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PubMed2001

The use of toxicodynamics in risk assessment.

Risk assessment of xenobiotics is a qualitative and quantitative assessment of toxic properties conventionally based on data resulting from tests in animals exposed to the substance. The assessment of dose-effect relationship includes evaluation of exposure at the site of action. More recently, emphasis is put on understanding the relationship between exposure at the site of action and the resulting effect, i.e. toxicodynamic. In this respect, results from genotoxicity studies may be a measure for exposure and at the same time of an effect. Results of toxicodynamic endpoints such as binding to receptors or release of hormones have been used when replacing default values for interspecies extrapolation. It may also be envisaged to use toxicodynamic endpoints in order to get an estimate of intraspecies variability. It was demonstrated that this approach may be helpful only if the relationship between the toxicodynamic endpoint and the definite endpoint is known by using the example of bisphenol A. Whereas there are clear effects of bisphenol A in in vitro and ex vivo studies, the classical two generation study has not been able to detect an effect on reproduction and/or fertility. Looking in the future development of toxicodynamic endpoints, gene profiling and the analysis of proteins ('proteomics') may be helpful tools employed in screening and being related to the mode of action are explored for their suitability in terms of toxicodynamic endpoints.

Animals↗

PubMedDate not supplied

The speciation of metals in mammals influences their toxicokinetics and toxicodynamics and therefore human health risk assessment.

Chemical form (i.e., species) can influence metal toxicokinetics and toxicodynamics and should be considered to improve human health risk assessment. Factors that influence metal speciation (and examples) include: (1) carrier-mediated processes for specific metal species (arsenic, chromium, lead and manganese), (2) valence state (arsenic, chromium, manganese and mercury), (3) particle size (lead and manganese), (4) the nature of metal binding ligands (aluminum, arsenic, chromium, lead, and manganese), (5) whether the metal is an organic versus inorganic species (arsenic, lead, and mercury), and (6) biotransformation of metal species (aluminum, arsenic, chromium, lead, manganese and mercury). The influence of speciation on metal toxicokinetics and toxicodynamics in mammals, and therefore the adverse effects of metals, is reviewed to illustrate how the physicochemical characteristics of metals and their handling in the body (toxicokinetics) can influence toxicity (toxicodynamics). Generalizing from mercury, arsenic, lead, aluminum, chromium, and manganese, it is clear that metal speciation influences mammalian toxicity. Methods used in aquatic toxicology to predict the interaction among metal speciation, uptake, and toxicity are evaluated. A classification system is presented to show that the chemical nature of the metal can predict metal ion toxicokinetics and toxicodynamics. Essential metals, such as iron, are considered. These metals produce low oral toxicity under most exposure conditions but become toxic when biological processes that utilize or transport them are overwhelmed, or bypassed. Risk assessments for essential and nonessential metals should consider toxicokinetic and toxicodynamic factors in setting exposure standards. Because speciation can influence a metal's fate and toxicity, different exposure standards should be established for different metal species. Many examples are provided which consider metal essentiality and toxicity and that illustrate how consideration of metal speciation can improve the risk assessment process. More examples are available at a website established as a repository for summaries of the literature on how the speciation of metals affects their toxicokinetics.

Biotransformation↗

PubMed1996

Multiple chemical sensitivities: distinguishing between psychogenic and toxicodynamic.

The fundamental issue in the multiple chemical sensitivity (MCS) debate is whether this phenomenon is primarily a psychogenic or toxicodynamic disorder, that is, whether symptoms are due to an emotional response to perceived chemical toxicity or to a pathological interaction between chemical agents and organ systems. The distinction between psychogenic or toxicodynamic is essential to the medical management of an MCS patient. A behavioral origin leads to a behavioral therapy, whereas a toxicodynamic etiology may necessitate avoidance and exposure control methodologies. Regulatory, legislative, judicial, and occupational control responses are also dependent upon the critical distinction between psychogenic and organic etiologies. If people are being poisoned by low levels of chemicals, one set of responses follows. If, on the other hand, MCS sufferers are symptomatic for emotional reasons, the response is different. Everything that is known about MCS to date strongly suggests behavioral and psychogenic explanations for symptoms. The premature use of the term multiple chemical sensitivities has hampered effective exploration of and response to this phenomenon, because it suggests, to the lay person, a physiological explanation. It is time that this disorder be properly characterized so that sufferers receive the care they need and so that new "victims" are not recruited.

Diagnosis, Differential↗

PubMed1995

Toxicodynamics and toxicokinetics of amikacin in the guinea pig cochlea.

An extensive overview of the relationship between cochlear toxicity and amikacin blood concentrations in the guinea pig is provided which should assist in the clinical application of this class of antibiotic. A data set previously used to relate the incidence of amikacin ototoxicity to dosing rates and blood concentrations was re-examined to assess the toxicodynamics of amikacin in terms of decibels of hearing loss across dosing rate, hearing frequency and time following drug exposure. Animals in this data set had received continuously i.v. infused amikacin over an 8-fold range of dosing rates. Preliminary analysis indicated that the data were consistent with a sigmoid relationship between hearing loss (decibels) and area under the amikacin plasma concentration vs time curve cumulated over the entire course of drug administration (cAUC). The sigmoid model was therefore used as the backbone of a far more comprehensive toxicodynamic model which described all the data with a single equation. Testing with this model showed that the cAUC required to produce half-maximum hearing loss (cAUC-1/2) was related to dosing rate (P < 0.01), to hearing frequency (P < 0.00001), and to post-drug interval (P < 0.00001). Maximum hearing loss (difference between upper and lower sigmoid asymptotes) was less than total and was significantly related to frequency (P < 0.00001). No effects could be detected on the sigmoid slope. Further modelling of the significant effects detected by the comprehensive toxicodynamic model was done to determine if they could be described by simple relationships or by biologically relevant sub-models. Modelling of maximum hearing loss (postulated to represent loss of mainly outer hair cell function) indicated that this parameter was constant at about 61 decibels for 2-12 kHz and linearly decreased with log frequency for frequencies > 12 kHz. Modelling of cAUC-1/2 on frequency indicated that there was a strong inverse linear relationship to log frequency. Modelling of cAUC-1/2 on post-drug interval indicated that delayed ototoxicity continued at progressively slower rates for at least 56 days after drug administration had ceased. Modelling of cAUC-1/2 on dosing rate showed an increased requirement for drug as the dosing rate decreased. However, cAUC-1/2 changed no more than 20% across the range of dosing rates compared to the 8-fold difference in mean steady-state plasma concentrations, suggesting that plasma concentration is not a primary determinant of ototoxicity. A toxicokinetic model was developed which explained the dosing rate effect on cAUC-1/2 very successfully.(ABSTRACT TRUNCATED AT 400 WORDS)

Amikacin↗

PubMed2002

The use of toxicokinetic and toxicodynamic data in risk assessment: an international perspective.

Risk assessment of chemicals is a process which is usually based on data derived from animal testing in which the exposure of animals results in toxicological effects. By extrapolation, the dose/exposure in humans, which will not result in toxicological effects ('safe dose', 'safe exposure'), is estimated. Traditional approaches use 'safety factors' or 'uncertainty factors' to extrapolate from animal to man and from the 'mean' subject to the general population, including sensitive subgroups. Traditionally, a default factor of 10 has been used to account for interspecies variation. It is proposed that this factor be subdivided into a subfactor to address the toxicokinetic aspects and a second subfactor for the toxicodynamic aspects. Likewise, a default factor of 10 with subfactors is proposed to account for the intraspecies variability. In the framework of the International Program on Chemical Safety's (IPCS) project on the Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals, an activity has been initiated to provide guidance to risk assessors on the use of quantitative chemical specific data to account for interspecies variation and interindividual variability in risk assessment. To address the toxicokinetic aspects, the active species, the relevant internal exposure and the adequate metrics must be considered. Data quality and availability, in vitro or in vivo, the route of administration and the relevant dose level are relevant information for interspecies extrapolation. The availability of experimental data, including the relevance of the population studied, the number of subjects and/or samples obtained in the relevant group allow one to estimate the population distribution, e.g. difference between central tendency and given percentiles. In a similar fashion, the toxicodynamic data must be addressed. In addition to the identification of the active chemical species, the relevant endpoint must be determined. In extrapolation from animal to man, in most of the cases, the definitive endpoint (e.g. anemia) is lacking. It can be substituted by in vitro data (e.g. in vitro hemolysis) if it is a key event and relevant for the toxicity in animal as well as in humans. In extrapolating from animal to man, the dose-effect relationship plays an important role. To account for the toxicodynamic variability in the human population, similar aspects have to be taken into consideration, which have been discussed for toxicokinetics. The IPCS document is available at the IPCS website and risk assessors are invited to use the framework and report back their experience with it to enable revision and improvement.

Animals↗

PubMed2003

Effect of neferine on toxicodynamics of dichlorvos for inhibiting rabbit cholinesterase.

AIM: To study the effect of neferine (Nef) on toxicodynamics of dichlorvos (DDVP) for inhibiting the rabbit cholinesterase (ChE) and search the relativity between in vivo and in vitro reactivating effect of Nef. METHODS: Calorimetric method was used to determine the blood concentraiton of DDVP, and 3P97 software was used to calculate the parameters of toxicokinetics. Ellman's method was used to determine the ChE activity in plasma. The toxicodynamics curve in vivo and the concentration-effect curve in vitro were drawn to compare the effects of Nef on these two curves. RESULTS: In the rabbit poisoned by ig DDVP 12.5 mg/kg there was almost no effect of Nef on the toxicokinetics of DDVP. The slope of toxicodynamics curves for depressed ChE increased about 3 times after treatment with Nef 7.5 mg/kg and pyratoxime methylchloride (2-PAM Cl) 50 mg/kg, compared with the untreated group, there was a higher significant difference (P<0.01). In vitro Nef shifted the cumulative concentration-effect curve of DDVP on ChE to the right and decreased the maximal inhibitory effect obviously. The shift tendency of concentration-effect curve for DDVP in vitro was similar to that of the curve in vivo, difference between their value b was not significant (P>0.05). CONCLUSION: Nef reactivates the ChE depressed by DDVP. The experiment in vitro may be used as a preliminary index to observe the reactivation of ChE inhibited by anticholinesterases.

Animals↗

PubMed1999

Situations with enhanced chemical risks due to toxicokinetic and toxicodynamic factors.

Recognizing toxicokinetic and toxicodynamic variability is important in risk assessment of chemicals and may help to explain interindividual differences in susceptibility in exposed populations. Both toxicokinetic and toxicodynamic factors may be influenced by age and disease processes and show genetic polymorphic variation. Decreased metabolic activity in the very young or very old may enhance chemical toxicity caused by the parent chemical. Similarly, disease processes affecting hepatic metabolism and renal excretion may delay inactivation of many xenobiotics. Genetic polymorphisms may enhance toxicity in rapid metabolizers when the toxicity is caused by a reactive intermediate and increase toxicity in slow metabolizers when the toxicity is caused by a parent chemical. Some cells of the developing conceptus are exquisitely sensitive to chemical exposure. Also, organs and tissues of newborns and elderly individuals may show increased responses toward xenobiotics. In addition, disease-induced altered receptor sensitivity and tissue repair may result in enhanced chemical toxicity. Further, tissue antioxidant defense against radical damage may be compromised under nutritional deficiencies and starvation. Hereditary peculiarities in individual responses to environmental chemicals may be due to polymorphic variation of receptor proteins and tissue repair enzymes, although the database for such variation is quite limited.

Aging↗

PubMed1995

Toxicodynamics of low level toxicant interactions of biological significance: inhibition of tissue repair.

Because of the complexity of studying the toxicological effects of mixtures of chemicals, much of the mechanistic information has become available through work with binary mixtures of toxic chemicals. Mechanisms derived from studies employing chemicals at individually nontoxic doses are more useful than the mechanisms of interactive toxicity at high doses from the perspective of environmental and public health. Several examples of chemical combinations and interactive toxicity at low doses are now available. Chlordecone-potentiated halomethane hepatotoxicity, where suppression of cell division and tissue repair response permits very high amplification of CCl4 injury culminating in animal mortality, is one such model. Phenobarbital-potentiated CCl4 injury does not lead to animal mortality in spite of much higher liver injury in comparison to the chlordecone+CCl4 model. Much higher stimulation of tissue repair allows the animals to survive despite higher liver injury. Similar interactions have been reported between alcohols and halomethane toxicants. These and other studies have revealed that infliction of toxicant-induced injury is accompanied by a parallel but opposing tissue repair stimulation response which allows the animals to overcome that injury up to a threshold dose. Beyond this threshold, tissue repair response is both diminished and delayed allowing unrestrained progression of injury. Large doses of chemicals can be predictably lethal owing to these two latter effects on tissue repair. Dose-response paradigms in which tissue repair response is measured as a parallel but opposing effect to toxic injury might be useful in more precise prediction of the ultimate outcome of toxic injury in risk assessment. Autoprotection experiments with CCl4, thioacetamide, 2-butoxyethanol and related chemicals as well as heteroprotection against acetaminophen-induced lethality with thioacetamide are examples where tissue repair stimulation has been shown to rescue the animals from massive and normally lethal liver injury. The concept of toxicodynamic interaction between inflicted injury and stimulated tissue repair offers mechanistic opportunity to fine-tune other aspects of human health risk assessment procedure. Tissue repair mechanisms may also offer a mechanistic basis to explain species and strain differences as well as to more accurately assess inter-individual differences in human sensitivity to toxic chemicals. Because tissue repair is affected by nutritional status, assessment of risk from exposure to chemicals without attention to nutritional status may be misleading. Finally, the concept of using maximum tolerated doses (MTDs) in long-term toxicity studies such as cancer bioassays may need to be re-examined. MTDs might be predictably expected to maximally stimulate cell division and it is known that increased cell division is likely to lead to increased number of errors in DNA replication thereby predisposing these animals to cancer. It is clear that detailed studies of toxicodynamic interaction between tissue injury and stimulated tissue repair are likely to yield significant dividends in fine-tuning risk assessment.

Animals↗

PubMedDate not supplied

Toxicodynamic approach to management of the poisoned patient.

We recommend a toxicodynamic approach to the management of the poisoned patient. We define the period between ingestion and onset of toxic manifestations (clinical or laboratory) as the preclinical phase, during which the management of the patient necessarily depends solely on the history of ingestion and the predicted toxicity. In the toxic phase during which the patient shows clinical or laboratory evidence of toxicity, the history, clinical status (signs, symptoms, drug levels, laboratory parameters), and toxicodynamics should guide the therapy. In the resolution phase, when the patient shows clinical improvement and declining drug levels, treatment should be based on clinical status. Gastrointestinal decontamination is critical in the first two phases and may be of value during the resolution phase until the body drug burden declines to safe levels. We recommend an aggressive approach to gastrointestinal decontamination, especially in the preclinical phase. With a history of a potentially toxic ingestion of an absorbable drug, an observation period until passage of a charcoal-laden stool should be achieved before discharge of the patient.

Cathartics↗

PubMed2007

On the translation of uncertainty from toxicokinetic to toxicodynamic models--the TCDD example.

When estimating human health risks from exposure to TCDD using toxicokinetic and toxicodynamic models, it is important to understand how model choice and assumptions necessary for modeling add to the uncertainty of risk estimates. Several toxicokinetic models have been proposed for the risk assessment of dioxins, in particular the elimination kinetics in humans has been a matter of constant debate. For a long time, a simple linear elimination kinetics has been common choice. Thus, it was used for the statistical analysis of the largest occupationally exposed cohort, the German Boehringer cohort. We challenge this assumption by considering, amongst others, a nonlinear modified Michaelis-Menten-type elimination kinetics, the so-called Carrier kinetics. Using the area under the lipid TCDD concentration time curve as dose metrics, we model the time to cancer-related death using the Cox proportional hazards model as toxicodynamic model. This risk assessment set-up was simulated in order to quantify uncertainty of both the dose (TCDD body burden) and the risk estimates, depending on the use of the kinetic model, variations of carcinogenic effect of TCDD and variations of latency period (lag time). If past exposure is estimated assuming a linear elimination kinetics although a Carrier kinetics actually holds, then high exposures in reality will be underestimated through statistical analysis and low exposures will be overestimated, respectively. This bias will carry over on the estimated individual concentration-time curves and the therefrom derived TCDD dose metric values. Using biased dose values when estimating a dose-response relationship will finally lead to biased risk estimates. The extent of bias and the decrease of precision are quantified in selected scenarios through this simulation approach. Our findings are in concordance with recent results in the field of dioxin risk assessment. They also reinforce the general demand for the scheduled uncertainty assessments in risk analyses.

Adult↗

PubMed1998

Toxicokinetics and toxicodynamics of iron poisoning.

Iron is a unique poison because it is not a xenobiotic. It is an essential element and highly reactive. Because of the critical dependence upon iron and its potential to damage tissues, elaborate mechanisms have evolved for its efficient absorption, transport, cellular uptake, storage and conservation. These are incompletely understood with even less being known after the ingestion of an overdose. Thus little is known of iron's toxicokinetics. Less is known regarding its absorption. A saturable active receptor mediated mechanism has been described, however, a passive mechanism is speculated to exist. After overdose, the amount absorbed is unknown but is likely in the order of 10%. Transferrin capacity is saturated after the absorption of a toxic dose resulting in much of the circulating iron being hydrated ferric ion. The liver clears most of the circulating iron and the plasma half-life after overdose is similar to the 4-6 h observed after therapeutic dosing. There is no mechanism for iron excretion. The toxicodynamics are a consequence of the chief mechanism for iron-induced tissue damage, free radical production with resultant lipid peroxidation. Therefore target organs and tissues are those exposed to high concentrations of iron and have a high metabolic activity. These are the gastrointestinal epithelium, cardiovascular system and the liver. Five distinct clinical phases are recognized: Gastrointestinal Toxicity, Relative Stability, Circulatory Shock and Acidosis, Hepatotoxicity and Gastrointestinal Scarring. Rational treatment of iron poisoning requires a thorough understanding of its toxicokinetics and toxicodynamics.

Free Radicals↗

PubMed1999

Pharmacodynamics and toxicodynamics of drug action: signaling in cell survival and cell death.

In therapeutic response to drugs, the plasma concentration range leads to the establishment of a safe and effective dosage regimen. Our hypothesis is that by studying drug concentration-dependent effect on signal transduction mechanisms, a better understanding of the beneficial pharmacodynamic and adverse toxicodynamic responses elicited by the drug may be achieved. Using two classes of chemopreventive compounds (phenolic antioxidants and isothiocyanates), we illustrate the potential utility of two signal transduction pathways elicited by these agents to predict the pharmacodynamic effect (induction of Phase II drug metabolizing enzymes) and the potential toxicodynamic response (stimulation of caspase activity and cytotoxic cell death). At lower concentration, phenolic antioxidants and isothiocyanates activate mitogen-activated protein kinase (MAPK; extracellular signal-regulated protein kinase 2, ERK2; and c-Jun N-terminal kinase 1, JNK1) in a concentration-and time-dependent manner. The activation of MAPK by these compounds may lead to the induction of cell survival/protection genes such as c-jun, c-fos, or Phase II drug metabolizing enzymes. However, at higher concentrations, these agents activate another signaling molecule, ICE/Ced3 cysteine protease enzymes (caspases) leading to apoptotic cell death. The activation of these pathways may dictate the fate of the cells/tissues upon exposure to drugs or chemicals. At lower concentrations, these compounds activate MAPK leading to the induction of Phase II genes, which may protect the cells/tissues against toxic insults and therefore may enhance cell survival. On the other hand, at higher concentrations, these agents may activate the caspases, which may lead to apoptotic cell death, and have toxicity. Understanding the activation of these and other signal transduction events elicited by various drugs and chemicals may yield insights into the regulation of gene expression of drug metabolizing enzymes and cytotoxicity. Thus, the study of signaling events in cell survival (hemeostasis) and cell death (cytotoxicity) may have practical application during pharmaceutical drug development.

Animals↗

PubMed1999

In vivo and in vitro toxicodynamic analyses of new quinolone-and nonsteroidal anti-inflammatory drug-induced effects on the central nervous system.

We investigated the correlation between an in vivo isobologram based on the concentrations of new quinolones (NQs) in brain tissue and the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) for the occurrence of convulsions in mice and an in vitro isobologram based on the concentrations of both drugs for changes in the gamma-aminobutyric acid (GABA)-induced current response in Xenopus oocytes injected with mRNA from mouse brains in the presence of NQs and/or NSAIDs. After the administration of enoxacin (ENX) in the presence or absence of felbinac (FLB), ketoprofen (KTP), or flurbiprofen (FRP), a synergistic effect was observed in the isobologram based on the threshold concentration in brain tissue between mice with convulsions and those without convulsions. The three NSAIDs did not affect the pharmacokinetic behavior of ENX in the brain. However, the ENX-induced inhibition of the GABA response in the GABAA receptor expressed in Xenopus oocytes was enhanced in the presence of the three NSAIDs. The inhibition ratio profiles of the GABA responses for both drugs were analyzed with a newly developed toxicodynamic model. The inhibitory profiles for ENX in the presence of NSAIDs followed the order KTP (1.2 microM) > FRP (0. 3 microM) > FLB (0.2 microM). These were 50- to 280-fold smaller than those observed in the absence of NSAIDs. The inhibition ratio (0.01 to 0.02) of the GABAA receptor in the presence of both drugs was well-fitted to the isobologram based on threshold concentrations of both drugs in brain tissue between mice with convulsions and those without convulsions, despite the presence of NSAIDs. In mice with convulsions, the inhibitory profiles of the threshold concentrations of both drugs in brain tissue of mice with convulsions and those without convulsions can be predicted quantitatively by using in vitro GABA response data and toxicodynamic model.

Animals↗

PubMed2000

Effect of buthionine sulphoximine, glutathione and methimazole on the renal disposition of cisplatin and on cisplatin-induced nephrotoxicity in rats: pharmacokinetic-toxicodynamic analysis.

The aim of this study was to classify the protective mechanisms of DL-buthionine-(S,-R)-sulphoximine, glutathione and methimazole on cisplatin-induced nephrotoxicity in rats. An Emax model was used to study the effect of these compounds on the pharmacokinetics of cisplatin, especially renal handling and intra-renal biotransformation. Cisplatin (5 mg kg(-1)) was administered as an intravenous bolus to rats treated with either 0.9% NaCl (control), buthionine sulphoximine, glutathione or methimazole. The blood urea nitrogen level was monitored to estimate cisplatin-induced nephrotoxicity. To estimate renal handling of cisplatin, cisplatin was infused intravenously to rats treated with 0.9% NaCl, buthionine sulphoximine, glutathione or methimazole. The concentrations of unchanged cisplatin in plasma, urine and kidney were determined by a post-column derivatization HPLC method. The relationship between the pharmacokinetics and toxicodynamics of cisplatin was analysed using a sigmoid Emax model. All compounds studied ameliorated significantly the nephrotoxicity of cisplatin. The renal accumulation of cisplatin was reduced significantly by pretreatment with buthionine sulphoximine but not by either glutathione or methimazole. Although glutathione treatment did not affect the renal accumulation of cisplatin, it significantly decreased the binding of cisplatin to the intrarenal organelle and the decreased binding was well correlated to the decrease of the blood urea nitrogen level. In summary, pharmacokinetic-toxicodynamic analysis will be useful for classifying the protective mechanism of cisplatin-induced nephrotoxicity.

Animals↗

PubMed1999

Duration of intake above the ADI/TDI in relation to toxicodynamics and toxicokinetics.

The duration of intake necessary for the production of a toxic response depends on the mechanism of toxicity and the accumulation of the chemical to reach a toxic body load. There is a paucity of data on the cellular processes and changes associated with non-cancer effects detected in subchronic and chronic studies, and which are usually the basis for calculation of health-based exposure limits, such as the ADI. Data on the time course for the critical mechanistic process are normally unknown at the cellular level. Consequently, the duration of an excess intake in humans must be compared with the time course for the generation of the overall toxic effects in animals, which will include both toxicodynamic and toxicokinetic components. The extent of accumulation of a chemical during chronic intake is directly proportional to the half-life. The duration of intake at dosages above the ADI, necessary to produce body loads greater than those resulting from intake at the ADI, depends on the magnitude of the excess intake, the elimination half-life of the chemical, and the initial intake and body load. The effect on the body load of a short period of intake above the ADI is inversely proportional to the half-life of the chemical.

Animals↗

PubMed1996

Interactive effect of combined exposure to glycol ethers and alcohols on toxicodynamic and toxicokinetic parameters.

Ethylene glycol monomethyl ether (EGME) exhibits testicular toxicity and ethylene glycol monobutyl ether (EGBE) is a solvent with haemolytic effects in rats. The study of the interaction of two glycol ethers (EGME and EGBE) and three alcohols (ethanol, n-propanol and n-butanol, 10 or 30 mmol/kg), orally co-administered in male rats, was carried out from a toxicodynamic and toxicokinetic point of view. Administered alone, EGME (10 mmol/kg) caused a 30- and 5-fold increase in the urinary creatine/creatinine ratio at 24 and 48 h, respectively, and 24 h urinary excretion of methoxyacetic acid was of 0.71 +/- 0.042 mmol 24 h (mean +/- SE). The simultaneous administration of one of the three alcohols at either of the doses mentioned above did not significantly modify the urinary creatine/creatinine ration (24 and 48 h), or the 24 h urinary excretion of methoxyacetic acid. Administered alone, EGBE (5 mmol/kg) caused an average decrease of 26% in the number of circulating red blood cells and a strong (250 times) increase in the level of plasma haemoglobin 4 h after treatment. Urinary excretion of butoxyacetic acid in rats treated with EGBE (1 mmol/kg) was 0.083 +/- 0.0039 mmol/24 h (mean +/- SE). The simultaneous injection of 30 mmol/kg alcohol (ethanol, n-propanol or n-butanol) almost totally inhibits the haemolytic effect of EGBE, and decreases the urinary excretion of butoxyacetic acid by 43-31%. A strong dose of alcohol (30 mmol/kg) decreases the haemolytic effect due to EGBE, and reduces the urinary excretion of butoxyacetic acid. In contrast, the coadministration of alcohol did not modify the testicular toxicity of EGME, or the 24 h urinary excretion of methoxyacetic acid. It is possible that competitive inhibition of alcohol dehydrogenase by alcohols results in the diversion of EGBE metabolism.

Alcohols↗

PubMed2005

Investigation of the influence of modulation of P-glycoprotein by a multiple dosing regimen of tamoxifen on the pharmacokinetics and toxicodynamics of doxorubicin.

PURPOSE: The in vivo effect of modulators of P-glycoprotein (Pgp) on organ accumulation of substrates of Pgp has not been fully investigated. We investigated the influence of a Pgp modulator (tamoxifen, TAM) on the pharmacokinetics and toxicodynamics of a Pgp substrate (doxorubicin, DOX) in rats. METHODS: TAM was administered daily for 11 days before the administration of DOX in male Sprague-Dawley rats, with all doses being clinically relevant. The experimental design of the project consisted of two different protocols. One was to investigate the effect of DOX on the time course of Pgp-ATPase activity, sarcoplasmic reticulum Ca(2+) -ATPase (SERCA) activity, and DOX concentration in the heart, liver, and kidneys of TAM-pretreated animals; the other protocol was to study the effect of TAM pretreatment on the disposition of DOX in the body by investigating its time course in plasma, urine and bile. RESULTS: The simultaneous curve fitting of plasma data with urine and bile data with the help of the related pharmacokinetic equations provided the calculated parameters and constants. The first-order rate constants between the central and the myocardial compartments (k(1H) and k(H1)) were decreased in the TAM-treated group. The treatment also significantly reduced the k(1H)/k(H1) ratio in comparison to that of the control group. The first-order biliary elimination rate constant (k(b)) was significantly decreased (29%) in the TAM-treated group. The reduction was estimated in comparison with that of the control group. This reduction could be attributed to the inhibitory effect of TAM on Pgp located on biliary canicular membranes. The initial reduction of Pgp activity in TAM-treated group was at 60% of the basal level. The activity declined and reached a plateau at 20% of the basal activity after 6 h and remained at that level for 24 h. The area under the curves of Pgp-ATPase activity time (AUC(Activity 0-24)) following DOX administration in TAM-treated group was significantly lower than that of the control group, indicating an overall inhibitory effect of TAM on Pgp-ATPase activity under the protocol of this study. The area under the curves of the SERCA activity-time curve following DOX administration in TAM-treated group demonstrated a 15% reduction in AUC(Activity 0-24) in comparison with that of the control group, an indication of increased toxicity. The amount of myocardial Pgp in the 24-h period following DOX administration was comparable to the control group and showed no significant deviation from the basal levels of the protein. CONCLUSIONS: The effect of TAM on DOX accumulation in the myocardial tissue and the increase in cardiotoxicity can be related to the net inhibitory effect of TAM on the efflux activity of Pgp in the heart. The results of the present study supported the hypothesis of the project that multiple regimen pretreatment with Pgp modulator TAM increases the DOX accumulation in the heart and promotes DOX-induced cardiotoxicity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Dihydropyrimidine dehydrogenase inactivation and 5-fluorouracil pharmacokinetics: allometric scaling of animal data, pharmacokinetics and toxicodynamics of 5-fluorouracil in humans.

UNLABELLED: The pharmacokinetics of 5-fluorouracil (5-FU) in different animal species treated with the dihydropyrimidine dehydrogenase (DPD) inactivator, 5-ethynyluracil (776C85) were related through allometric scaling. Estimates of 5-FU dose in combination with 776C85 were determined from pharmacokinetic and toxicodynamic analysis. METHOD: The pharmacokinetics of 5-FU in the DPD-deficient state were obtained from mice, rats and dogs treated with 776C85 followed by 5-FU. The pharmacokinetics of 5-FU in humans were then estimated using interspecies allometric scaling. Data related to the clinical toxicity for 5-FU were obtained from the literature. The predicted pharmacokinetics of 5-FU and the clinical toxicity data were then used to estimate the appropriate dose of 5-FU in combination with 776C85 in clinical trials. RESULTS: The allometric equation relating total body clearance (CL) of 5-FU to the body weight (B) (CL = 0.47B0.74) indicates that clearance increased disproportionately with body weight. In contrast, the apparent volume of distribution (Vc) increased proportionately with body weight (Vc = 0.58 B0.99). Based on allometric analysis, the estimated clearance of 5-FU (10.9 l/h) in humans with DPD deficiency was comparable to the observed values in humans lacking DPD activity due to genetic predisposition (10.1 l/h), or treatment with 776C85 (7.0 l/h) or (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdUrd, 6.6 l/h). The maximum tolerated dose (MTD) of 5-FU in combination with 776C85 was predicted from literature data relating toxicity and plasma 5-FU area under the concentration-time curve (AUC). Based on allometric analysis, the estimated values for the MTD in humans treated with 776C85 and receiving 5-FU as a single i.v. bolus dose, and 5-day and 12-day continuous infusions were about 110, 50 and 30 mg/m2 of 5-FU, respectively. DISCUSSION: The pharmacokinetics of 5-FU in the DPD-deficient state in humans can be predicted from animal data. A much smaller dose of 5-FU is needed in patients treated with 776C85.

Animals↗