Simultaneous determination by APCI-LC/MS/MS of hydroxylated and methoxylated polybrominated diphenyl ethers found in marine biota.

A method has been developed for the simultaneous analysis of hydroxylated and methoxylated analogs of tetrabromodiphenyl ethers (OH-tetraBDEs and MeO-tetraBDEs) and of hydroxylated and methoxylated analogs of tetrabromobiphenyl (diOH-tetraBB and diMeO-tetraBB) using high performance liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry (APCI-LC/MS/MS) in negative ion mode. Chromatographic separation was performed on a 150 mm ODS column with acetonitrile:water (9:1, v/v) in mobile phase. Multiple reaction monitoring (MRM) was performed using the precursor [M-H]- ion for hydroxylated analogs, and the [M-Br+O]- ion for tetraBDEs and tetraBB, and their methoxylated analogs. The method was validated using cod liver oil samples spiked with nine analytes (100 ng/g) for linearity (r2 > 0.998), recovery (75-95%), repeatability (8-36% RSD), and sensitivity (limits of quantification (LOQ), 0.1-0.25 ng/g lipid for phenolic analytes and 6-80 ng/g lipid for neutral brominated compounds). The APCI-LC/MS/MS was applied to analyze tiger shark and bull shark liver samples, where their concentrations were up to 8 ng/g (lipid weight) for OH-BDEs, whereas they were up to 540 ng/g (lipid weight) for MeO-BDEs. The results were consistent with values determined by electron ionization (EI)-GC/MS. The first detection of 2,2'-dihydroxy-3,3',5,5'-tetrabromobiphenyl (2,2'-diOH-BB80) by this method was in marine sponge from Micronesia. The advantage of the LC/MS/MS method over GC/MS is that it provides rapid and simultaneous determination of OH-BDEs, MeO-BDEs, and their related analogs with a single preparation step and without the involvement of chemical derivatives. Although the method provides the different LOQ ranges between hydroxylated and neutral brominated analogs, future work could apply the method to the full range of PBDE-like contaminants present in the environment and in biota tissues.

Negative APCI-LC/MS/MS method for determination of natural persistent halogenated products in marine biota.

A sensitive and selective method utilizing high performance liquid chromatography coupled to negative atmospheric pressure chemical ionization tandem mass spectrometry (APCI-LC/MS/MS) was developed to enable analysis of selected natural persistent organohalogens accumulated in marine biota. The analytes were three methoxylated tetrabromodiphenyl ethers (6-MeO-BDE47, 2'-MeO-BDE68, and 2',6-diMeO-BDE68), a dimethoxylated tetrabromobiphenyl (2,2'-diMeO-BB80), and two halogenated methyl bipyrroles (Cl(7)-MBP and Br(4)Cl(2)-DBP). These products were well resolved on a 150 mm reversed-phase column with methanol as the mobile phase. The fragmentation pathways of the Cl(7)-MBP and Br(4)Cl(2)-DBP produced characteristic multiple reaction monitoring (MRM) transitions. Determination was performed in the MRM mode using phenoxide ion [M-Br+O](-) and product Br(-) ions for MeO-BDE analogues, or the precursor [M-Cl+O](-) to Br(-) ion for Br(4)Cl(2)-DBP, and to C(4)NCl(4)(-) ion for Cl(7)-MBP. The APCI-LC/MS/MS method is acceptable for calibration of the linearity and repeatability of all products studied in the low ng/g (lipid weight) level and with similar sensitivity to the electron ionization (EI)-GC/MS method. The proposed method was applied for quantification of natural organohalogens accumulated in melon-headed whale (Peponocephala electra) blubber (N = 15) in the Asia-Pacific Ocean. The concentration was positively correlated between different groups of compounds except for 2'-MeO-BDE68. The use of the analytical method based on negative ion APCI-LC/MS/MS would provide a new way for rapid monitoring of halogenated natural products from marine biota, such as sponges or algae.

Optimal sampling and limited sampling strategies for estimation of unbound platinum AUC after nedaplatin infusion.

The aim of this study was to determine the optimal sampling design for empirical Bayesian forecasting for nedaplatin, and also to develop a simple formula for estimating the area under the plasma concentration-time curve (AUC) of platinum which relates to hematological toxicity after nedaplatin dosing using limited sampling points. Plasma unbound platinum concentration data were retrospectively collected from 27 courses administered to 20 Japanese adult patients. To determine the optimal sampling points, 1 - 5 data point(s) were selected with all combinations and clearance in each patient was estimated by the empirical Bayesian method. As measures for the Bayesian predictive performance, mean prediction error and root mean squared error were estimated. These indices suggested that the sampling time(s) of 4 hours in case of the one-point sampling gives better estimates for individual clearance. As for the limited sampling strategy, a simple formula to calculate AUC, AUC = 0.039x dose + 11.6 x Cp4h - 0.88, was obtained, where Cp4h is the concentration at 4 hours after the end of infusin. These results should be helpful for adjusting dosage to achieve the target AUC.

Determination of optimal dosage for nedaplatin based on pharmacokinetic and toxicodynamic analysis.

Nedaplatin is a platinum derivative anticancer drug. To determine its target AUC in cancer patients, the relationship between platinum AUC and hematological toxicity after administration of nedaplatin was analyzed. The data for plasma unbound platinum concentration, platelet (PLT) and white blood cell (WBC) counts were retrospectively obtained from 108 courses administered to 74 Japanese adult cancer patients. PLT and WBC decreased significantly after nedaplatin administration. The results of linear regression analysis suggested that the relative reduction ratio of PLT significantly correlated with AUC after nedaplatin administration and the relationship was not affected by the dosing course of nedaplatin nor the combination of other cancer drugs. From these findings, it became possible to determine the target AUC based on the pre-dose value of PLT and the tolerable or target nadir of PLT after nedaplatin administration. By using a simple formula to predict the individual platinum clearance of nedaplatin from a patient's renal function, it is possible to determine the optimal dose for individuals by taking into consideration the adequate maximum tolerable AUC and individual platinum clearance.

Evaluation of Bayesian predictability of vancomycin concentration using population pharmacokinetic parameters in pediatric patients.

The objective of this study was to evaluate the Bayesian predictability of vancomycin (VCM) pharmacokinetics in Japanese pediatric patients using one-compartment population pharmacokinetic (PPK) parameters, which we reported previously. The validity of the PPK model was evaluated by bootstrap method and cross validation method, and the Bayesian predictive performance was examined. The predictive performance of the PPK model for premature patients was also examined. The cross validation method showed the predictability to be acceptable for practical use, especially for predicting trough concentration using other trough data. However, for the external premature patient data, this PPK model did not seem to be adequate. A theoretical approach using a simulation technique was also examined to evaluate the predictive performance. The results suggested that the predictability at the peak was not necessarily good at all sampling times and the predictability at the trough was better when a later time point was used. The optimal sampling time for prediction of VCM concentration in pediatric patients is discussed.

Prediction of human pharmacokinetic profile in animal scale up based on normalizing time course profiles.

The aim of the present study was to develop a method for predicting the concentration-time profile in humans based on pharmacokinetic data for animals. The method is based on the assumptions that concentration-time profiles of a drug are similar among species and "normalized curves" from a variety of animal species including humans can be superimposed. Normalized curves are obtained by normalizing the time axis with the MRT (mean residence time) and the concentration axis with dose/Vdss, where Vdss is the volume of distribution at steady state. The concentration-time profile in humans after intravenous injection can be simulated using the normalized curve for an animal and the predicted values of clearance (CL) and Vdss for humans. Although the general idea of our method is similar to the Dedrick plots, ours is superior in that it enables the use of predicted CL and Vdss values from any method. Our method was applied to some drugs using actual published data sets, and the assumption of the similarity of concentration-time profiles among species was found to be acceptable for these drugs. The results for the prediction of concentration-time profiles for humans were also acceptable. This method can be applied to any drug on the assumption that normalized curves from a variety of species can be superimposed.

Prediction of human pharmacokinetics from animal data and molecular structural parameters using multivariate regression analysis: oral clearance.

The aim of the study reported here was to develop a regression equation for predicting oral clearance of various kinds of drugs in humans using experimental data from rats and dogs and molecular structural parameters. The data concerning the oral clearance of 87 drugs from rats, dogs, and humans were obtained from literature. The compounds have various structures, pharmacological activities, and pharmacokinetic characteristics. In addition, the molecular weight, calculated partition coefficient (c log P), and the number of hydrogen bond acceptors were used as possible descriptors related to oral clearance in human. Multivariate regression analyses, multiple linear regression analysis, and the partial least squares (PLS) method were used to predict oral clearance in human, and the predictive performances of these techniques were compared by allometric approaches, which have been used in interspecies scaling. Interaction terms were also introduced into the regression analysis to evaluate the nonlinear relationship. For the data set used in this study, the PLS model with the tertiary term descriptors gave the best predictive performance, and the value of the squared cross-validated correlation coefficient (q(2)) was 0.694. This PLS model, using animal oral clearance data for only two species and easily calculated molecular structural parameters, can generally predict oral clearance in human better than the allometric approaches. In addition, the molecular structural parameters and the interaction term descriptors were useful for predicting oral clearance in human by PLS. Another advantage of this PLS model is that it can be applied to drugs with various characteristics.

Population pharmacokinetics of platinum after nedaplatin administration and model validation in adult patients.

AIMS: The pharmacokinetics of unbound platinum after administration of an anticancer drug nedaplatin, cis-diammineglycolateplatinum were examined using population analysis. The relevant covariates and the extent of inter- and intra-individual variability were evaluated. METHODS: In order to clarify the pharmacokinetic profile of nedaplatin, unbound platinum concentrations (789 points) in plasma after intravenous infusion of nedaplatin were obtained from 183 courses for 141 patients. Plasma concentration data were analysed by nonlinear mixed effect modelling using NONMEM to evaluate the population mean parameters and variances for inter- and intra-individual random effects. The final population model was validated by parameter sensitivity analysis using objective function mapping, the bootstrap resampling and a data-splitting technique, i.e. the Jackknife method, and the predictive performance of the final model was evaluated. RESULTS: A two-compartment pharmacokinetic model with zero-order input and first order elimination described the current data well. The significant covariates were creatinine clearance (CLcr) for clearance of platinum (CL) [population mean [95% confidence interval (CI)] CL (l h(-1)) = 4.47 (3.27, 5.67) + 0.0738 (0.0581, 0.0896) x CLcr (CLcr: ml min(-1))] and body weight (BW: kg) for volume of distribution of platinum (Vc) [Vc (l) = 12.0 (7.5, 16.5) + 0.163 (0.081, 0.246) x BW]. Inter-individual variations (CV%, 95% CI) for CL and Vc were 25.5% (20.7, 29.6) and 21.4% (17.0, 24.1), respectively, and intra-individual variation (CV%, 95% CI) was 12.6% (10.5, 14.4). The effects of pretreatment with nedaplatin or other platinum agents on clearance and volume of distribution were also tested, but no significant effect was found. The relationship between the observed and predicted unbound platinum concentration by empirical Bayesian prediction showed good correlation with no bias, suggesting that the final model explains well the observed data in the patients. The mean prediction error and root mean square prediction error (95% CI) were - 0.0164 micro g ml(-1) (- 0.4379, 0.4051) and 0.2155 micro g ml(-1) (not calculable, 0.6523), respectively. The values of mean, standard error and 95% CI for objective function mapping, the bootstrap resampling, the Jackknife estimates and the final model coincided well. CONCLUSIONS: A population pharmacokinetic model was developed for unbound platinum after intravenous infusion of nedaplatin. Only creatinine clearance was found to be a significant covariate of clearance, and BW was found to be a significant covariate of volume of distribution. These population pharmacokinetic estimates are useful for setting initial dosing of nedaplatin using its population mean and can also be used for setting appropriate dosage regimens using empirical Bayesian forecasting.

Prediction of human pharmacokinetics from animal data and molecular structural parameters using multivariate regression analysis: volume of distribution at steady state.

The aim of this study was to develop a regression equation for predicting volume of distribution at steady state (Vd(ss)) in humans to enable application to various types of drugs using animal experimental data for rats and dogs and some molecular structural parameters. The Vd(ss) data for rats, dogs and humans of 64 drugs were obtained from literature. The compounds have various structures, pharmacological activities and pharmacokinetic characteristics. In addition, the molecular weight, calculated partition coefficient (clogP), and the number of hydrogen bond acceptors were used as possible descriptors related to the Vd(ss) in humans. Multivariate regression analyses, multiple linear regression analysis and the partial least squares (PLS) method were used to predict Vd(ss) in humans. Interaction terms were also introduced into the regression analysis to evaluate the non-linear relationship. For the data set used in the present study, PLS with quadratic term descriptors gave the best predictive performance. The PLS model using Vd(ss) data for only two animal species and using easily calculated structural parameters could generally predict Vd(ss) in humans better than an allometric method. In addition, the PLS model with only animal data gave almost the same predictive performance as the PLS model with quadratic term descriptors. This model may be easier to use and be practical in a realistic situation, and could predict Vd(ss) in humans better than the allometric method.

Prediction of human clearance from animal data and molecular structural parameters using multivariate regression analysis.

The aim of the study reported here was to develop a method for predicting human clearance that can be applied to various kinds of drugs using clearance values for rats and dogs and some molecular structural parameters. The clearance data for rats, dogs, and humans of 68 drugs were obtained from literature. The compounds have various structures, pharmacological activities, and pharmacokinetic characteristics. In addition, molecular weight, c log P, and the number of hydrogen bond acceptors were used as possible descriptors related to the human clearance value for each drug. Three types of regression methods, multiple linear regression (MLR) analysis, partial least squares (PLS) method, and artificial neural network (ANN), were used to predict human clearance, and their predictive performances were compared with allometric approaches, which have been widely used in interspecies scaling. In MLR and PLS analyses, interaction terms were introduced to evaluate the nonlinear relationships. For the data sets used in the present study, MLR and PLS with quadratic terms gave the same equation and the best predictive performance. The value of the squared cross-validated correlation coefficient (q(2)) was 0.682. In conclusion, the MLR method using animal clearance data from only two species and using easily calculated structural parameters can generally predict human clearance better than allometric methods. This approach can be applied to drugs with various characteristics.

A pharmacokinetic model for analysis of drug disposition profiles undergoing enterohepatic circulation.

A new and simple pharmacokinetic model that can explain enterohepatic circulation profiles for both single and repeated dosing was developed, and its applicability and usefulness were assessed by an actual published data set and simulation study. The model is basically a conventional compartment model, and the transfer rate from the bile compartment to the central compartment is assumed to change periodically, with the sine function being used to describe this periodical change. Using this model, the effect of the parameter values on plasma time-course profiles was examined by simulation, and the applicability of the model was tested by curve fitting to obtain the parameter estimates using an actual published data set. These studies confirmed that our model can simulate the periodical increase of the concentration due to re-absorption. By averaging the sine function in the transfer rate from the bile compartment to the central compartment, a smoothed time-course profile in the elimination phase that is independent of the enterohepatic cycle can be obtained. Also, the apparent half-life in the elimination phase can be estimated, whith is useful especially for evaluating drug accumulation during repeated dosing. It was suggested that the present model can be used to evaluate the drug disposition profile with enterohepatic circulation. The effects of sampling points and sampling time on parameter estimation are also discussed.

Study of the pharmacokinetics of vancomycin in patients with impaired liver function.

Infections caused by methicillin-resistant Staphylococcus aureus pose a serious problem postoperatively. Patients with hepatic dysfunction can be considered to be more susceptible to infection. Since little is known about the effects of the severity of hepatic dysfunction on the pharmacokinetics of vancomycin, we studied the pharmacokinetics of vancomycin in preoperative patients with hepatic dysfunction, after the intravenous infusion of 500 mg. In patients with liver disease and normal renal function, an enhancement of renal clearance caused by a reduction in percent protein binding was canceled out by a reduction in non-renal clearance caused by liver dysfunction, resulting in liver disease having no effect on the total clearance of the drug. In patients with impaired liver and renal functions and/or obstructive jaundice, the unbound fraction of vancomycin increased, whereas the renal excretion of vancomycin was delayed. It should be noted that an excessive increase in blood vancomycin concentration may be brought about even with a conventional dose in patients with hepatic dysfunction.

Phase I Clinical Studies of S-1090: Safety and Pharmacokinetics.

S-1090, an oral cephem antibiotic, was given to healthy male volunteers in single (10 to 400mg) and multiple (200mg, twice a day) doses. There were no abnormalities in subjective and objective signs, or physical findings, in any subjects. The intestinal and oropharyngeal bacterial flora were not significantly affected by S-1090. These results suggest that S-1090 is a safe and well-tolerated drug. Food intake increased the absorption of S-1090, but did not affect its half-life. The plasma concentration increased with increasing doses, but at a rate less than proportional to the dose, in the single-dose studies. S-1090 was eliminated with a half-life of 2 to 3 hours after oral administration under nonfasting conditions, independent of dose. Urinary recovery rate decreased with increasing doses. The maximum plasma concentration, half-life, and area under the concentration-time curve at the dose of 100mg in nonfasting conditions were 3.78µg/ml, 2.77 hours, and 25.51µg·h/mL, respectively. S-1090 may be absorbed by both unsaturable passive and saturable active transport systems. During multiple dosing, the extent of absorption decreased slightly, but steady state was achieved within several days without changes in half-life. S-1090 binds to serum protein constantly, at a very high 97%, which might cause the long half-life of this drug. The high plasma concentration and long half-life of S-1090 are favorable for clinical use.