SEARCH · PubMed Health

Results for “BLOOD/plasma”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 109 records · Page 6Linked to original sources

PubMed1986

A sudden death due to tocainide overdose.

The details of a fatal self-poisoning with the anti-arrhythmic drug tocainide are described. The authors are unaware of another such case. The physiological and toxicological results are post mortem are presented and discussed, with emphasis on the method of analysis of the drug in the body fluids and tissues. Stomach content was analysed by direct solvent extraction followed by ultraviolet spectrophotometry and thin-layer chromatography. Blood, urine and liver concentrations were obtained by high-pressure liquid chromatography, blood and liver samples being extracted under basic conditions and urine analysed directly. Two methods are compared for the liver analysis; an alkaline extraction of an enzymic digestion yielded lower levels of drug than did a mechanical maceration followed by alkaline extraction and 'salting out'. The latter is an adaptation of the method used for analysis of blood. Details of therapeutic and toxic blood/plasma concentrations are taken from the literature and compared with the analytical data, leading to the conclusion that the only logical cause of death was tocainide poisoning.

Aged↗

PubMed2002

Biodistribution and pharmacokinetics of O-palmitoyl tilisolol, a lipophilic prodrug of tilisolol, after intravenous administration in rats.

The purpose of this study was to modify the biodistribution and pharmacokinetics of tilisolol, a beta-blocker, using the palmitoyl prodrug approach. After intravenous administration of tilisolol and O-palmitoyl tilisolol in rats, drug concentrations were determined in blood, bile, urine, and several tissues. The concentration-time profiles of tilisolol and O-palmitoyl tilisolol were analyzed pharmacokinetically. The blood concentrations of O-palmitoyl tilisolol after intravenous administration of O-palmitoyl tilisolol were about 10-fold higher than those of tilisolol after intravenous administration of tilisolol. The biliary excretion rates of O-palmitoyl tilisolol and tilisolol after intravenous administration of O-palmitoyl tilisolol were about 10- to 100-fold larger than those of tilisolol after intravenous administration of tilisolol. In addition, the hepatic uptake clearance of O-palmitoyl tilisolol after intravenous administration of O-palmitoyl tilisolol was 3.6-fold higher than that of tilisolol after the intravenous administration of tilisolol. In the in vitro experiments, it was demonstrated that the distribution ratios between blood cells and plasma (blood/plasma) of O-palmitoyl tilisolol and tilisolol was 95.7 and 55.5%, respectively. These findings suggest that O-palmitoyl tilisolol exists as a binding form with biological components, especially blood cells, in systemic circulation. In conclusion, the palmitoyl prodrug approach is useful as a drug delivery system to deliver the parent drug to the liver.

Animals↗

PubMed2004

Oxygen-carrying blood substitutes: a microvascular perspective.

Development of a viable blood substitute began by focusing on recreating the oxygen-carrying capacity of blood, leading to the recognition that haemoglobin (Hb) is presently unequalled for this function. However, as human Hb is the only realistic source of this protein, the production of a blood substitute that solves transfusional blood availability problems and shortages must introduce a multiplying factor between supply of natural blood and blood substitute, while maintaining equivalency of function/efficacy. In other words, a unit of blood should produce several units of equivalent blood substitute. This expansion is now possible because of new understanding of how blood delivers oxygen in the microcirculation and the consequences of reducing oxygen-carrying capacity in haemorrhage. This information is used to provide improved resuscitation capacity and maintenance of tissue metabolism by tailoring the properties of a blood substitute to the task of maintaining microvascular function, rather than oxygen delivery capacity. Resuscitation in an organism that is haemorrhaging requires maintenance perfusion, a process directly linked to the maintenance of adequate levels of shear stress on the endothelium, induced by either increased blood/plasma viscosity or increased blood flow velocity in the microcirculation. This process must also be intimately coupled with the requirement that no portion of the tissue is anoxic. This disparate set of requirements can be satisfied with high viscosity Hb solutions that have high affinity for oxygen, a combination of properties that causes the microcirculation to remain functional, and a requirement that supersedes restoration of oxygen-carrying capacity in the treatment of haemorrhage.

Animals↗

PubMedDate not supplied

Clinical pharmacokinetics of dothiepin. Single-dose kinetics in patients and prediction of steady-state concentrations.

The pharmacokinetics of dothiepin were evaluated in 9 depressed patients following a single oral dose of 75 mg. Blood and plasma concentrations of dothiepin and 2 major metabolites, northiaden and dothiepin S-oxide, were measured by gas chromatography/mass fragmentography. The mean (+/-SD) peak plasma concentrations of dothiepin were 49 +/- 27 micrograms/L at 3 +/- 1.2h. Mean (+/-SD) estimates of other parameters were as follows: absorption half-life 1.1 +/- 1.1h; distribution half-life 2.2 +/- 0.8 h; elimination half-life 25 +/- 7h; apparent volume of distribution 70 +/- 62 L/kg; and oral clearance 2.1 +/- 1.6 L/kg/h. The mean (+/-SD) peak plasma concentration of dothiepin S-oxide was 125 +/- 43 micrograms/L at 3.5 +/- 1.3h with an elimination half-life of 22 +/- 12 h. The mean peak plasma concentration of northiaden was 6 +/- 3 micrograms/L at 4.5 +/- 1.1h, with an elimination half-life of 31 +/- 12 h. No significant differences were found in pharmacokinetic parameters compared with a previous study in 7 healthy volunteers. When data for the patients and healthy volunteers were combined (n = 16), pharmacokinetic parameters were not found to be affected by age. However, a significant difference was found between males and females for the elimination half-lives of dothiepin and northiaden, and for the apparent volume of distribution of dothiepin. The 24-hour blood/plasma concentrations of dothiepin and dothiepin S-oxide accurately predicted the steady-state concentrations obtained following 4 weeks' treatment with dothiepin 150 mg nocte.

Dibenzothiepins↗

PubMed2026

Multi-omics Mendelian Randomization Prioritizes Neutrophil Extracellular Trap-related Genes Associated with Atrial Fibrillation Risk.

BACKGROUND: Neutrophil extracellular traps (NETs) participate in thrombosis, inflammation, and cardiovascular remodeling, yet whether NET-related genes (NRGs) are associated with atrial fibrillation (AF) risk across multiple molecular layers remains unclear. This study used a multiomics Mendelian randomization framework to prioritize NRGs supported by methylation, expression, and protein quantitative trait loci (QTL) data. METHODS: Genome-wide significant cis instruments (P < 5 × 10-8) were obtained for 90 methylation QTLs (mQTLs), 100 expression QTLs (eQTLs), and 38 protein QTLs (pQTLs) mapped to 137 literature- curated NRG entries. Summary-data-based Mendelian randomization (SMR) coupled with the heterogeneity in dependent instruments (HEIDI) test was applied using whole-blood mQTL data (n = 1,980), eQTLGen blood eQTL data (n = 31,684), and deCODE plasma pQTL data (n = 35,559). AF outcome data were obtained from a meta-analysis including 60,620 cases and 970,216 controls of European ancestry. RESULTS: At the methylation level, 21 CpG-feature associations across 13 genes remained significant after HEIDI filtering and false discovery rate (FDR) correction. Expression-level analysis identified eight significant gene-AF associations, whereas protein-level analysis identified seven significant features representing five unique proteins. Cross-omics integration prioritized C3, MAPK3, and STAT3 as Tier 1 genes, CTSC, LPAR3, and THBD as Tier 2 genes, and fourteen additional genes as Tier 3 candidates. C3 showed risk-increasing protein-level associations together with multiple significant CpG signals, whereas MAPK3 and STAT3 showed directionally protective expression/protein or methylation/protein patterns. DISCUSSION: The cross-omics convergence on C3, MAPK3, and STAT3 is consistent with complement activation, immune-fibrotic signaling, and cytokine-regulatory pathways implicated in AF biology, but the findings should be interpreted as genetic prioritization rather than definitive intervention-ready causality. CpG-level heterogeneity at the C3 locus and the blood/plasma origin of the QTL resources further support a cautious interpretation. Modest colocalization support and the unresolved possibility of pQTL sample overlap further support this cautious, hypothesis-generating interpretation. CONCLUSION: Multi-omics SMR prioritizes C3, MAPK3, and STAT3 as the most consistently supported NET-related genes associated with AF risk. These findings provide a framework for atrialtissue replication and mechanistic validation of NET-related pathways in AF.

Atrial fibrillation↗

PubMed1976

Normal disposition of oxazepam in acute viral hepatitis and cirrhosis.

Oxazepam (Serax) is a tranquilizer-sedative of the benzodiazepine group that is predominantly metabolized to a pharmacologically inactive glucuronide and subsequently excreted by way of the kidneys. We administered this drug as a single oral dose to seven patients with acute viral hepatitis, to six with cirrhosis, and to age-matched control subjects. Elimination half-life (T1/2) and the apparent oral plasma clearance for the drug in patients with hepatitis and cirrhosis were comparable to values obtained in age-matched controls (P greater than 0.05). In addition, the apparent volume of distribution of oxazepam, its plasma binding, blood/plasma ratio, and the rate of urinary excretion of oxazepam, predominantly as the glucuronide, were comparable (p greater than 0.05) in the two groups of patients with liver disease and their respective controls. Unlike many other sedatives, oxazepam is eliminated normally in patients with parenchymal liver disease an therefore, on pharmacokinetic grounds, seems to be an excellent sedative for use in such persons.

Acute Disease↗

PubMed1999

Interaction of diclofenac and quinidine in monkeys: stimulation of diclofenac metabolism.

The cytochrome P-450 (CYP)3A4-mediated metabolism of diclofenac is stimulated in vitro by quinidine. A similar effect is observed in incubations with monkey liver microsomes. We describe an in vivo interaction of diclofenac and quinidine that leads to enhanced clearance of diclofenac in monkeys. After a dose of diclofenac via portal vein infusion at 0.055 mg/kg/h, steady-state systemic plasma drug concentrations in three male rhesus monkeys were 87, 104, and 32 ng/ml, respectively (control). When diclofenac was coadministered with quinidine (0.25 mg/kg/h) via the same route, the corresponding plasma diclofenac concentrations were 50, 59, and 18 ng/ml, representing 57, 56, and 56% of control values, respectively. In contrast, steady-state systemic diclofenac concentrations in the same three monkeys were elevated 1.4 to 2.5 times when the monkeys were pretreated with L-754,394 (10 mg/kg i.v.), an inhibitor of CYP3A. Further investigation indicated that the plasma protein binding (>99%) and blood/plasma ratio (0.7) of diclofenac remained unchanged in the presence of quinidine. Therefore, the decreases in plasma concentrations of diclofenac after a combined dose of diclofenac and quinidine are taken to reflect increased hepatic clearance of the drug, presumably resulting from the stimulation of CYP3A-catalyzed oxidative metabolism. Consistent with this proposed mechanism, a 2-fold increase in the formation of 5-hydroxydiclofenac derivatives was observed in monkey hepatocyte suspensions containing diclofenac and quinidine. Stimulation of diclofenac metabolism by quinidine was diminished when monkey liver microsomes were pretreated with antibodies against CYP3A. Subsequent kinetic studies indicated that the K(m) value for the CYP-mediated conversion of diclofenac to its 5-hydroxy derivatives was little changed (75 versus 59 microM), whereas V(max) increased 2.5-fold in the presence of quinidine. These data suggest that the catalytic capacity of monkey hepatic CYP3A toward diclofenac metabolism is enhanced by quinidine.

Animals↗

PubMed2001

Effect of vitamin E supplementation on hypoxia-induced oxidative damage in male albino rats.

BACKGROUND: There is growing evidence that free radicals mediated oxidative injury due to inadequate oxygen availability is an important factor in various pathologies at high altitude. Since vitamin E is known to protect the cells from oxidative damage due to its potent antioxidant properties, the present study was carried out to explore the effect of vitamin E supplementation on various hematological and biochemical parameters in hypoxia-induced oxidative stress in albino rats. METHODS: The experiments were conducted on male albino rats by intermittently exposing them to a simulated altitude of 7,576 m (25,000 ft), daily for 6 h for 15 d at 32 +/- 2 degrees C. The control group was fed vehicle only (1% Tween 80) and the experimental group was given vitamin E (40 mg per rat x d(-1)) orally, 5 d prior to and during the period of hypoxic exposure. The variables studied include: hemoglobin, hematocrit, RBC deformability index, alpha-tocopherol level, malondialdehyde (MDA), reduced glutathione (GSH), oxidized glutathione (GSSG), lactate dehydrogenase (LDH) and protein level in blood/plasma and various tissues. RESULTS: Significant increase in hematocrit and hemoglobin and decrease in RBC deformability index was observed on exposure to hypoxia while vitamin E supplementation maintained them at the normal level. Hypoxia led to the decrease in plasma vitamin E and blood glutathione (GSH) level and two-fold increase in the plasma malondialdehyde (MDA) level. Vitamin E supplementation, on the other hand, resulted in less of an increase in MDA and increased the GSH concentration significantly. LDH activity, which was elevated on exposure to hypoxia, was arrested on vitamin E supplementation. CONCLUSION: The results indicate that vitamin E supplementation results in preventing oxidative damage due to high altitude stress.

Altitude↗

PubMed2000

[The survey of prevalence of HIV infection among paid blood donors in one county in China].

OBJECTIVE: To estimate the prevalence rate of HIV infection among paid blood donors and to analyse high risk factors. METHOD: All residents between 18 to 60 years old were selected from on county in March 1999. RESULTS: There were 210 paid blood donors among 730 interviewed subjects. The HIV prevalence rate among paid blood donors was higher (9.1% or 19/210) than that of others (0.6% or 3/520). The HIV prevalence rate was higher in plasma donors (25.9%) than that (2.6%) among 210 blood donors. Donors who donated blood/plasma more than 10 times each year had a higher prevalence rate (13.5%) than those who donated less than 10 times each year (2.8%). Donors who had donated blood but stopped donation before 1995 had a higher prevalence rate (18.3%) than those who started donation after 1996 (1.4%). The results of KAP survey showed that blood donors had a low knowledge about AIDS. CONCLUSION: There was a higher prevalence rate of HIV infection among paid blood donors in some regions. It should take measures to prevent further transmission HIV through paid blood donors.

Adolescent↗

PubMed2003

Blood gases, hematology, and renal blood flow during prolonged mountain sojourns at 3500 and 5800 m.

BACKGROUND: This study mainly focused on renal blood flow, hematological parameters, blood gases, and blood pH, which are affected on exposure to moderate (3500 m) and extreme altitudes (5800 m) in sea level residents. HYPOTHESIS: Acute and prolonged exposure to high or extreme altitude may cause pathophysiological changes in kidney and renal plasma/blood flow, leading to retention of fluids in the tissues. Combined with the decreased availability of oxygen to the tissues, these may be responsible for high altitude maladies. METHOD: Fifteen male sea level (SL) volunteers, 22-25 yr old, were studied for blood gases, blood viscosity, hematocrit, hemoglobin concentration, and effective renal blood/plasma flow at Delhi (260 m), 3500 m (60 d stay), 5800 m (70 d stay), and 7 d after return to SL. RESULTS: Compared with SL, a significant increase from 7.34 to 7.43 (p < 0.01) in blood pH was observed at 3500 m that remained significantly increased at 5800 m. PO2 was about 39% less at 5800 m than at SL. PCO2 reduced significantly from 42.07 to 28.05 mm Hg on return from 5800 m to SL. The blood viscosity increased significantly (38%) at 5800 m and decreased significantly by 38% (p < 0.01) after return to SL. The effective renal plasma flow reduced significantly (p < 0.01) from 615.6 at SL to 381.5 ml x min(-1) x 1.73 m(-2) at 5800 m. CONCLUSION: The study suggests a crucial role of renal function in the acclimatization process; renal function also appears to be one factor by which the body protects itself against severe hypoxia.

Acclimatization↗

PubMed2005

The role of laboratory examinations in medical toxicology.

Medical toxicology is a medical subspecialty focusing on the diagnosis, management and prevention of poisoning and other adverse health effects due to medications, occupational and environmental toxins, and biological agents. The medical toxicology laboratories operates an analytical facility for clinical toxicology (intentional or unintentional drug overdose), environmental medicine (occupational and environmental toxicology, workplace drug monitoring), drug of abuse management, therapeutic drug monitoring (TDM) and in some cases forensic toxicology. This article is focus on clinical toxicology, monitoring of drug abused patients and TDM. Still the most popular in medical toxicology is determination of xenobiotics in classic biological materials (blood/plasma, urine) however alternative materials (saliva, hairs) cause increasing attention. Alternative materials has special value in drug of abuse management (evaluation of drug abstinence), when collecting the blood create some problems and urine samples can be adulterated. For screening usually immunology based assays are applied and for some xenobiotics thin-layer chromatography (TLC) method. Conformation and quantitative analysis are carrying on using chromatographic method. In clinical toxicology chemical analysis are performed for diagnostic, therapeutic and some time for legal purposes. If results of toxicological analysis have direct influence on diagnosis or treatment they should be available during 2 hours other determination ought to be performed during 24 or 48 hours. Integral part of toxicological analysis is interpretation of results carried over by well-trained analyst with close co-operation with clinical toxicologist (physician).

Biomarkers↗

PubMed2005

[A cross-sectional survey on hepatitis C virus infection among residents aged 18-59 years in a former commercial blood donating community, Shanxi Province].

OBJECTIVE: To determine sero-prevalence of and risk factors for hepatitis C virus infection (HCV) among residents aged 18-59 years in a former commercial blood donating community, Shanxi province. METHODS: A community-based cross-sectional survey was conducted among 660 randomly selected residents aged 18-59 years from 12 villages in a rural county of Shanxi province. Structured questionnaire was administered to collect socio-demographic,medical and risk behavioral information. 7 ml-volume venous blood was collected for HCV antibody testing. RESULTS: The overall HCV sero-prevalence rates were 8.2% and 27.7% among former commercial blood donors in the community. Data from multivariate logistic regression analysis showed that people ever selling blood (adjusted OR = 14.28, 95% CI: 6.83-29.87) and receiving blood transfusion (adjusted OR = 8.66,95% CI: 2.31-32.47) were the primary risk factors for HCV infection. Subgroup analysis in blood donors explored that ever selling plasma (adjusted OR = 8.56,95% CI: 2.87-25.54) was the risk factor for HCV infection. Villagers who stopped selling blood in 1994 and thereafter were less likely to be HCV positive than those stopping selling blood before 1994 (adjusted OR = 0.32,95% CI: 0.11-0.93). Female donors had a lower risk than male ones (adjusted OR = 0.28, 95% CI: 0.10-0.83). CONCLUSION: A HCV epidemic was once existing in rural community residents in the province that former commercial blood/plasma donation was the main reason for HCV epidemic in the community. It is urgent to make efficient measures to prevent HCV secondary transmission and provide patients with care and treatment to this community.

Adolescent↗

PubMed2006

The human cornea proteome: bioinformatic analyses indicate import of plasma proteins into the cornea.

Increased biochemical knowledge of normal and diseased corneas is essential for the understanding of corneal homeostasis and pathophysiology. In a recent study, we characterized the proteome of the normal human cornea and identified 141 distinct proteins. This dataset represents the most comprehensive protein study of the cornea to date and provides a useful reference for further studies of normal and diseased human corneas. The list of identified proteins is available at the Cornea Protein Database. In the present paper, we review the utilized procedures for extraction and fractionation of corneal proteins and discuss the potential roles of the identified proteins in relation to homeostasis, diseases, and wound-healing of the cornea. In addition, we compare the list of identified proteins with high quality gene expression libraries (cDNA libraries) and Serial Analysis of Gene Expression (SAGE) data. Of the 141 proteins, 86 (61%) were recognized in cDNA libraries from the corneas of dogs and rabbits, or humans with keratoconus, and 98 (69.5%) were recognized in SAGE data of mouse and human corneas. However, the percentages of identified genes in each of the protein functional groups differed markedly. Thus, exceptionally few of the traditional blood/plasma proteins and immune defense proteins that were identified in the human cornea were recognized in the gene expression libraries of the cornea. This observation strongly indicates that these abundant corneal proteins are not expressed in the cornea but originate from the surrounding pericorneal tissue.

Animals↗

PubMedDate not supplied

Stereoselective differences in propranolol disposition in female Sprague-Dawley and Dark Agouti rats.

Although genetic constitution is recognized as an important factor in drug elimination, there is still only a modest amount of information about its impact on stereoselective drug disposition. To examine how strain differences in cytochrome P-450 expression may affect stereoselective drug elimination, the disposition of R- and S-propranolol was examined in female Sprague-Dawley (SD) and Dark Agouti (DA) rats. The half-life of R-propranolol was increased and its apparent oral clearance decreased significantly in DA rats relative to the SD strain [85 +/- 41 min (DA) vs. 26 +/- 10 min (SD) and 0.020 +/- 0.014 liter/min/kg (DA) vs. 0.31 +/- 0.14 liter/min/kg (SD)], respectively. Strain differences in S-propranolol half-life and apparent oral clearance also were observed, but were not as marked [97 +/- 36 min (DA) vs. 52 +/- 35 min (SD) and 0.20 +/- 0.13 liter/min/kg (DA) vs. 0.70 +/- 0.68 liter/min/kg (SD)], respectively. Due to a more pronounced effect of rat strain on the disposition of R-propranolol, the stereoselective S-/R- oral clearance ratio for propranolol was also strain-dependent [10 +/- 3 (DA) vs. 2.1 +/- 0.9 (SD)]. These differences could not be accounted for by propranolol stereoselective plasma protein binding or by a difference in the blood/plasma ratio for R- or S-propranolol in these separate strains. This represents one of the few examples where an increase in stereoselective drug disposition has been observed due to strain differences that diminish drug elimination.

Animals↗

PubMedDate not supplied

Pharmacokinetics of methysergide and its metabolite methylergometrine in the rat.

The pharmacokinetics of methysergide (MS) and its metabolite methylergometrine (MEM) was studied in male Sprague-Dawley rats. MS was administered iv in doses of 0.71 (0.25 mg/kg) or 2.8 mumol/kg (1.0 mg/kg). The metabolite MEM was administered as iv doses of 0.74 (0.25 mg/kg) or 2.9 mumol/kg (1.0 mg/kg). The steady state characteristics of these compounds were also studied after constant rate iv infusion of MS at two different rates, 0.70 and 14.0 nmol/min per kg. Plasma protein binding and blood/plasma partitioning for MS were determined over a range of concentrations. Plasma and blood concentrations of MS and MEM were measured by HPLC with fluorescence detection. The plasma clearance of MS was high and ranged from 74.2-102 ml/min per kg. The two iv doses of MS were not equivalent after dose correction; clearance, volume of distribution at steady-state and terminal half-life were significantly greater for the higher dose. Plasma clearance from the two iv infusions of MS were in accordance with that from the lower iv dose. Protein binding as well as the plasma/blood partitioning, of MS was constant over the range of concentrations observed in the disposition studies, averaging 84.2% and 1.67%, respectively. The metabolite MEM had a plasma clearance five to six times lower than that of the parent drug but a similar volume of distribution at steady state. The formation of MEM after MS administration was relatively low and appeared to be saturable since the formation clearance of MEM decreased significantly from 3.5 to 1.9 ml/min per kg for the low and the high rate of iv infusion of MS, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Serum levels of mepivacaine-HCl during continuous axillary brachial plexus block.

In order to find out whether repeated doses of plain mepivacaine are appropriate for long-lasting microvascular surgery, a catheter-induced axillary plexus block was performed in 17 patients by using 400 mg of mepivacaine-HC1 every two hours. All patients underwent replantation surgery of one or more amputated fingers. Duration of operation varied from 8 to 24 hours. In all cases, there was adequate analgesia and muscle relaxation for the surgical procedure. Serum levels of mepivacaine were determined before, and 15 and 60 minute after the initial injection. With each following injection of mepivacaine, blood samples were taken at the same time schedule. Within the first eight hours, after four 400 mg doses of mepivacaine were given, all serum levels remained below the level of 5 to 6 micrograms/ml, which is said to be the lower level for mild cerebral toxic reactions in venous blood (blood/plasma distribution 0.92 +/- 0.04). After this time, when more than 1600 mg of mepivacaine had been administered, two patients exceeded the level of 6 micrograms/ml. The highest serum concentration observed in any of the patients was 7.0 micrograms/ml. This was 15 minutes after the 12th injection of 400 mg of mepivacaine and an overall dosage of 4800 mg. None of the patients showed evident signs of central nervous system or cardiovascular toxicity.

Adult↗

PubMedDate not supplied

Phencyclidine-specific Fab fragments alter phencyclidine disposition in dogs.

High affinity antibodies (K0 = 3 X 10(9) M-1) against the widely abused drug phencyclidine (PCP) were produced in goats and then purified and extensively characterized for use in in vivo pharmacokinetic studies. An iv dose of 3H-PCP was administered to three dogs, followed 2 hr later by an equimolar dose of PCP-specific antigen-binding fragments (Fab). Within 10 min after Fab administration, the concentration of PCP in the serum had increased 17-56-fold in the three dogs. The Fab administration also produced a 10-fold decrease in volume of distribution and in systemic and renal clearances. The concentration of PCP metabolites decreased for a period of time after Fab administration. Equilibrium dialysis studies showed that the percentage of unbound PCP changed from about 50% before Fab administration to less than 1% unbound after Fab. In addition, the blood/plasma ratio of PCP changed from a near-equal distribution between red blood cells and plasma before Fab to virtually all of the drug being confined to the plasma fraction after Fab administration. Although Fab produced a dramatic redistribution and extensive protein binding of PCP, the route of elimination of PCP was not altered. These data suggest that high affinity anti-PCP Fab could reverse the toxicity of PCP.

Animals↗

PubMedDate not supplied

Glucuronidation in vitro and in vivo. Comparison of intestinal and hepatic conjugation of morphine, naloxone, and buprenorphine.

The glucuronidation of morphine, naloxone, and buprenorphine by the liver and intestine has been assessed both in vitro and in vivo in the rat. Using microsomes, Vmax/Km ratios were estimated as measures of intrinsic enzyme activity, and a wide range of ratios were obtained (500-fold). The ratio for the intestine was consistently less than for the liver, and the rank order of activities within each tissue was morphine less than naloxone less than buprenorphine. Using various routes of administration, plasma concentration-time profiles for each compound were determined and used to estimate hepatic and intestinal extraction ratios. These extraction ratios were dose-independent and more substantial for the liver than the intestine. For each tissue, buprenorphine and naloxone showed similar extraction, whereas morphine was less. Plasma binding and blood/plasma concentration ratios were determined, and perfusion models were used to calculate intrinsic clearance. This in vivo parameter of enzyme activity showed a wide range (200-fold), comparable to the spread of microsomal Vmax/Km ratios. Although the in vivo parameters consistently gave measures 10- to 30-fold higher than the in vitro parameters, the rank order was identical for the two sets. These data suggest that a comparative approach to correlate in vitro and in vivo data has advantages over the use of absolute drug characteristics.

Animals↗