Pharmacokinetics extraction ratio

By use of these basic concepts, Wu et al. [87] conducted an examination of the pharmacokinetics of cyclosporine after administration in the presence of two known CYP3A inhibitors, ketaconazole and erythromycin and the CYP3A inducer rifampin. Alterations to the cyclosporin hepatic extraction ratio were measured in the presence of the inducer/inhibitor, and oral cyclosporin biovailability (relative to IV administration in the presence/absence of the interacting species) was calculated. These data are reproduced in Table 3 and provide several impor-... 

Usually, the pharmacokinetic parameters are calculated from plasma rather than from whole blood data. The use of plasma-related parameters to measure organ extraction ratios and intrinsic clearance could, however, be misleading. When drug binding is similar in plasma and red blood cells, Cb Cp because /b /p. However, if the binding in plasma is greater than that in red blood cells, Cb < Cp and AUCb < AUCp and use of plasma clearance will provide an underestimate of the blood clearance. Maximum errors are of the order of 40%. If the B/P ratio is >1, the clearance determined from plasma concentrations would significantly overestimate blood clearance and could exceed hepatic blood flow. 

Because identification of a saturable process occurs only for low extraction ratio compounds (i.e., CL, etaboiism = /uCLint), the relationship between classical enzyme kinetics and pharmacokinetics is revealed ... 

Stereoselectivity has been reported in the pharmacokinetic properties of some of the chiral antimalarial drugs (chloroquine, hydroxychloroquine, halofantrine, and mefloquine Tables 1 and 3). Each of these drugs possesses low hepatic extraction ratios, large Vd and ranging from one day to months. Plasma protein binding has been reported to range from about 50% (chloroquine and hydroxychloroquine. Table 3) to over 99% (halofantrine [19]). Chloroquine and its hydroxylated congener. 

The stereoselective pharmacokinetics of the selective serotonin reuptake inhibitor, citalopram, have been studied in 10 healthy young subjects [139]. After administration of 40 mg racemate daily for 21 days by the oral route, stereoselectivity was found in citalopram plasma concentrations. The R(—) S(+) ratios of Cmax and AUCss were 1.5 and 1.6, respectively. No difference was noted in suggesting similar absorption rates of the enantiomers. The terminal phase values were 47 and 35 h for the R and S enantiomers, respectively. Renal clearance comprised 20% of each enantiomer s total clearance and was nonstereoselective. Although both enantiomers are extensively metabolized, both possess low hepatic extraction ratios [139]. Serotonin reuptake inhibition of citalopram primarily resides with the S enantiomer (see Chap. 5, Sec. 3.4 for more details), which attains lower concentrations in plasma. In eight geriatric patients (mean 77 y) given... 

To provide further appreciation for the hepatic extraction ratio and its interrelationship with other pharmacokinetic parameters, we introduce the following physiological approach. 

Pick s ffrst law law that governs the rate of diffusion across a membrane first-order process a process whose rate is directly proportional to the current amount of the compound being transferred by the process linear elimination pharmacokinetic is an example of a first-order process first pass effect the situation whereby the fraction of a dose of orally administered drug that reaches the systemic circulation is equal to 1 minus its hepatic extraction ratio formulation a dosage form of a particular drug... 

It is interesting to note that around three-quarters of the top 200 prescribed drugs in the United States are primarily cleared by hepatic metabolism [11]. The hepatic extraction ratio (Eh) is a pharmacokinetic parameter that is widely used to assess the liver s ability to extract drug from the systemic circulation [10]. Eh is defined as the fraction of a drug in the blood that is cleared (extracted) on each passage through the liver and is a function of hepatic blood CL (CLh p) and the hepatic blood flow (Q) [10] ... 

In addition to the mechanistic simulation of absorptive and secretive saturable carrier-mediated transport, we have developed a model of saturable metabolism for the gut and liver that simulates nonlinear responses in drug bioavailability and pharmacokinetics [19]. Hepatic extraction is modeled using a modified venous equilibrium model that is applicable under transient and nonlinear conditions. For drugs undergoing gut metabolism by the same enzymes responsible for liver metabolism (e.g., CYPs 3A4 and 2D6), gut metabolism kinetic parameters are scaled from liver metabolism parameters by scaling Vmax by the ratios of the amounts of metabolizing enzymes in each of the intestinal enterocyte compart-... 

A sensitive, simple, and specific liquid chromatographic method coupled with electrospray ionization-mass spectrometry for the determination of donepezil in plasma was developed, and its pharmacokinetics in healthy, male, Chinese was studied [34]. Using loratadine as the IS, after extraction of the alkalized plasma by isopropyl alcohol-n-hexane (3 97, v/v), solutes are separated on a Cig column with a mobile phase of methanol-acetate buffer (pH 4.0) (80 20, v/v). Detection is performed with a TOF mass spectrometer equipped with an electrospray ionization source operated in the positive-ionization mode. Quantitation of donepezil is accomplished by computing the peak area ratio (donepezil [M + H](+) m/z 380-loratadine [M + H](+) mlz 383) and comparing them with the calibration curve (r = 0.9998). The linear calibration curve is obtained in the concentration range 0.1-15 ng/ml. The limit of quantitation is 0.1 ng/ml. The mean recovery of donepezil from human plasma is 99.4 6.3% (range 93.4-102.6%). The inter- and intra-day RSD is less than 15%. After an oral administration of 5 mg donepezil to 20 healthy Chinese volunteers, the main pharmacokinetic parameters of donepezil are as follow T(max), 3.10 0.55 h tV2j 65.7 12.8 h C(max), 10.1 2.02 ng/ml MRT,... 

To establish chiral separation method for donepezil hydrochloride enantiomers by capillary electrophoresis (CE) and to determine the two enantiomers in plasma [39], alkalized plasma was extracted by isopropa-nol-n-hexane (3 97) and L-butefeina was used as the IS. Enantioresolution was achieved using 2.5% sulfated-beta-cyclodextrin as chiral selector in 25 mmol/1 triethylammonium phosphate solution (pH 2.5) on the uncoated fused-silica capillary column (70 cm x 50 fim i.d.). The feasibility of the method to be used as quantitation of donepezil HC1 enantiomers in rabbit plasma was also investigated. Donepezil HC1 enantiomers were separated at a baseline level under the above condition. The linearity of the response was evaluated in the concentration range from 0.1 to 5 mg/1. The linear regression analysis obtained by plotting the peak area ratio (A(s)/A(i)) of the analyte to the IS versus the concentration (C) showed excellent correlation coefficient The low limit of detection was 0.05 mg/1. The inter- and intra-day precisions (RSD) were all less than 20%. Compared with chiral stationary phase by HPLC, the CE method is simple, reliable, inexpensive, and suitable for studying the stereoseletive pharmacokinetics in rabbit. 

Guy GW, Robson PJ (2004a) A phase 1, double blind, three-way crossover study to assess the pharmacokinetic profile of cannabis based medicine extract (CBME) administered sublingually in variant cannabinoid ratios in normal healthy male volunteers (GWPK0215). J Cannabis Ther 3 121-152... 

A potentially important use of MTX diesters has been proposed to be in the treatment of tumours of the central nervous system [292]. Rosowsky et al. [309] examined the pharmacokinetics and metabolism of DBMTX in Rhesus monkeys, and demonstrated that when only free (i.c., not protein-bound) drug was considered, the CSF/plasma ratio for the diester, as well as for its major metabolite, MTX y-w-butyl ester, was indeed higher than the ratio for MTX. However, when account was taken of the fact that binding to plasma proteins was 90-95% for DBMTX as compared to only 50% for MTX, the ratios of total drug in the CSF and plasma compartments for the two compounds were not very different. A greater fraction of the injected dose of ester was excreted in bile than in urine, whereas the opposite was true for MTX. This was consistent with the idea that hepatic extraction is favoured for the lipophilic diester derivative in comparison with the more water-soluble parent acid. 

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