Calibration curves pharmacokinetics

A selective, sensitive, and rapid hydrophilic interaction liquid chromatography with electrospray ionization tandem mass spectrometry was developed for the determination of donepezil in human plasma [32], Donepezil was twice extracted from human plasma using methyl-ferf-butyl ether at basic pH. The analytes were separated on an Atlantis HILIC Silica column with the mobile phase of acetonitrile ammonium formate (50 mM, pH 4.0) (85 15, v/v) and detected by tandem mass spectrometry in the selective reaction monitoring mode. The calibration curve was linear (r = 0.9994) over the concentration range of 0.10-50.0 ng/ ml and the lower limit of quantification was 0.1 ng/ml using 200 /d plasma sample. The CV and relative error for intra- and inter-assay at four quality control levels were 2.7% to 10.5% and —10.0% to 0.0%, respectively. There was no matrix effect for donepezil and cisapride. The present method was successfully applied to the pharmacokinetic study of donepezil after oral dose of donepezil hydrochloride (10 mg tablet) to male healthy volunteers. 

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,... 

A plasma calibration curve for ll-nor-A9-THC-9-carboxylic acid, 5a, is shown in Figure 9. There was reasonable linearity from 1.0-50 ng/ml plasma with detection limits of 0.5 ng or less per ml. Figure 10 presents similar data for a urine calibration curve. The method showed reasonable linearity between 2.0-100 ng/ ml urine. Figure 11 presents pharmacokinetic data. for plasma levels of a human volunteer, BS, over a 0.5 hour to 48 hour period comparing A9-THC and 11-nor acid levels after a dose of 5.0 mg of A9-THC by the intravenous route. Both parent compound and acid metabolite exhibited a biphasic elimination pattern although the levels of the acid did not fall as rapidly as parent compound. Elimination of the acid metabolite 5a in urine is shown in Figure 12. It is evident that urinary elimination proceeded rapidly as 80% of the total 11-nor-acid excreted was eliminated in the urine during... 

Lithium metabolism and transport cannot be studied directly, because the lack of useful radioisotopes has limited the metabolic information available. Lithium has five isotopes, three of which have extremely short half lives (0.8,0.2, 10 s). Lithium occurs naturally as a mixture of the two stable isotopes Li (95.58%) and Li (7.42%), which may be determined using Atomic Absorption Spectroscopy, Nuclear Magnetic Resonance Spectroscopy, or Neutron Activation analysis. Under normal circumstances it is impossible to identify isotopes by using AAS, because the spectral resolution of the spectrometer is inadequate. We have previously reported the use of ISAAS in the determination of lithium pharmacokinetics. Briefly, the shift in the spectrum from Li to Li is 0.015 nm which is identical to the separation of the two lines of the spectrum. Thus, the spectrum of natural lithium is a triplet. By measuring the light absorbed from hollow cathode lamps of each lithium isotope, a series of calibration curves is constructed, and the proportion of each isotope in the sample is determined by solution of the appropriate exponential equation. By using a dual-channel atomic absorption spectrometer, the two isotopes may be determined simultaneously. - ... 

Substrate Depletion Versus Metabolite Formation In many cases multiple enzymes will catalyze the formation of multiple metabolites from the compound of interest, which presents a level of complexity for analysis of metabolite formation that may not be justifiably resourced in the earlier stages of development compared to the later stages. The substrate depletion approach provides a method to determine relative contributions of individual enzymes using a single analytical assay and appropriate calibration curves for the parent compound (Williams et al., 2003). This would therefore offer an opportunity to understand potential intersubject variability in pharmacokinetics of the parent compound as opposed to variability in the individual clearance pathways. It also provides a method to determine the Vmax, and therefore the potential for nonlinear pharmacokinetics (Obach and Reed-Hagen, 2002). A key assumption of the substrate depletion approach is that the substrate concentration is well below Km- Therefore, 1 p,M is an appropriate default concentration. 

An LC-MS-MS method to determine cefixime in human plasma. Linear calibration curve was found between 0.05 and 8.0 p-g/ml. Quantitative measurements were possible down to 0.05 p,g/ml. Intra- and interday standard deviations are <12.7%. Accuracy is better than 2% (relative error) for the whole linear calibration range. Test time 3.2 min. The method was successfully used in pharmacokinetic tests. 

A reverse-phase HPLC method with ESI-MS detection to characterize the pharmacokinetic behavior of procarbazine, a cytotoxic chemotherapeutic agent used in the treatment of lymphomas and hrain tumors. The data are used in a phase I trial concentrations are measured in human plasma. The calibration curve is linear in the 0.5-50 ng/ml concentration range. Average recovery rate 102.9%. Lower limit of quantitation 0.5 ng/ml accmacy 105.2% interday precision 3.6% RSD sample volume 150 p,l. Interday precisions at widely different concentrations 97-98%. The stability of the drug under storage and sample preparation conditions have also been thoroughly tested. Sensitivity is sufficient for monitoring plasma levels after oral administration. 

Sixth, and finally, the adequacy of model structure as well as parameter values should be evaluated based on comparison of mode predictions with experimental data that had not been used for calibration purpose. This process essentially evaluates whether the PBPK model is capable of providing reliable predictions of the various dose metrics of potential use in a cancer risk assessement. The model should not only reprodnce consistently the shape of the pharmacokinetic time-course curve (i.e., including bnmps and valleys) and not jnst provide satisfactory fit only to a portion of the cnrve. Evaluation or validation of PBPK models should be regarded... 

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