Methyl mercury pharmacokinetics in man: a reevaluation.

Data taken from Aberg et al. ((1969) Arch. Environ. Health 19, 478-484) and Miettinen et al. ((1971) Ann. Clin. Res. 3, 116-122) were analyzed by means of models that describe methyl mercury pharmacokinetics in man in terms of parent compound only (Model I) or in terms of parent compound plus metabolite, inorganic mercury (Model II). Fecal and urinary excretion of mercury are linear for both models. In Model I all excreted mercury arises from a common pool. This model successfully simulates the time profiles for body total mercury and fecal excretion but fails to explain the continuous increase in daily urinary mercury that occurs for several weeks following methyl mercury administration. In Model II fecal mercury arises from the methyl mercury compartment and urinary mercury from the inorganic mercury compartment. Simulations from this model are comparable to those from Model I for body total mercury and fecal excretion but are significantly more precise for urinary excretion. Model II also accounts for the observation (Miettinen et al., 1971) that blood mercury comprises a steadily declining proportion of body mercury burden for at least 91 days after methyl mercury dosing. Data simulated by means of Model II, using parameters estimated from Aberg's and Miettinen's data sets, predict methyl mercury half-lives of 51 and 56 days, respectively. These values are comparable to the methyl mercury half-life of 44 days reported by Smith et al. ((1994) Toxicol. Appl. Pharmacol. 128, 251-256) and are approximately 70% of half-lives reported by Aberg and Miettinen.

Physiological model for the pharmacokinetics of methyl mercury in the growing rat.

We describe a physiological pharmacokinetic model for methyl mercury and its metabolite mercuric mercury in the growing rat. Demethylation appears to occur in both host tissues and gastrointestinal flora with elimination dominated by biliary secretion of inorganic mercury and by transport of methyl mercury into the gut lumen followed by substantial bacterial metabolism. Biliary transport of both organic and inorganic mercury is modeled in terms of the known secretion of glutathione from the hepatic pool. At 98 days following an oral tracer dose of 203Hg-labeled methyl mercury chloride, 65% of the administered dose had been recovered in the feces as inorganic mercury and 15% as organic mercury. Urinary excretion is a minor elimination route, accounting for less than 4% of the dose as methyl mercury and 1% of the dose as inorganic mercury. Irreversible incorporation of the mercurials into hair is a significant route of elimination. Ten percent of the administered dose was contained in the hair shed during the 98 days and over 12% of the dose (almost 90% of the body burden) remained in the hair at the end of that time period. Apparent ingestion of hair by the rats during grooming represents a novel form of toxin recirculation. Transport of both chemical species between blood and tissues is bidirectional and symmetric with relatively slow movement into and out of the brain. Transport mechanisms for both mercurial species are discussed in the context of capillary transport physiology and the blood-brain barrier to small molecules and proteins.

Absorption of methylmercury from hair ingested by rats.

Hair taken from rats dosed with 203Hg-labeled methylmercury was fed to previously untreated rats in order to determine if the organomercurial was available for release from the hair matrix within the gut lumen and for subsequent systemic absorption. Cumulative fecal excretion data were consistent with an absorption of about 80% of the ingested methylmercury. The relative amounts of methylmercury and of its metabolite, inorganic mercury, in the feces indicated that the percentage of the parent compound released from hair within the intestine equaled or exceeded the estimated bioavailability. Radioactivity in tissues of animals killed 42 hr following hair consumption confirmed that mercury absorption had occurred.

Cisplatin pharmacokinetics: applications of a physiological model.

A physiological pharmacokinetic model for the disposition of the antineoplastic drug cis-diamminedichloroplatinum(II) (cisplatin or DDP) in several mammalian species is reviewed. The significance of the model's key parameters and of their interspecies relationships is discussed. Methods for estimating two of these parameters (the rate constants for formation of the fixed and mobile metabolites) from in vitro experiments are presented. Fixed and mobile metabolites are formed by the irreversible binding of cisplatin to macromolecules and low molecular weight nucleophiles, respectively. Use of the model to simulate and predict the pharmacokinetic behavior of cisplatin and its metabolites in different animal species following intravenous and intraperitoneal administration is illustrated. Fixed metabolite formation rate constants can be used in conjunction with mass transport parameters to estimate tissue exposures to cisplatin following systemic or regional drug administration. The model logically can serve as the basis for a pharmacodynamic model that incorporates cisplatin reactions with DNA. The model also provides a means for comparing the pharmacokinetic characteristics of cisplatin analogs and for assisting in rational analog development.

Permeability of latex and polyvinyl chloride gloves to fluorouracil and methotrexate.

The permeability of latex surgical and polyvinyl chloride (PVC) examination gloves to fluorouracil and methotrexate was studied using a radiotracer method. Drug-tracer solutions for both drugs were prepared by combining tritiated fluorouracil or methotrexate with fluorouracil or methotrexate injection, respectively. Drug-free solutions were also prepared to be as similar as possible to the vehicles of the commercial injections. Each half of a total of 40 equilibrium-dialysis cells (20 for each glove type) was filled with either the drug-tracer solution or the drug-free solution. The cell halves were then sealed with glove membranes cut from each type of glove and fastened together so that the drug-tracer and drug-free solutions of each respective drug were opposite one another. Samples were collected after 5 to 45 minutes from each dialysis-cell well and analyzed for drug using liquid scintillation counting techniques. Microgram levels of both drugs were detected in the drug-free dialysis wells for both glove types at each sampling time. Except for the methotrexate drug-labeled well sealed with the PVC glove membrane, the amount of drug in the dialysis wells was significantly different at different sampling times. The variability in results using gloves from different lots was also significantly different for both types of gloves. Overall, latex gloves were significantly less permeable than PVC gloves to fluorouracil, and PVC gloves were significantly less permeable to methotrexate than latex gloves. The latex and PVC gloves used in this study both exhibit time-dependent permeability to fluorouracil and methotrexate.(ABSTRACT TRUNCATED AT 250 WORDS)

Physiological pharmacokinetic modeling of cis-dichlorodiammineplatinum(II) (DDP) in several species.

A physiological pharmacokinetic analysis of cis-dichlorodiammineplatinum(II) (DDP) is presented for the rabbit, dog, and human. The results are compared to a previous analysis for the rat. DDP binds irreversibly to low-molecular weight nucleophiles and macromolecules to form mobile and fixed metabolites at rates which are tissue-specific. The rate constant for the formation of fixed metabolite in plasma, determined by in vitro incubation, ranges from 0.004 to 0.008 min-1 in all species. Urinary excretion is the major route of platinum elimination in all species, with a kidney clearance of DDP approximating GFR in all species. Biliary clearance accounts for the elimination of 1-5% of dose and was neglected. The tissue-specific DDP-to-protein binding rates are in the order: kidney/skin/liver/gut/muscle for the beagle dog and rat. The rate constants for the rabbit and mongrel dog are similar, except that the skin and liver are reversed. The binding rate constants for various tissues are similar for all species. The rate constants for release of Pt from macromolecules are similar to protein turnover rate constants and decrease with increasing body weight. Human pharmacokinetic behavior was predicted by estimating human parameters by extrapolation of the animal data. The simulations in humans are compared to experimental plasma concentration and urine excretion profiles for several doses and durations of infusion.

Physiological model for the pharmacokinetics of cis-dichlorodiammineplatinum (II) (DDP) in the tumored rat.

A physiological model has been developed to describe the disposition of cis-dichlorodiammine-platinum(II) (DDP) following i.v. dosing in the female rat bearing the Walker 256 carcinoma. The model simulates concentrations of DDP and its mobile and fixed metabolites in plasma, liver, gut, skin, muscle, tumor, carcass, and kidney, and DDP and mobile metabolite excretion following a 4 mg/kg dose. In the kinetic model, DDP binds irreversibly to low MW nucleophiles and macromolecules (largely proteins) within the plasma and tissue compartments to form mobile and fixed metabolites, respectively. Reaction rates for the formation of each metabolite are tissue/organ specific. The rate constant for the biotransformation of DDP to fixed metabolite in plasma (k2P = 0.0082 min-1) was determined from in vitro incubation studies. This rate was used as the basis for estimating the biotransformation rate constants for DDP to fixed and mobile metabolites in other compartments. Both DDP and mobile metabolite are assumed to follow flow-limited transport, to freely traverse compartmental barriers, and to partition equally in all compartments. Both are excreted in the urine, the major route of Pt elimination. Urinary excretion is modeled as a linear process involving filtration only; an assumption based on a calculated renal clearance of 1.1 ml/min, a value very similar to the estimated GFR. Biliary excretion is a minor route of mobile metabolite elimination and is modeled as a linear process occurring in the liver. Four hours after dosing, approximately 60% of the administered Pt remains in the tissues and plasma. Of this, over 75% of the plasma Pt and 90% of the metal ion in every other compartment is fixed (protein bound). Fixed Pt can be eliminated from a compartment only after its biotransformation to mobile metabolite. In most compartments this rate of elimination corresponds closely to the average rate of protein turnover in that compartment.

Nonparametric pharmacokinetic calculations: one-compartment open model.

A nonparametric method suitable for estimation of parameters in nonlinear problems was developed for one-compartment pharmacokinetic data. The method was tested by running 500 simulations with various types of error and comparing the results with a standard nonlinear regression computation. The nonparametric method was superior to nonlinear regression techniques if the assumptions for the error structure of the regression were not true.

Atomic absorption spectroscopic determination of lead extracted from acid-solubilized tissues.

A method is presented for determining lead in a variety of tissues. Lyophilized samples are solubilized with nitric acid at room temperature in glass screw-cap culture tubes. Following neutralization with sodium hydroxide and sodium bicarbonate, the lead is extracted into methyl isobutyl ketone as the pyrrolidine dithiocarbamate complex and analyzed by flame atomic absorption spectrophotometry. Brain, heart, liver, lung, and spleen gave recoveries ranging from 92 to 102% with standard deviations of less than 8%. Aorta, kidney, and rib were unsuitable for analysis by this method. A large number of samples can be analyzed without specialized equipment or intricate experimental steps. The detection limit is 35 ng/g tissue (wet weight) and sensitivity is approximately 140 ng/g tissue (wet weight).

Chemical type of mercury in patients in the outbreak of organomercury poisoning in Iraq.

Gas chromatography was employed to identify the mercurial compound involved in the Iraq outbreak of organomercury poisoning. Only methylmercury was detected in human blood, hair, and tissues. The quantity of methylmercury present correlates well with the quantity of organic mercury determined by selective atomic absorption.