COMMUNICATIONSPharmacokinetics of Drugs in Blood III: Metabolism of Procainamide and Storage Effect of Blood Samples
REFERENCES (7)
- M.G. Lee et al.
Res. Commun. Chem. Pathol. Pharmacol
(1981) - M.A.F. Gadalla et al.
J. Pharm. Sci.
(1978) - R.L. Nation et al.
J. Pharm. Sci.
(1979)
Cited by (22)
Estimation of blood sampling errors resulting from metabolism and solute exchange between plasma and formed elements
1994, Journal of Pharmacological and Toxicological MethodsThe origin and magnitude of potential errors in whole-blood sampling are prredicted on the basis of a mathematical model. The model describes the kinetics of solute metabolism, breakdown, and interphase distribution (i.e., partitioning and exchange between formed elements and plasma) within a blood sample during sample withdrawal and storage. The model is applied to the determination of the integral over time of solute concentration in the plasma (area-under-the-curve, or AUC) from a sample withdrawn through an arterial or venous catheter. Errors in AUC determination can be substantial and are strongly dependent on the duration of sampling (T), the rate constants for solute degradation processes, the rate constant for solute exchange between the formed elements and the plasma (ke). ,nd the equilibrium ratio for distribution of the solute between formed elements and plasma (R). When the value of the dimensionless group keT/R is small, little solute exchanges between plasma water and formed elements before the two phases of the blood are separated. When keT/R is large, the solute distribution is close to equilibrium at all times. In these two keT/R limits, the contribution of solute redistribution to sampling error is small. Sizable errors resulting from redistribution are associated with intermediate values of keT/R, even in the absence of metabolism and despite rapid separation of the phases at the end of the withdrawal period. Chemical conversion within either of the blood phases introduces additional sampling error under most circumstances.
Pharmacokinetics of FT-ADM after intravenous administration of DA-125, a prodrug of FT-ADM or FT-ADM to rats. A new adriamycin analog containing fluorine
1994, International Journal of PharmaceuticsThe pharmacokinetics of DA-125 or its active metabolite, M1 (FT-ADM), an adriamycin analog containing fluorine were compared after intravenous (i.v.) administration of DA-125 or M1 in rats. DA-125, 20 mg kg−1 was dissolved in 1 mM lactic acid/0.9% NaCl solution (treatment I) or 100% dimethylsulfoxide (DMSO, treatment II), and M1, 20 was dissolved in 100% DMSO (treatment III) due to its poor water solubility. The plasma concentrations of DA-125 and M1, and the pharmacokinetic parameters of DA-125, such as terminal half-life (, 1.64 vs 2.07 min), mean residence time (MRT, 1.52 vs 2.60 min), total body clearance (CL, 165 vs 186 ml min−1 kg−1) and apparent volume of distribution at steady state (Vdss, 254 vs 411 ml kg−1), and of M1 (based on plasma data up to 1 h), such as ( (30.2 vs 38.7 min), MRT (19.1 vs 31.6 min), CL (187 vs 189 ml min−1 kg−1) and Vdss(2670vs 5700 ml kg−1were similar between treatments I and II, indicating that the effect of 100% DMSO on the pharmacokinetics of DA-125 or M1 seemed to be negligible, if any. The plasma concentrations of M1, and the pharmacokinetic parameters of M1 (based on plasma data up to 8 h when the dose of M1, 20 mg kg−1 was normalized to the dose of DA-125, 20 mg kg−1), such as ( (255 vs 221 min), MRT (269 vs 235 min), CL (103 vs 112 ml min−1 kg−1) and Vdss (28 500 vs 26300 ml kg−1) were also similar between treatments II and III. The above results indicate that DA-125 is rapidly hydrolyzed to M1 after i.v. administration of DA-125. Therefore, the estimation of the pharmacokinetic parameters of M1 after i.v. administra- tion of DA-125 appeared not to cause any differences, if any when compared with the values after i.v. dose of M1. The rapid hydrolysis of DA-125 to M1 was demonstrated during an in vitro study; the ( values of hydrolysis of DA-125 were 1.97, 1.72, 0.54 and 0.54 min in the plasma from mouse, rat, dog and human, respectively, when the plasma containing DA-125 was incubated in a shaking water bath kept at 37°C and at a rate of 300 rpm.
Intravenous Drug Administration
1994, Handbook of Behavioral NeuroscienceThis chapter provides an overview of the intravenous drug administration. Intravenous drug administration offers various advantages over other routes of administration. Intravenous (and intra-arterial) drug administration provides the most complete drug availability with a minimal delay. By control of the administration rate, constant plasma concentrations can be obtained at a required level. Unexpected side effects observed during the administration period can be halted by stopping the infusion (pleading for an extended infusion time). Compounds that are poorly absorbed by the gastrointestinal tract may be advantageously administered intravenously. Compounds that are unacceptably painful when administered intramuscularly or subcutaneously may present no difficulties by the intravenous route. The chapter also highlights that with intravenous drug administration strict control is needed of the pharmaceutical qualities of the drug solution. In general, it seems advisable to restrict the injection volume in rodents to a maximum of 3 ml/kg and to extend the duration of injection to minutes. When interpreting experimental results, the possibility of a disequilibrium phase during and shortly after drug administration must be taken into consideration.
Erythrocytes as a total barrier for renal excretion of hydrochlorothiazide: Slow influx and efflux across erythrocyte membranes
1992, Journal of Pharmaceutical SciencesThe potential barrier effect of erythrocytes (RBC) on renal excretion (mainly by tubular secretion) of hydrochlorothiazide (HCTZ) was evaluated in nine anesthetized rats during steady-state iv infusion. Drug concentrations in plasma and blood from the carotid artery and renal vein were assayed by a simple modified HPLC method. Renal extraction ratios were concentration-independent with a mean of 0.17 ± 0.05 (SD). The renal excretion was found to occur primarily from the drug in plasma; the mean net fractional removal from plasma was 0.57 ±0.12, while that from RBC was <0.008 ± 0.041. The virtual total unavailability of HCTZ from RBC (containing ~70% of drug in arterial blood) for renal excretion is attributed to relatively slow efflux of drug from RBC to plasma during each passage through the kidney compared with the blood transit time (in seconds). Preliminary in vitro influx and efflux kinetics of HCTZ across RBC membranes were studied using rat and human blood. The flux data could be adequately described by a linear, reversible, closed two-component system model, and the mean equilibration half-times (ET1/2) in rat and human blood were 10.9 and 20.5 min, respectively. The mean residence time of drug in blood circulation of rats was estimated to be 8.32 ± 1.06 min, which is shorter than the ET1/2. This is consistent with data indicating that distribution equilibrium of HCTZ in arterial blood might not be reached in vivo even at steady state. Other implications of slow transport kinetics of drugs across RBC membranes are discussed.
Analysis of drugs and other toxic substances in biological samples for pharmacokinetic studies
1990, Journal of Chromatography B: Biomedical Sciences and ApplicationsThe importance of the role of analysis of drugs and other toxic substances in biological samples (bioanalysis) in medicine, toxicology, pharmacology, forensic science, environmental research and other biomedical disciplines is self-evident. Among these disciplines, bioanalysis plays a special pivotal role in pharmacokinetics. The pharmacokinetic parameters, such as half-life, volume of distribution, clearance and bioavailability, of drugs and other compounds are derived from the concentrations of these analytes assayed in the biological samples collected at specified time points. The capability of analysts to develop sensitive and specific analytical methods for the assay of low concentrations of drugs and other toxic compounds in small amounts of biological samples has contributed significantly to the theoretical advances in pharmacokinetics and its applications in clinical pharmacology and the management of drug therapy in patients. The increased demands for pharmacokinetic applications in turn have stimulated the innovation and improvement in bioanalytical technologies.
The reliability of the pharmacokinetic conclusions depends on the accuracy and precision of the analytical methods employed to assay the biological samples. Factors that affect the integrity of the bioanalytical data should therefore be controlled in analysis of biological samples for pharmacokinetics studies. The biological samples for drug concentration determination should be collected as specified in the study protocol with respect to the time and site of sampling. These samples should be processed to avoid extraneous interactions between the analytes and sampling devices or additives resulting in the redistribution of the analytes between components of the biological samples, such as displacement of drug binding and changes in the distribution of the analytes between plasma and red blood cells. The stability of the drugs and other analytes in the samples should also be evaluated to establish the conditions suitable for the transportation and storage of the samples to avoid chemical, photochemical and enzymatic degradation of the analytes.
Various technologies have been utilized to assay biological samples for pharmacokinetic studies. The most frequently used are chromatography (high-performance liquid chromatography, gas chromatography and thin-layer chromatography), immunoassays and mass spectrometry. Except for some immunoassays, the biological samples are usually prepared by liquid—liquid or solid-phase extraction taking advantage of the pH ionization and partition characteristics of the analytes for preliminary separation of the analytes from other components in the sample matrices. Such extraction procedures should be optimized to obtain high and, most importantly, reproducible recovery. Approaches to simplify the sample preparation procedures have been actively pursued and some advances such as immunoaffinity purification prior to chromatographic separation or other means of quantification and direct introduction of the biological samples for chromatography using column-switching techniques and special stationary phases have been made.
Validation of bioanalytical methods is an important task to assure the reliability of the assay data. In addition, validation of analytical methods has also been required by various regulatory agencies. Such validation generally requires the demonstration of the specificity, sensitivity, calibration linearity, extraction recovery, precision and accuracy of the assay methods. However, despite the importance of assay method validation, many of these terms have been defined differently and the criteria for validation of bioanalytical methods are often dependent on the intended application of the assay. For pharmacokinetic evaluations, it is most important that the analytical methods should be specific with no interferences from endogenous and exogenous substances; that the methods should have a low limit of quantification capable of accurate measurement of the compounds over a sufficient period of time following drug dosing or exposure necessary to characterize the pharmacokinetic parameters; and that the accuracy and precision of the assay are demonstrated by appropriate calibration standards and seeded control samples.
Analysis of drugs and other toxic substances in biological samples is a challenging task because the concentration of the analytes in the complex matrices are often very low. The interest in free drug concentrations in plasma further requires that the assay method is sensitive to measure even lower concentrations of the free drugs and metabolites. The renewed interest in stereoselectivity of drug disposition has also added the demands for measurement of drug enantiomers. New bioanalytical technologies in chromatography, immunoassays, radioreceptor assays, mass spectrometry and biological sensors are emerging. These, together with the development in automation in bioanalytical laboratories in sample preparation, analysis and data management, provide analysts with an ample armamentarium to meet the present analytical requirements for pharmacokinetic studies. These changes also present an opportunity for innovation and improvement of the bioanalytical technologies to meet the ever demanding requirements of pharmacokinetics and other biomedical sciences that rely on accurate measurement of lower and lower levels of drugs and toxic substances in biological samples.
Inter-individual variation of human blood N-acetyltransferase activity in vitro
1988, Biochemical PharmacologyInter-individual variation in the in vitro acetylation of the antibacterial drug sulphamethazine by human whole blood was studied using reverse phase HPLC. The mean (range) values of blood N-acetyltransferase activity in vitro were 0.50 (0.29–0.83) nmol per 109 red blood cells (rbc) (N = 23), 3.33 (2.22–5.27) nmol per 109 rbc (N = 27) and 9.36 (6.72–15.76) nmol per 109 rbc (N = 23) at initial sulphamethazine concentrations of 0.018 mM, O.18 mM and 1.44 mM respectively. The mean (range) values of the initial rate of sulphamethazine acetylation at these substrate concentrations were 28.1 (20.9–35.0) per 109 rbc (N = 11), 0.26 (0.18–0.42) per 109 rbc (N = 19) and 0.91 (0.61–1.50) per 109 rbc (N = 14) respectively. The mean (range) half life of thermal inactivation of blood acetylation capacity at 50° was 0.91 (0.59–1.27) min (N = 12) at an initial substrate concentration of 0.18 mM. In each of these cases, there was no significant differences between the values obtained using blood samples from rapid and slow acetylators.
Intra-individual variation of blood N-acetyltransferase activity was studied in a single subject on 24 separate occasions during a two year period and was less than 10% at each of the three sulphamethazine concentrations studied. The correlation between the in vitro blood N-acetyltransferase activity of eight volunteers measured on two separate occasions at least 6 weeks apart was 0.84, 0.98 and 0.98 at initial sulphamethazine concentrations of 0.018 mM, 0.18 mM and 1.44 mM respectively.
Increasing the acetyl-CoA concentration of blood samples from 4 subjects by 0.34, 0.85 and 1.67 mM significantly increased both the initial acetylation rate of sulphamethazine and the amount of acetylsulphamethazine produced after an incubation time of 24 hr (initial sulphamethazine concentration = 0.18 mM).