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Drug Elimination (drug + elimination)
Selected AbstractsOn the possibility of self-induction of drug protein bindingJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 10 2010Leonid M. Berezhkovskiy Abstract The equilibrium unbound drug fraction (fu) is an important pharmacokinetic parameter, which influences drug elimination and distribution in the body. Commonly the drug plasma concentration is substantially less then that of drug binding proteins, so that fu can be assumed constant independent of drug concentration. A general consideration of protein binding based on the mass-action law provides that the unbound drug fraction increases with the increase of drug concentration, which is also a usual experimental observation. For several drugs, though, a seemingly unusual sharp decrease of the unbound drug fraction with the increase of total drug concentration (Ro) in the interval 0,<,Ro,,,5,µM was experimentally observed. A possible explanation of this apparently strange phenomenon is presented. The explanation is based on the consideration of a two-step mechanism of drug protein binding. The first step occurs as a drug binding to the site with relatively low affinity. Consequently this binding leads to the activation of a high affinity site, which otherwise is not available for binding. The suggested binding scheme yields the curves for fu dependence on the total drug concentration that are in good agreement with experimental measurements. The interpretation of pharmacokinetic data for the drugs with such unusual concentration dependence of fu appears to be a formidable problem. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4400,4405, 2010 [source] The influence of drug kinetics in blood on the calculation of oral bioavailability in linear pharmacokinetics: The traditional equation may considerably overestimate the true value,JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2006Leonid M. Berezhkovskiy Abstract A common calculation of oral bioavailability is based on the comparison of the areas under the concentration-time curves after intravenous and oral drug administration. It does not take into account that after the oral dosing a drug enters the systemic circulation in different states, that is, as free fraction, protein bound and partitioned into blood cells, and plasma lipids, while after intravenous input it is introduced into the systemic circulation only as a free fraction. Consideration of this difference leads to a novel equation for the oral bioavailability. In general, the traditional calculation overestimates the oral bioavailability. For a widely applied model of a linear pharmacokinetic system with central (plasma) drug elimination it is shown that the traditional calculation of the oral bioavailability could substantially overestimate the true value. If the existence of an immediate equilibrium between different drug fractions in blood is assumed, the obtained equation becomes identical to the traditional one. Thus the deviation of oral bioavailability from the value given by a common calculation appears to be a kinetic phenomenon. The difference could be significant for the drugs with the rate constant of elimination from plasma of the same order of magnitude or greater than the dissociation rate constant of drug,protein complexes, or the off-rate constant of partitioning from the blood cells, if the blood concentration profiles were used to calculate the oral bioavailability. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95:834,848, 2006 [source] Volume of distribution at steady state for a linear pharmacokinetic system with peripheral eliminationJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 6 2004Leonid M. Berezhkovskiy Abstract The problem of finding the steady-state volume of distribution Vss for a linear pharmacokinetic system with peripheral drug elimination is considered. A commonly used equation Vss,=,(D/AUC)*MRT is applicable only for the systems with central (plasma) drug elimination. The following equation, Vss,=,(D/AUC)*MRTint, was obtained, where AUC is the commonly calculated area under the time curve of the total drug concentration in plasma after intravenous (iv) administration of bolus drug dose, D, and MRTint is the intrinsic mean residence time, which is the average time the drug spends in the body (system) after entering the systemic circulation (plasma). The value of MRTint cannot be found from a drug plasma concentration profile after an iv bolus drug input if a peripheral drug exit occurs. The obtained equation does not contain the assumption of an immediate equilibrium of protein and tissue binding in plasma and organs, and thus incorporates the rates of all possible reactions. If drug exits the system only through central compartment (plasma) and there is an instant equilibrium between bound and unbound drug fractions in plasma, then MRTint becomes equal to MRT,=,AUMC/AUC, which is calculated using the time course of the total drug concentration in plasma after an iv bolus injection. Thus, the obtained equation coincides with the traditional one, Vss,=,(D/AUC)*MRT, if the assumptions for validity of this equation are met. Experimental methods for determining the steady-state volume of distribution and MRTint, as well as the problem of determining whether peripheral drug elimination occurs, are considered. The equation for calculation of the tissue,plasma partition coefficient with the account of peripheral elimination is obtained. The difference between traditionally calculated Vss,=,(D/AUC)*MRT and the true value given by (D/AUC)*MRTint is discussed. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1628,1640, 2004 [source] Effect of recombinant porcine somatotropin (rpST) on drug disposition in swineJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2010J. C. KAWALEK Kawalek, J.C., Howard, K.D. Effect of recombinant porcine somatotropin (rpST) on drug disposition in swine. J. vet. Pharmacol. Therap.33, 69,75. Treatment of pigs with recombinant porcine somatotropin (rpST) causes a marked increase in feed utilization with increased weight-gain over untreated controls. Physiological parameters such as creatinine clearance were increased by rpST treatment. Clearance of drugs eliminated by hepatic extraction, like indocyanine green (ICG), were also increased by rpST treatment. However, clearance of intravenous (i.v.)-dosed propranolol (PPL) was not affected by rpST treatment and data from oral (p.o.) - dosing was inconclusive because of the low bioavailability, probably because of a high first-pass effect. The very low oral bioavailability indicates that intestinal metabolism of PPL is probably quite high. Analysis of urinary metabolites indicated production of the two phenolic isomers, but there was no metabolite corresponding to N-dealkylase activity; although the latter metabolite could have been eliminated in the bile with subsequent fecal elimination. PPL was an excellent in vitro substrate for measuring hepatic DME activity in vitro; two phenolic and one N-dealkylated metabolite were formed. The overall conclusions regarding this study must be that the effects of rpST on drug bioavailability and elimination were equivocal. As ICG and creatinine clearances were both increased significantly, one cannot rule out the probability that rpST would increase drug elimination in pigs as a result of increased hepatic uptake and/or renal clearance. One can only speculate that clearance of concurrently administered drugs would be increased. This would reduce residue levels, but it might also reduce efficacy. [source] Pharmacokinetics of the calcium-channel blocker diltiazem after a single intravenous dose in horses,JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2006C. C. SCHWARZWALD The pharmacokinetics of diltiazem were determined in eight healthy horses. Diltiazem HCl, 1 mg/kg i.v., was administered over 5 min. Venous blood samples were collected at regular intervals after administration. Plasma concentrations of diltiazem and desacetyldiltiazem were determined by high-performance liquid chromatography. A second, putative metabolite was detected, but could not be identified due to the lack of an authentic standard. Data were analyzed by nonlinear least-squares regression analysis. The median (minimum,maximum) peak plasma concentration of diltiazem was 727 (539,976) ng/mL. Plasma diltiazem concentration vs. time data were best described by a two-compartment model with first-order drug elimination. The distribution half-life was 12 (6,23) min, the terminal half-life was 93 (73,161) min, the mean residence time was 125 (99,206) min, total plasma clearance was 14.4 (10.4,18.6) mL/kg/min, and the volume of distribution at steady-state was 1.84 (1.46,2.51) L/kg. The normalized ratio of the area under the curve (AUC) of desacetyldiltiazem to the AUC of diltiazem was 0.088 (0.062,0.179). The disposition of diltiazem in horses was characterized by rapid distribution and elimination and a terminal half-life shorter than reported in humans and dogs. Because of the reported low pharmacologic activity, plasma diltiazem metabolite concentrations were not considered clinically important. [source] Pharmacokinetics of TDP223206 following intravenous and oral administration to intact rats and intravenous administration to bile duct-cannulated ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2008Yanmin Chen Abstract The pharmacokinetics of TDP223206 was studied following single intravenous and oral administrations in rats. A mixture of TDP223206 and 14C-TDP223206 were administered to intact and bile duct-cannulated rats. Following intravenous administration, plasma concentrations declined biphasically. The AUCinf increased linearly with dose but was not dose proportional. The PK parameters of TDP223206 indicated low clearance (254,386,ml/h/kg) and a moderate volume of distribution (968,1883,ml/kg). The bioavailability was 32.95% and 24.46% for 10 and 50,mg/kg oral doses, respectively. 14C-TDP223206 was distributed widely into different tissues with small intestine, liver, kidneys and large intestine having large tissue to plasma ratios. 14C-TDP223206 was the major circulating component in the plasma. A total of 91.2% of administered radioactivity of 14C-TDP223206 was recovered in bile indicating that biliary excretion was the major pathway for drug elimination. 14C-TDP223206-acyl glucuronides were the major metabolites in bile. The oxo- 14C-TDP223206 was the major metabolite in plasma and an important metabolite in bile. Two forms of diastereomeric acyl glucuronides of 14C-TDP223206 were detected in bile with similar LC/MS intensities suggesting a similar biotransformation capacity. Only one form of these 14C-TDP223206-acyl glucuronides was detected in plasma suggesting that enterohepatic recirculation was related to the nature of the stereo-isomers. Copyright © 2008 John Wiley & Sons, Ltd. [source] The relationships between half-life (t1/2) and mean residence time (MRT) in the two-compartment open body modelBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2004Eyal Sobol Abstract Rationale. In the one-compartment model following i.v. administration the mean residence time (MRT) of a drug is always greater than its half-life (t1/2). However, following i.v. administration, drug plasma concentration (C) versus time (t) is best described by a two-compartment model or a two exponential equation: C=Ae,,t+Be,,t, where A and B are concentration unit-coefficients and , and , are exponential coefficients. The relationships between t1/2 and MRT in the two-compartment model have not been explored and it is not clear whether in this model too MRT is always greater than t1/2. Methods. In the current paper new equations have been developed that describe the relationships between the terminal t1/2 (or t1/2,) and MRT in the two-compartment model following administration of i.v. bolus, i.v. infusion (zero order input) and oral administration (first order input). Results. A critical value (CV) equals to the quotient of (1,ln2) and (1,,/,) (CV=(1,ln2)/(1,,/,)=0.307/(1,,/,)) has been derived and was compared with the fraction (f1) of drug elimination or AUC (AUC-area under C vs t curve) associated with the first exponential term of the two-compartment equation (f1=A/,/AUC). Following i.v. bolus, CV ranges between a minimal value of 0.307 (1,ln2) and infinity. As long as f1
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