Plasma Concentration-time Profiles Of Drugs Research Articles

Microsurgical Skills of Establishing Permanent Jugular Vein Cannulation in Rats for Serial Blood Sampling of Orally Administered Drug.

Blood sampling in small laboratory animals is necessary for pharmaceutical lead optimization but can cause great harm and stress to experimental animals, which could potentially affect results. The jugular vein cannulation (JVC) in rats is a widely used model for repeated blood collection but requires adequate training of surgery skills and animal care. This article details the microsurgical procedures for establishing and maintaining a permanent JVC rat model with specific focus on the placement and sealing of the jugular cannula. The importance of monitoring physiological (e.g., body weight, food, and water intake) and hematological parameters, was highlighted with results presented for 6 days post-surgery during the rat's recovery. The drug-plasma concentration-time profile of orally administered natural phenol ellagic acid was determined in the JVC rat model.

Predictability of human pharmacokinetics of drugs that undergo hepatic organic anion transporting polypeptide (OATP)-mediated transport using single-species allometric scaling in chimeric mice with humanized liver: integration with hepatic drug metabolism

We previously reported a prediction method for human pharmacokinetics (PK) using single species allometric scaling (SSS) and the complex Dedrick plot in chimeric mice with humanized liver to predict the total clearance (CLt), distribution volumes in steady state (Vdss) and plasma concentration-time profiles of several drugs metabolized by cytochrome P450 (P450) and non-P450 enzymes. In the present study, we examined eight compounds (bosentan, cerivastatin, fluvastatin, pitavastatin, pravastatin, repaglinide, rosuvastatin, valsartan) as typical organic anion transporting polypeptide (OATP) substrates and six compounds metabolized by P450 and non-P450 enzymes to evaluate the predictability of CLt, Vdss and plasma concentration-time profiles after intravenous administration to chimeric mice. The predicted CLt and Vdss of drugs that undergo OATP-mediated uptake and P450/non-P450-mediated metabolism reflected the observed data from humans within a threefold error range. We also examined the possibility of predicting plasma concentration-time profiles of drugs that undergo OATP-mediated uptake using the complex Dedrick plot in chimeric mice. Most profiles could be superimposed with observed profiles from humans within a two- to threefold error range. PK prediction using SSS and the complex Dedrick plot in chimeric mice can be useful for evaluating drugs that undergo both OATP-mediated uptake and P450/non-P450-mediated metabolism.

Prediction of Plasma Concentration-time Profiles of Drugs in Humans from Animals Following Oral Administration: An Allometric Approach.

Allometric scaling is regularly used for the prediction of human pharmacokinetic (PK) parameters from animal PK studies. The predicted human PK parameters can also be used for the prediction of plasma concentration-time profiles in humans. The main objective of this work is to predict human concentration-time profiles of drugs (one-compartment model) following oral administration using animal oral pharmacokinetic parameters. Six drugs from the literature were chosen that were described by one-compartment model in both humans and animals following oral administration. Pharmacokinetic parameters such as oral clearance, oral volume of distribution of the central compartment, time to reach maximum plasma concentration, absorption rate constant, and half-life in humans were predicted from animals using allometric scaling. These predicted human pharmacokinetic parameters were then used to predict human plasma concentrations-time profiles of drugs. The results of this study indicate that the proposed method can be used to predict human plasma concentrations- time profiles of drugs with reasonable accuracy (≤50% prediction error). Given the complexity in the pharmacokinetics of oral drugs there remains some uncertainty in this entire exercise. One can minimize the prediction error by experience in allometric scaling, scientific judgment, and unconventional or innovative thinking.

Exploration of PBPK Model—Calculation of Drug Time Course in Tissue Using IV Bolus Drug Plasma Concentration-Time Profile and the Physiological Parameters of the Organ

An uncommon innovative consideration of the well-stirred linear physiologically based pharmacokinetic model and the drug plasma concentration-time profile, which is measured in routine intravenous bolus pharmacokinetic study, was applied for the calculation of the drug time course in human tissues. This cannot be obtained in the in vivo pharmacokinetic study. The physiological parameters of the organ such as organ tissue volume, organ blood flow rate, and its vascular volume were used in the calculation. The considered method was applied to calculate the time course of midazolam, alprazolam, quinidine, and diclofenac in human organs or tissues. The suggested method might be applied for the prediction of drug concentration-time profile in tissues and consequently the drug concentration level in the targeted tissue, as well as the possible undesirable toxic levels in other tissues.

On the accuracy of calculation of the mean residence time of drug in the body and its volumes of distribution based on the assumption of central elimination

1. The steady state and terminal volumes of distribution, as well as the mean residence time of drug in the body (Vss, Vβ, and MRT) are the common pharmacokinetic parameters calculated using the drug plasma concentration–time profile (Cp(t)) following intravenous (iv bolus or constant rate infusion) drug administration.2. These traditional calculations are valid for the linear pharmacokinetic system with central elimination (i.e. elimination rate being proportional to drug concentration in plasma). The assumption of central elimination is not valid in general, so that the accuracy of the traditional calculation of these parameters is uncertain.3. The comparison of Vss, Vβ, and MRT calculated by the derived exact equations and by the commonly used ones was made considering a physiological model. It turned out that the difference between the exact and simplified calculations does not exceed 2%.4. Thus the calculations of Vss, Vβ, and MRT, which are based on the assumption of central elimination, may be considered as quite accurate. Consequently it can be used as the standard for comparisons with kinetic and in silico models.

Prediction of Drug Terminal Half-Life and Terminal Volume of Distribution After Intravenous Dosing Based on Drug Clearance, Steady-State Volume of Distribution, and Physiological Parameters of the Body

The steady state, V(ss), terminal volume of distribution, V(β), and the terminal half-life, t(1/2), are commonly obtained from the drug plasma concentration-time profile, C(p)(t), following intravenous dosing. Unlike V(ss) that can be calculated based on the physicochemical properties of drugs considering the equilibrium partitioning between plasma and organ tissues, t(1/2) and V(β) cannot be calculated that way because they depend on the rates of drug transfer between blood and tissues. Considering the physiological pharmacokinetic model pertinent to the terminal phase of drug elimination, a novel equation that calculates t(1/2) (and consequently V(β)) was derived. It turns out that V(ss), the total body clearance, Cl, equilibrium blood-plasma concentration ratio, r; and the physiological parameters of the body such as cardiac output, and blood and tissue volumes are sufficient for determination of terminal kinetics. Calculation of t(1/2) by the obtained equation appears to be in good agreement with the experimentally observed vales of this parameter in pharmacokinetic studies in rat, monkey, dog, and human. The equation for the determination of the pre-exponent of the terminal phase of C(p)(t) is also found. The obtained equation allows to predict t(1/2) in human assuming that V(ss) and Cl were either obtained by allometric scaling or, respectively, calculated in silico or based on in vitro drug stability measurements. For compounds that have high clearance, the derived equation may be applied to calculate r just using the routine data on Cl, V(ss), and t(1/2), rather than doing the in vitro assay to measure this parameter.

On the Accuracy of Estimation of Basic Pharmacokinetic Parameters by the Traditional Noncompartmental Equations and the Prediction of the Steady-State Volume of Distribution in Obese Patients Based Upon Data Derived from Normal Subjects

The steady-state and terminal volumes of distribution, as well as the mean residence time of drug in the body (V(ss), V(β), and MRT) are the common pharmacokinetic parameters calculated using the drug plasma concentration-time profile C(p) (t) following intravenous (i.v. bolus or constant rate infusion) drug administration. These calculations are valid for the linear pharmacokinetic system with central elimination (i.e., elimination rate being proportional to drug concentration in plasma). Formally, the assumption of central elimination is not normally met because the rate of drug elimination is proportional to the unbound drug concentration at elimination site, although equilibration between systemic circulation and the site of clearance for majority of small molecule drugs is fast. Thus, the assumption of central elimination is practically quite adequate. It appears reasonable to estimate the extent of possible errors in determination of these pharmacokinetic parameters due to the absence of central elimination. The comparison of V(ss), V(β), and MRT calculated by exact equations and the commonly used ones was made considering a simplified physiologically based pharmacokinetic model. It was found that if the drug plasma concentration profile is detected accurately, determination of drug distribution volumes and MRT using the traditional noncompartmental calculations of these parameters from C(p) (t) yields the values very close to that obtained from exact equations. Though in practice, the accurate measurement of C(p) (t), especially its terminal phase, may not always be possible. This is particularly applicable for obtaining the distribution volumes of lipophilic compounds in obese subjects, when the possibility of late terminal phase at low drug concentration is quite likely, specifically for compounds with high clearance. An accurate determination of V(ss) is much needed in clinical practice because it is critical for the proper selection of drug treatment regimen. For that reason, we developed a convenient method for calculation of V(ss) in obese (or underweight) subjects. It is based on using the V(ss) values obtained from pharmacokinetic studies in normal subjects and the physicochemical properties of drug molecule. A simple criterion that determines either the increase or decrease of V(ss) (per unit body weight) due to obesity is obtained. The accurate determination of adipose tissue-plasma partition coefficient is crucial for the practical application of suggested method.

Pharmacokinetics and efficacy of amoxycillin in thetreatment of an experimental Streptococcus bovis Infection in racing pigeons ( Columba livia)

The pharmacokinetics of amoxycillin in pigeons (Columba livia) and the efficacy of amoxycillin treatment in pigeon streptococcosis, were investigated. After intravenous administration of 150 mg.kg-1 amoxycillin, the drug plasma concentration-time profile fitted an open two-compartment model. Amoxycillin was quickly cleared from the circulation with a mean half-life of 66 min and showed a distribution volume of 0.9 L.kg-1. The absolute oral bioavailability of amoxycillin was 50.1%. A 5-day drinking water treatment with amoxycillin (1500 mg.L-1, corresponding to 112.0 mg.kg-1.day-1 during day-light hours) significantly reduced the postinoculation morbidity in pigeons experimentally infected with Streptococcus bovis, compared to untreated infected controls.

Pharmacokinetics and anti-trichomonal efficacy of a dimetridazole tablet and water-soluble powder in homing pigeons (Columba livia).

The anti-trichomonal efficacy and pharmacokinetics of dimetridazole were investigated in the homing pigeon (Columba livia). Dimetridazole was formulated for drinking water medication and as a prolonged-release tablet. To suppress a Trichomonas gallinae infection successfully, medicated drinking water containing dimetridazole (400 mg/L) had to be administered for at least 3 days. A two-day treatment with a dimetridazole tablet (20 mg/tablet) in fasted, as well as in fed, pigeons was shown to be ineffective. After intravenous administration of 20 mg dimetridazole, the drug plasma concentration-time profile fitted a one-compartment open model with a mean half-life of 3.9 h. The absolute bioavailability of the tablet in fasted pigeons was 83.8%. The bioavailability of the tablet administered with food was reduced by 20%. Dimetridazole was rapidly metabolised to (1-methyl-5-nitroimidazol-2-yl) methanol.

Celiprolol double-peak occurrence and gastric motility: nonlinear mixed effects modeling of bioavailability data obtained in dogs.

Investigation of the underlying mechanism leading to inter- and intrasubject variations in the plasma concentration-time profiles of drugs (1) can considerably benefit rational drug therapy. The significant effect of gastric emptying on the rate and extent of celiprolol absorption and its role with respect to double-peak formation was demonstrated in the present study. In four dogs racemic celiprolol was dosed perorally in a crossover design during four different phases of the fasted-state gastric cycle and gastric motility was recorded simultaneously using a manometric measurement system. Intravenous doses were also given to obtain disposition and bioavailability parameters. The blood samples were assayed by a stereoselective HPLC method (2). The time to onset of the active phase of the gastric cycle showed an excellent correlation with the time to celiprolol peak concentration. Furthermore, bioavailability was increased when celiprolol was administered during the active phase. Double peaks were observed when the first active phase was relatively short, suggesting that a portion of the drug remained in the stomach until the next active phase. Population pharmacokinetic modeling of the data with a two-compartment open model with two lag times incorporating the motility data confirmed the effect of time to gastric emptying on the variability of the oral pharmacokinetics of celiprolol. The fasted-state motility phases determine the rate and extent of celiprolol absorption and influence the occurrence of double peaks. Peak plasma levels of celiprolol exhibit less variability if lag times, and therefore gastric emptying times, are taken into consideration.