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At least 19 recordsLinked to original sources
PubMed1993

Modeling blood/plasma concentrations in dosed feed and dosed drinking water toxicology studies.

A computer model for predicting blood/plasma concentrations of test chemicals in dosed feed and dosed drinking water toxicology studies was developed. The model was constructed based on linear theory. The animal's feeding and drinking habits and the linear disposition kinetics of the test chemical obtained after a bolus gavage dose were built into the model. Blood/plasma concentrations of oxazepam and pentachlorophenol in dosed feed and dosed drinking water studies were predicted and compared with the experimentally determined data. The model proved highly reliable in predicting the blood/plasma concentrations of test chemical in dosed feed and dosed drinking water studies. The results suggest that if the kinetics of test chemicals fit a one-compartment model then bioaccumulation of the test chemical will occur in dosed feed or in dosed drinking water studies when absorption half-lives are less than 1.38 hr and elimination half-lives are longer than 5 hr. The extent of accumulation is mainly dependent on the elimination half-lives. For chemicals with absorption half-lives less than 1.38 hr and elimination half-lives less than 2 hr, the extent of bioaccumulation will be minimal. Blood/plasma concentrations of test chemicals in rats and mice will fluctuate daily and a quasi-steady state will be achieved after ad libitum exposure to dosed feed or dosed drinking water for approximately 4 days. If a daily 12-hr light cycle is used with the light cycle starting at 7:00 AM, the expected peak and trough blood concentrations in dosed feed studies will occur approximately in the early morning (5:00 AM) and in the late afternoon (4:00 PM), respectively. Similar results were obtained for dosed drinking water studies. The model should be applicable to dosed feed and dosed drinking water studies using other species.

Animals↗
PubMed1984

Determination of progabide and its main acid metabolite in biological fluids using high-performance liquid chromatography and electrochemical detection. Application to the measurement of blood/plasma partition ratio.

A method for the measurement in plasma, blood and urine of progabide, its main acid metabolite, and the corresponding benzophenone is described. This assay allows the determination of progabide and its acid metabolite for therapeutic drug monitoring, and with a minimum detectable concentration of 1-10 ng/ml for progabide and its acid metabolite, it is sensitive enough for pharmacokinetic studies. Progabide and its metabolites are extracted from biological samples with toluene at pH 4.5. Following reduction of the imine bond with sodium borohydride, the reduced drugs are back-extracted into an aqueous phase at acid pH and reextracted by diethyl ether at alkaline pH. Progabide, its acid metabolite and the benzophenone are separated by high-performance liquid chromatography using a 3-micron ODS column with a quaternary solvent mixture of methanol-acetonitrile-phosphate buffer (0.033 M, pH 5.5)-sodium chloride (1.5 M) (30:30:40:9, v/v), and detected electrochemically at a potential of +850 mV vs. an Ag/AgCl electrode. Antiepileptic drugs like carbamazepine, carbamazepine epoxide, phenytoin, valproic acid and ethosuximide do not interfere with the assay. Blood/plasma partition ratios of 0.69 and 0.55 for progabide and its acid metabolite, respectively, indicate that the former but not the latter is present in red blood cells.

Anticonvulsants↗
PubMed2006

Air to muscle and blood/plasma to muscle distribution of volatile organic compounds and drugs: linear free energy analyses.

Distribution coefficients, K(mus), from the gas phase to the muscle have been collected for volatile organic compounds (VOCs). For 114 VOCs, a linear free energy relationship (LFER) yields an equation for log K(mus) with R(2) = 0.944 and SD = 0.267; construction of a training and test set shows that the LFER can predict further values to around 0.30 log units. The combination of the log K(mus) values with values for air to blood yields distribution coefficients from blood to muscle, log P(mus), for 110 VOCs; the corresponding LFER has R(2) = 0.537 and SD = 0.207 and a predictive capability of 0.22 log units. We also collected data on the distribution of drugs from blood or plasma to muscle and showed that the two sets of data can be combined. A LFER for blood/plasma to muscle for 59 drugs has R(2) = 0.745 and SD = 0.253 and a predictive capability of 0.25 log units. Finally, we show that the in vitro data on VOCs and the in vivo data on drugs can be combined; a LFER on the total data for 163 compounds has R(2) = 0.595, SD = 0.220, and a predictive capability of about 0.25 log units.

Air↗
PubMed2006

Correlates of HIV infection among former blood/plasma donors in rural China.

BACKGROUND: In 1995, when the first cases of HIV infection were reported among former plasma donors (FPDs), the Chinese government closed all commercial plasma collection stations. OBJECTIVE: To determine the prevalence of HIV among FPDs and non-donors in affected villages in Anhui, China. METHODS: A cross-sectional survey was conducted among residents, aged 25-55 years, in 40 villages randomly selected from villages with many former blood/plasma donors, using a two-stage clustered sampling method. A questionnaire was administered face-to-face to 1997 villagers without collecting any identifying information, and venous blood specimens were collected for HIV testing with two enzyme-linked immunosorbent assays and western blotting. EpiData was used for data entry, and STATA was used for data analysis. RESULTS: Overall HIV prevalence was 10.8%, with values of 15.1% among FPDs and 4.8% among non-donors. Among FPDs, factors associated with HIV infection included: donating plasma more than 10 times [odds ratio (OR) 4.09; P < 0.001] compared with subjects who donated 1-3 times; spouse being HIV-positive (OR, 4.06; P = 0.001); and being male (OR, 2.04; P = 0.011). Condom use was rare, and was not associated with HIV infection (OR, 1.09; P = 0.872). Among non-plasma donors, spouse being HIV-positive (OR, 11.07, P < 0.001) and having multiple sexual partners (OR, 7.04; P = 0.006) were associated with HIV infection. CONCLUSIONS: The prevalence of HIV infection is high among rural residents in villages with former commercial plasma businesses. Plasma but not blood donations were associated with HIV infection. The HIV/AIDS epidemic has spread to non-donors primarily through sexual transmission. HIV/AIDS education, testing, and condoms should be promoted urgently to prevent further transmission.

Adult↗
PubMed2006

Characterization of the gp120 of circulating HIV type 1 in a group of infected Chinese blood/plasma donors with asymptomatic and symptomatic stages of the disease.

The C2-V5 regions of the HIV envelope gene were cloned and sequenced from DNA samples of four asymptomatic and five AIDS patients from a cohort of HIV-1-infected Chinese plasma and blood donors. Sequence analysis revealed that regardless of the stage of disease, all the patient's HIV-1 belonged to either clade B' or circulating recombinant form 15 (CRF15) subtype. However, since these blood donors were infected at a time when circulating CRF15 was not known in that region, it is likely these HIV-1 types belong to clade B'. However, the C2-V5 sequences from AIDS patients clustered differently in the phylogenetic tree than those present in asymptomatic patients and showed a significantly higher divergence and lower diversity compared to those from asymptomatic patients. In addition, more syncytia-inducing viral genotypes were present in AIDS patients than in asymptomatic patients. These results contribute to a better understanding of the pathogenesis of circulating HIV-1 in infected Chinese plasma and blood donors, warrant additional investigation of the possible presence of CRF15 in Chinese blood donors, and may have important implications in the future design of therapeutic strategies for treating these infected patients.

Asian People↗
PubMed1999

R-hirudin as anticoagulant in regular hemodialysis therapy: finding of therapeutic R-hirudin blood/plasma concentrations and respective dosages.

Recently heparin-induced thrombocytopenia type II has been diagnosed more frequently and does not exclude hemodialysis patients. Up to now, recombinant hirudin is the only available anticoagulant showing no immunologic cross reactions with heparin. However, the use of r-hirudin in hemodialysis patients with different degrees of residual renal functions is impossible using standard dosages because elimination of r-hirudin varies depending on the degree of residual renal function. Therefore the first study was carried out using consecutive r-hirudin anticoagulated hemodialyses to determine the appropriate dose of r-hirudin. Ten hemodialysis patients with creatinine clearance values ranging between 0 and 13 mL/min/1.73m2 were anticoagulated with r-hirudin. An initial bolus of 0.1 mg/kg bwt before the first hemodialysis, resulted in an average r-hirudin blood concentration of 305 ng/mL at the end of treatment. The dose for each of the following four hemodialyses was adjusted individually to reach the minimum therapeutic r-hirudin blood concentration. At the end of these treatments the mean blood r-hirudin concentration was 422 ng/mL. The necessary mean doses ranged between 0.008 and 0.125 mg/kg bwt correlating to the creatinine clearance values of the patients. All hemodialyses of the study were effective and safe. Bleeding times determined during r-hirudin anticoagulation were significantly lower than control values measured 2 days after a heparin administration. The study proved that r-hirudin may be an efficient and safe heparin alternative as a hemodialysis anticoagulant when the individual's residual renal function is noted for dosage and dose adjustment and is controlled by drug monitoring using the ecarin clotting time.

Adult↗
PubMed1993

Transient blood/plasma density and hematocrit effects after passive (sitting) thermoneutral water immersion in men.

At the beginning and with ceasing of suction which is exerted upon the lower parts of the body, we have recently discovered transient hemodilution/hemoconcentration effects by use of the high-precision so-called mechanical oscillator technique. Since transient effects are useful for biological systems analysis, we addressed the question if such transients in blood and plasma mass density also occur with and immediately after water immersion in humans. Water immersion (WI) has been used as an analog of microgravity conditions. The effects on blood volume depend on the test conditions, particularly body position before immersion, and the time of measurement. Consequently, hemodilution has been found as an early effect of WI in many but not all studies. If test persons are immersed after sitting or standing on air, WI counteracts postural hemoconcentration and consistently produces a decrease in hematocrit, hemoglobin, and plasma protein concentration and, hence, plasma and blood mass density. In this paper we present evidence that, like with termination of lower body suction, there might be transient hemoconcentration in the first minutes of thermoneutral WI in a sitting position in men, but no evidence could be obtained for any counterdirected transient hemodilution when test subjects are passively brought out (in sitting position) from the water, as was found with starting lower body suction (in supine position).

Blood Viscosity↗
PubMed1992

Effect of head-down bedrest on blood/plasma density after intravenous fluid load.

Using the mechanical oscillator technique, the mass density of antecubital venous blood and plasma samples was measured in 6 men before and after infusion of 22 ml/kg isotonic NaCl solution before, on day 7 during, and on day 3 after ten days of 6 degrees head-down bedrest. We studied 1) the distribution volumes of the infused NaCl solution, 2) the magnitude and time-course of induced fluid shifts to the extravascular spaces after rapid volume expansion, and 3) the protein concentration of the translocated fluid. The NaCl distribution volume was 16.7 +/- 2.9% body weight (BW) before, 15.0 +/- 3.0% BW during (P less than 0.05) and 13.0 +/- 1.3% BW after the head-down tilt (HDT) period (P less than 0.01). The volume of fluid shifted 120 min after infusion was not different in the control (12.9 +/- 7.4% plasma volume and 8.3 +/- 3.2% blood volume), during HDT (14.7 +/- 3.8% plasma volume and 7.4 +/- 5.6% blood volume), during HDT HDT conditions (14.6 +/- 2.2% plasma volume, and 8.2 +/- 1.3% blood volume, respectively). The density of the shifted fluid which reflects protein concentration was also unchanged (1004.2 +/- 4.2 g/l, 1002.6 +/- 4.3 g/l and 1003.9 +/- 8.2 g/l in the control, during, and after HDT periods, respectively). The mass density of red cells did not change with any condition. It is concluded that the distribution volume of isotonic saline solution decreases with diminished body mass. Densitometry provides a means of monitoring volume changes and protein shifts under the circumstances of our study.

Adult↗
PubMed1997

Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration.

In this 2-week, ascending dose study, the pharmacokinetic activity of sirolimus was examined in 40 stable renal transplant patients treated with cyclosporine and prednisone. Nine dose levels (range, 0.5-6.5 mg/m2/12 hr) of sirolimus were studied in a parallel design. Mean values for the pharmacokinetic parameters of sirolimus calculated in all dose groups were as follows: time to peak blood concentration, 1.4 +/- 1.2 hours; terminal half-life, 62 +/- 16 hours; oral dose clearance, 208 +/- 95 mL/h/kg; apparent oral steady-state volume of distribution, 12 +/- 5 L/kg; and blood/plasma ratio, 38 +/- 13. The intersubject variabilities in dose clearance, steady-state volume of distribution, and blood/plasma ratio were 4.5-fold. Preliminary assessments suggests linear dose proportionality. An excellent correlation existed between area under the concentration-time curve and trough blood concentration at steady state. Sirolimus did not produce any significant changes in area under the concentration-time curve of cyclosporine. Preliminary analysis suggested that values for the pharmacokinetic parameters of sirolimus vary among races (black versus nonblack) but not among genders.

Administration, Oral↗
PubMed1983

Pharmacokinetics of betamethasone in healthy adults after intravenous administration.

The pharmacokinetics of betamethasone and its phosphate ester are described in 8 healthy adults after i.v. bolus injection of 10.6 mg betamethasone phosphate. Both compounds were measured by high-performance liquid chromatography with ultraviolet detection using sample handling methods which prevented hydrolysis of the ester in vitro. Betamethasone phosphate disappeared rapidly from plasma (mean half-life = 4.7 min) as betamethasone levels rose. Betamethasone plasma levels reached a peak 10-36 min after administration of the phosphate before declining in a biexponential manner. The terminal slow disposition phase had a mean half-life of 6.5 h. Only about 5% of the dose was recovered from urine as betamethasone, indicating extensive extrarenal clearance of betamethasone. Protein binding and blood/plasma concentration ratio were also determined. In comparison with its stereoisomer, dexamethasone, betamethasone is also cleared mainly by metabolism but has a lower plasma clearance, is less plasma bound, has a higher blood/plasma concentration ratio, and a higher volume of distribution. Endogenous cortisol levels were measured in the subjects who received betamethasone phosphate and in a matched control group of 4 subjects who did not. Betamethasone abolished the normal episodic secretion of cortisol and rapidly reduced its plasma concentration to a basal level. Cortisol plasma levels were not restored at 24 h but had returned to normal by 48 h after dosing.

Adult↗
PubMed2002

Blood and plasma pharmacokinetics of vinorelbine in elderly patients with advanced metastatic cancer.

PURPOSE: As vinorelbine is 78% bound to platelets, it seems interesting to investigate the pharmacokinetic profile of this drug from blood and to compare it to that determined from plasma. Thus, in this study, the comparative blood/plasma pharmacokinetics of vinorelbine were investigated in 15 elderly patients with advanced metastatic cancer. METHODS: The drug was given as a short (10 min) peripheral intravenous infusion; the administered dose ranged from 20 to 30 mg/m2 depending on the patient. Chemotherapy was repeated weekly. During the first and the fifth courses, each patient underwent pharmacokinetic evaluation. Toxicity evaluation was performed after each course of chemotherapy; a total of 109 courses was studied. Plasma and blood vinorelbine determinations were performed by high-performance liquid chromatography with spectrofluorimetric detection. Individual pharmacokinetic parameters were estimated with an empirical Bayes methodology. An open three-compartment pharmacokinetic model was used to describe the kinetics of vinorelbine. RESULTS: The half-lives of the terminal part of the curves, determined from blood and plasma data, were of the same order of magnitude: 31-35 h. Mean total clearances were about 0.71 l/h/kg from plasma and 0.45 l/h/kg from blood. Except during the first 15-20 min following the end of infusion, vinorelbine concentrations were 1.9 times higher in blood than in plasma. The ratio AUC(B)/AUC(P) (AUC(B) and AUC(P) are the area under the concentration-time curve from blood and plasma data, respectively) averaged 1.7; it was comparable to the blood/plasma ratio of 1.6 that remained constant over the 72 h of the study. There was substantial intra- and interpatient variability in vinorelbine pharmacokinetic parameters. This variability is similar within and between patients, and between pharmacokinetic parameters computed from blood and plasma. The elimination half-life is the parameter with the lowest intra- and interindividual variability (10-14%), while the AUC is the parameter presenting the highest variability (20-65%). The main haematological toxicity was anaemia (12 patients) and neutropenia (10 patients). Thrombocytopenia occurred in only one patient. At the first cycle, significant correlations were found between AUC(B) and AUC(P) and the decrease in neutrophil count (P < 0.05). The highest haematological toxicities encountered in this study occurred in patients presenting the lowest platelet count. AUC computed from plasma data decreased significantly with the increase of platelet count (P = 0.03). CONCLUSION: From the results of this study, blood did not appear to be a better predictor of haematological toxicity than plasma, but the decrease of platelet count seems to be a good predictor of this toxicity. Indeed, changes in platelet count are likely to produce strong variations in the unbound fraction of vinorelbine; this exposes the patient to a high risk of toxicity.

Aged↗
PubMed1995

Pharmacokinetics of tacrolimus in liver transplant patients.

OBJECTIVE: To characterize the pharmacokinetics of the immunosuppressive agent tacrolimus (FK 506) in liver transplant patients. METHODS: Patients (n = 16) were assessed during and after 1- to 3-day intravenous infusions followed by a 2-week course of oral dose therapy. Plasma and whole blood data were fitted simultaneously with equations accounting for nonlinear drug binding by red blood cells to generate clearance (CL) and volume of distribution (V). RESULTS: The maximum blood/plasma ratio of tacrolimus was 55.5 +/- 26.8 (SD) and half-life averaged 12.1 +/- 4.7 hours. The CL and V were relatively high based on plasma concentrations (CL, 1.7 L/hr/kg; V, 30 L/kg) and low based on whole blood (CL, 54 ml/hr/kg; V, 0.9 L/kg), with moderate variability (coefficient of variation, 34% to 49%) among the patients. Correlations of plasma CL and V with maximum blood/plasma ratios (ranging from 13 to 114) were strong (r = 0.65 and r = 0.73). Blood binding affects the disposition of tacrolimus, and plasma concentrations are indirectly and inversely related to red cell binding. The oral dose data for tacrolimus yielded a brief absorption lag time (tlag, 0.39 hour), a variable first-order absorption rate constant (ka, 4.5 +/- 3.0 hr-1), and consistent bioavailability (F, 25% +/- 10%). The area under the concentration-time curve versus 12-hour minimum concentration relationships for both whole blood and plasma were nearly linear, confirming the utility of trough values for monitoring drug exposure. CONCLUSION: This study provides pharmacokinetic guidelines for the use of tacrolimus in patients undergoing hepatic transplantation. Nonlinear blood binding is a major source of interpatient variation in the disposition of tacrolimus.

Administration, Oral↗
PubMed2006

Air to fat and blood to fat distribution of volatile organic compounds and drugs: linear free energy analyses.

Partition coefficients, K(fat), from air to human fat and to rat fat have been collected for 129 volatile organic compounds, VOCs. A linear free energy relationship, LFER, correlates the 129 values of log K(fat) with R(2)=0.958 and a standard deviation, S.D., of 0.194 log units. Use of training and test sets gives a predictive assessment of around 0.20 log units. Combination of log K(fat) with our previously listed values of log K(blood) enables blood/plasma to fat partition coefficients, as log P(fat), to be obtained for 126 VOCs. These values can be correlated with R(2)=0.847, S.D.=0.304 log units; the latter is also our assessment of the predictive capability of the LFER. Values of log P(fat) have been collected for 46 drugs, and can be fitted to an LFER with R(2)=0.811 and S.D.=0.355 log units. Unlike partition into brain or muscle, the data for VOCs and drugs cannot be combined. There are marked discrepancies for PCBs for which partition from blood/plasma into fat is very much less than that calculated from the data on VOCs or from the data on drugs.

Adipose Tissue↗
PubMed2006

Blood or plasma to skin distribution of drugs: a linear free energy analysis.

Data on distribution coefficients from blood or plasma to rat skin and rabbit skin have been compiled. From previous work on blood/plasma to brain or to muscle it is apparent that distributions from blood and plasma can be combined, and we show that it is possible to combine data on distribution to rat skin and rabbit skin. The combined set of blood/plasma distribution to rat and rabbit skin for 59 compounds, as logPskin, can be correlated through a linear free energy equation with a correlation coefficient of 0.856 and a standard deviation of 0.26 log units. The predictive capability of the equation has been assessed through training and test sets, and it is shown that the S.D. value of 0.26 log units is a good estimate of the predictive ability. The equation for logPskin has been compared to equations for a large number of possible model processes, using two mathematical methods. It is shown that there is no process amongst those we have examined that has any advantage over the present in silico linear free energy equation for the estimation of further values of logPskin.

Animals↗