or to membranes of intracellular organelles (6) or are stored within the latter (7). In these cases, Vapp can exceed the actual size of the available fluid volume. The significance of Vapp as a pharmacokinetic parameter is discussed on p. 44. 

The pharmacokinetic information that can be obtained from the first study in man is dependent on the route of administration. When a drug is given intravenously, its bioavailabihty is 100%, and clearance and volume of distribution can be obtained in addition to half-life. Over a range of doses it can be established whether the area under the plasma concentration-time curve (AUC) increases in proportion to the dose and hence whether the kinetic parameters are independent of dose (see Figure 4.1). When a drug is administered orally, the half-life can still be determined, but only the apparent volume of distribution and clearance can be calculated because bioavailability is unknown. However, if the maximum concentration (Cmax) and AUC increase proportionately with dose, and the half-life is constant, it can usually be assumed that clearance is independent of dose. If, on the other hand, the AUC does not increase in proportion to the dose, this could be the result of a change in bioavailability, clearance or both. 

Pharmacokinetics In healthy adults treated with IV doses of iron sucrose, its iron component exhibits first order kinetics with an elimination half-life of 6 hours, total clearance of 1.2 L/h, non-steady-state apparent volume of distribution of 10 L, and steady-state apparent volume of distribution of 7.9 L. 

The duration and degree of reversal of benzodiazepine effects are related to the dose and plasma concentrations of flumazenil. The onset of reversal is usually evident within 1 to 2 minutes after the injection is completed. Within 3 minutes, 80% response will be reached, with the peak effect occurring at 6 to 10 minutes. Pharmacokinetics After IV administration, flumazenil has an initial distribution half-life of 7 to 15 minutes and a terminal half-life of 41 to 79 minutes. Peak concentrations of flumazenil are proportional to dose, with an apparent initial volume of distribution of 0.5 L/kg. After redistribution the apparent volume of distribution ranges from 0.77 to 1.6 L/kg. Protein binding is approximately 50%. 

Ghafourian, T, Barzegar-Jalali, M., Hakimha, N. and Cronin, M.T.D. (2004) Quantitative structure-pharmacokinetic relationship modeling apparent volume of distribution. Journal of Pharmacy and Pharmacology, 56, 339-350. 

Pharmacokinetics The bioavailability of a subcutaneous dose of epoetin alfa, relative to an intravenous bolus, has been estimated at 22% to 31%. The elimination half-life of epoetin alfa after an intravenous dose is 6 to 13 hours in patients with chronic renal failure. Mean clearance ranges from 0.032 to 0.055 ml/min per kg. The apparent half-life after a subcutaneous dose is 27 hours. Volume of distribution estimates range from 0.021 to 0.0631/kg. 

The apparent volume of distribution allows one to estimate the amount of drug in the body at any time after administration based on the concentration (amount=concentrationxvolume). If the plasma concentration of a drug with a VD of 500 litres is 10 ng-mL-1, the amount in the body will be 500000 ml X lO ng or 5 mg. Most pharmacokinetic texts describe several volumes of distribution, e.g. VDarea and VDSS. Following a single rapid intravenous injection, VDarea can be calculated by ... 

Significant differences in the pharmacokinetics of methyl-prednisolone have been described in black and white renal transplant patients. Black patients had a slower clearance rate and a lower apparent volume of distribution. They had higher cortisol concentrations throughout the day, with higher nadir concentrations. Some of them had glucocorticoid-associated diabetes, and no white patients did. Further studies are needed to define the differences between the races (SEDA-20, 377 404). 

The pharmacokinetics of a single oral dose of exemestane 25 mg have been studied in postmenopausal subjects with normal hepatic function (n = 9), moderately impaired hepatic function (n = 9), severely impaired hepatic function (n = 8), normal renal function (n = 6), moderately impaired renal function (n = 6), and severely impaired renal function (n = 7) (36). Exposure to exemestane was increased two- to three-fold in patients with hepatic impairment the apparent oral clearance and apparent volume of distribution of exemestane were reduced. Renal impairment was also associated with two- to three-fold increases in exposure due to reduced clearance. However, because exemestane has a relatively large safety margin, the authors considered that these effects were of no clinical significance. 

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