Linking internal dosimetries of the propyl metabolic series in rats and humans using physiologically based pharmacokinetic (PBPK) modeling.

The metabolic series approach has successfully linked internal dosimetries of metabolically related compounds reducing cost and time for chemical risk assessments. Here, we developed a physiologically based pharmacokinetic (PBPK) model in rats and humans for the propyl metabolic series including propyl acetate, 1-propanol, propionaldehyde, and propionic acid. Manufacturers use these compounds as organic solvents and intermediates during chemical synthesis. Public exposures can occur through using consumer products containing propyl compounds like cosmetics, aerosol sprays, or foods, and occupational exposures can occur at manufacturing facilities. To develop the PBPK model, we measured in vitro metabolism of propyl acetate in blood and liver S9 fractions. We measured concentrations of propyl compounds in blood following intravenous (iv) infusion of 13C-propanol or 13C-propionic acid and closed chamber inhalation exposures to propyl acetate or propanol in rats. Using these studies and other published data, we modified an existing PBPK model for the butyl metabolic series to simulate time course concentrations of propyl compounds in rats and humans. Consistent with measured in vitro and in vivo data, the optimized propyl series model predicts rapid clearance of propyl acetate, higher concentrations of propanol in blood from propyl acetate inhalation compared to propanol inhalation in rats but not in humans, and low concentrations of propionic acid in blood from exposures to propyl acetate or propanol. Regulators can use this model as a tool for propyl compound risk assessment by linking internal dosimetries under various exposure scenarios.

Enantioselective LC/ESI-MS/MS analysis and pharmacokinetic and tissue distribution study of (2RS)-1-(7-methoxy-1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)-propan-2-ol in rats.

A sensitive and stereospecific liquid chromatography-tandem mass spectrometry method for the quantitative determination of TWo8 enantiomers ((2RS)-1-(7-methoxy-1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)-propan-2-ol) was developed and validated in rat serum and some tissues. Racemic TWo8 is a new chemical entity, and it has been shown to possess pharmacological activity in vivo. The assay involved the diastereomeric derivatization of racemic TWo8 with 2,3,4,6-tetra-O-acetyl-beta-glucopyranosyl isothiocyanate. The TWo8 diastereoisomers quantification was performed on a triple quadrupole mass spectrometer employing an electrospray ionization technique. The precursor to the product ion transition for TWo8 derivatives and for the internal standard (carbamazepine) was m/z 776.4 → 387.2 and 237.4 → 194.4, respectively. The assay was validated with a linear range of 10-2000 ng/ml of racemic TWo8. The inter-day precisions for (-)-(S)-TWo8 and (+)-(R)-TWo8 were 2.1% to 14.9% and 1.3% to 14.8%, respectively. The inter-day accuracy for (-)-(S)-TWo8 and (+)-(R)-TWo8 was within 86% to 114% and 91% to 114%, respectively. A pilot pharmacokinetic study of this new ß-adrenolytic compound has shown that (-)-(S)-TWo8 is eliminated faster than its antipode. The terminal half-lives of (-)-(S)-TWo8 and (+)-(R)-TWo8 were 3.2 and 3.9 h, respectively. The compound distribution into different organs, evaluated in tissue homogenate samples following TWo8 intravenous administration, showed an enantioselective penetration of TWo8 enantiomers in the liver (p < 0.03), in the kidney (p < 0.001), and in the lungs (p < 0.05). The developed method using liquid chromatography-tandem mass spectrometry method with electrospray ionization could be employed for quantitative determination of compounds with similar structure.

Dermal and pulmonary absorption of propan-1-ol and propan-2-ol from hand rubs.

BACKGROUND: It has been shown that nontoxic concentrations of ethanol are absorbed after hand hygiene using ethanol-based hand rubs. This study investigated whether absorption of propan-1-ol and propan-2-ol from commercially available hand rubs results in measurable concentrations after use. METHODS: The pulmonary and dermal absorption of propanol during hand rubs was investigated. Rubs contained 70% (w/w) propan-1-ol, 63.14% (w/w) propan-2-ol, or 45% (w/w) propan-2-ol in combination with 30% (w/w) propan-1-ol. RESULTS: Peak median blood levels were 9.15 mg/L for propan-1-ol and 5.3 mg/L for propan-2-ol after hygienic hand rubs and 18.0 mg/L and 10.0 mg/L, respectively, after surgical hand rubs. Under actual surgical conditions, the highest median blood levels were 4.08 mg/L for propan-1-ol and 2.56 mg/L for propan-2-ol. The same procedure performed with prevention of pulmonary exposure through the use of a gas-tight mask resulted in peak median blood levels of 1.16 mg/L of propan-1-ol and 1.74 mg/L of propan-2-ol. CONCLUSION: Only minimal amounts of propanols are absorbed through the use of hand rubs. Based on our experimental data, the risk of chronic systemic toxic effects caused by hand rubs is likely negligible. However, our study did not evaluate the consequences of long-term daily and frequent use of hygienic hand rubs.

Transdermal absorption of ethanol- and 1-propanol-containing hand disinfectants.

BACKGROUND AND AIMS: Ethanol- or 1-propanol-containing hand disinfectants are widely used as surgical hand antisepsis. The primary objective of this study was to investigate transdermal absorption of ethanol and 1-propanol from combination of 45% ethanol and 18% 1-propanol with skin protecting ingredients (Softa-Man®) within 1 h after application in comparison to the absorption of these alcohols from the product in the absence of the cosmetic additives. The secondary objective was to evaluate the dermal tolerability. MATERIALS AND METHODS: Following the double-blind, randomized cross-over design for this clinical trial, 20 ml of two different alcohol-containing disinfectants was applied with a 200-cm(2) gauze swab on a skin area, identical in size and location, of 14 healthy volunteers for 10 min to investigate the absorption rate of ethanol and 1-propanol. Local dermal tolerability was evaluated using a four-point erythema scale. RESULTS: No clinically relevant dermal absorption, with respect to ethanol and 1-propanol, could be observed within 1 h after application. Disinfectant-related mild local skin erythema was observed in three cases. CONCLUSION: The use of the tested formulations containing ethanol and 1-propanol can be considered as safe. The tested formulation containing skin protecting additives (Softa-Man®) does not result in more alcoholic absorption than the formulation without protective additives.

Investigation of the species-dependent in vitro metabolism of BAL30630 by stable isotope labeling and isotope exchange experiments analyzed by capillary liquid chromatography coupled to mass spectrometry.

The in vitro metabolic profile of BAL30630, an antifungal piperazine propanol derivative, which inhibits the 1,3-beta-D-glucansynthase, was investigated by incubation with microsomes of several species and with rat hepatocytes. For the spotting of the metabolites, mixtures of BAL30630 with a stable isotope (deuterium) labeled analogue were incubated. The metabolic pattern comprises several oxidized metabolites. Based on isotope exchange experiments, their structures could be assigned to epoxide- and hydroxylated metabolites. In hepatocyte incubations, several glucuronides formed from these oxidized metabolites could be observed. From the analysis of the metabolic pattern in microsomes, products of carbamate hydrolysis were characterized. This hydrolysis was highly species dependent. In activated incubations and in rat hepatocytes, those metabolites were further oxidized. In incubations without NADPH activation, the resulting hydrolytic metabolites could be enriched without the subsequent oxidation. Final structural elucidation of the metabolites was performed using accurate mass determination and isotope exchange experiments, in which incubations were analyzed by deuterium exchange and capillary HPLC-QTof-MS and MS/MS. The use of non-radioactive, stabile isotope labeled drug analogues in combination with isotope exchange studies was essential in particular for a defined assignment of the functional groups in the structures of the investigated metabolites.

Poisoning with 1-propanol and 2-propanol.

1-Propanol and 2-propanol are isomers of an alcohol with three carbons. They are colorless liquids with a sweet odor. 1-Propanol is metabolized by alcohol dehydrogenase to propionic acid and presents with metabolic acidosis and elevated anion gap, whereas 2-propanol is metabolized by alcohol dehydrogenase to acetone and presents with rapidly developing (within 3-4 h after exposure) ketosis and ketonuria but without metabolic acidosis. We report a patient who simultaneously ingested a lethal dose of 1-propanol and 2-propanol as a hand disinfectant in hospital. The patient lost consciousness and stopped breathing within half an hour after ingestion. He was intubated and artificially ventilated. Initial laboratory results showed mixed acidosis with elevated anion gap, but ketonuria appeared only 12 h after admission and 6 h following the regaining of consciousness. Therefore, laboratory results in simultaneous poisoning with two isomers of alcohol are not just a sum of laboratory results obtained in isolated poisoning with each isomer because they influence each other's metabolism: 1-propanol retards the metabolism of 2-propanol to acetone. In conclusion, 1-propanol and 2-propanol poisoning presents early with mixed acidosis and elevated anion gap and only later with ketonuria.

Pharmacokinetics of propranolol after single and multiple dosing with sustained release propranolol or propranolol CR (innopran XL) , a new chronotherapeutic formulation.

Blood pressure rises rapidly upon waking and may be responsible, in part, for the increased incidence of myocardial infarction and stroke during the morning hours. Current formulations and dosing of antihypertensive drugs do not provide maximum coverage during this vulnerable period. This study was performed to demonstrate that propranolol CR (Innopran XL), a novel chronotherapeutic formulation of propranolol designed for nighttime dosing, has appropriate pharmacokinetics to provide maximum cardioprotective effect in the morning. Pharmacokinetics of propranolol CR and sustained-release propranolol after single and multiple doses were determined in normal male volunteers in this open-label, 2-period crossover study. The drugs were dosed in the evening and serial blood samples were taken for determination of propranolol concentration the next 24 to 72 hours. After a single 160-mg dose of propranolol CR administered at 10 pm, absorption was delayed by about 4 hours, after which plasma concentration rose steadily, reaching a peak at about 10:00 am. In contrast, after dosing with sustained release propranolol, plasma levels of propranolol began to rise almost immediately, reaching a plateau between 4:00 am and 10:00 am. During multiple dosing, steady-state trough plasma concentrations were achieved after 2 days with either drug. After the final dose, the plasma profiles of both drugs were similar to those observed in the single-dose study. Bioavailability was similar for both formulations of propranolol. Propranolol CR exhibited appropriate pharmacokinetics for a chronotherapeutic approach to the treatment of hypertension.

Disposition of short-chain aliphatic alcohols in rabbit vitreous by ocular microdialysis.

Anatomic and physiological barriers limit drug delivery to the posterior segment of the eye via topical or systemic administration. Intravitreal administration has proven to be a safe and effective means of treating various posterior segment diseases. Elimination of a compound from the vitreous chamber may depend on lipophilicity, diffusivity, and aqueous solubility. This information is critical for optimizing intravitreal dosing which in turn can aid in the design of drug delivery systems. The purpose of this study is to determine the vitreous disposition of an ascending homologous series of short chain aliphatic alcohols ranging from hydrophilic methanol to lipophilic 1-heptanol by microdialysis. Radiolabelled 14C-methanol, 14C-1-propanol, 14C-1-pentanol, and 14C-1-heptanol with log partition coefficient values ranging from -0.77 to 2.7 were studied. Microdialysis probes were implanted in both anterior and vitreous chamber of the rabbit eye to sample aqueous and vitreous humors simultaneously. Concentric probe was implanted in vitreous chamber about 3mm below the cornealscleral limbus. Linear probe was implanted in the anterior chamber using a 25-guage needle. Isotonic phosphate buffer saline (IPBS) (pH 7.4) was perfused through the probe with a flow rate of 2 microlml(-1). Alcohols (2.0 microg-130.72 microg) were injected into the vitreous body. In vitro recovery for the probes was calculated using respective alcohols in IPBS. Pharmacokinetic parameters were determined by non-compartmental analysis. Vitreal elimination half-lives of methanol, 1-propanol, 1-pentanol and 1-heptanol are 52.0+/-5.7, 58.5+/-5.8, 72.9+/-5.8 and 153.7+/-21.6 min, respectively. Dose normalized area under the aqueous concentration time curve values of methanol, 1-propanol and 1-pentanol are 33.8+/-13.4, 28.3+/-11.9 and 29.2+/-4.9 microgminml(-1)microg(-1)10(-2), respectively. Time taken to reach maximum concentration in the anterior chamber for methanol, 1-propanol and 1-pentanol is 120+/-42, 160+/-26, and 260+/-26 min, respectively. The maximum concentration of methanol, 1-propanol and 1-pentanol achieved in the anterior chamber is 18.6+/-10.3, 9.4+/-3.2, and 5.9+/-1.3 microgml(-1)10(-4) respectively. Detectable 1-heptanol levels were not observed in the anterior chamber with the intravitreal dose administered. The shorter vitreal elimination half-lives of the alcohols studied suggest retina as major route of elimination from the vitreous body. The elimination rate constants of alcohols from the vitreous appear to be progressively decreasing with ascending chain length and lipophilicity (methanol to 1-heptanol). Among the alcohols studied, methanol produced the highest concentration in the anterior chamber following vitreal administration.

Transfer of tritiated water, tyrosine, and propanol from the nasal cavity to cranial arterial blood in rats.

Respiration cools the nasal vein blood. This may, via counter current transfer in the cavernous sinus/carotid artery complex, cool the brain arterial blood and, therefore, decrease the brain temperature during heat stress. We investigated the possible local transfer of substances from the nasal cavities to the brain via a similar transfer between nasal venous blood and brain arterial blood. Tritiated water (TW), 3H-tyrosine (T) and 14C-propanol (P) were infused into the nasal cavity of anesthetized rats that had two catheters inserted into the same, occluded carotid artery, one pointing towards the head, the other towards the heart. Continuous, parallel blood samples were collected throughout 30-s periods for 10 min, and the radioactivity measured in the separated plasma. After nasal application of TW, the radioactivity increased in the head arterial plasma samples compared with the parallel heart samples. When recirculation to the general circulation was diminished, a larger and significant difference was found for all three substances during the last 5 min of the collection period. No difference between the parallel samples was observed after intravenous administration of the three substances. Absorption of all three substances from the nasal cavity was rapid and high. The results indicate that local transfer takes place between the venous and arterial blood in the head, probably in the area of the cavernous sinus-carotid artery complex, which in rat and man lacks a Rete Mirabile. The local transfer raises the possibility of treating brain diseases in man locally through nasal application of drugs.

Bacterial endotoxin enhances the hepatotoxicity of allyl alcohol.

Lipopolysaccharide (LPS), or bacterial endotoxin, causes liver damage at relatively large doses in rats. Smaller doses, however, may influence the response to other hepatotoxicants. The purpose these studies was to examine the effect of exposure to relatively all doses of LPS on the hepatotoxic response to allyl alcohol, which causes periportal necrosis in laboratory rodents through an known mechanism. Rats were pretreated with LPS (100 micrograms/kg) 2 hr before treatment with a minimally toxic dose of allyl alcohol mg/kg), and liver toxicity was assessed 18 hr later from activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma and from histologic changes in liver sections. Plasma ALT and AST activities were not elevated significantly in rats treated with vehicle, LPS, or allyl alcohol alone, but pronounced increases were observed in rats treated with LPS and allyl alcohol. Significant liver injury occurred as early as 2 hr after allyl alcohol treatment in LPS-pretreated rats and peaked at 6 hr. LPS treatment did not affect the activity of alcohol dehydrogenase and did not affect the rate of production of NADH in isolated livers perfused with allyl alcohol; thus, LPS does not appear to increase the metabolic bioactivation of allyl alcohol into acrolein. On the other hand, pretreatment with 4-methylpyrazole, an inhibitor of alcohol dehydrogenase, abolished the hepatotoxicity of allyl alcohol in LPS-treated rats, indicating that production of acrolein was needed for LPS enhancement of the toxicity of allyl alcohol. Pretreatment of rats with gadolinium chloride (10 mg/kg), a known inactivator of Kupffer cell phagocytic function, decreased LPS augmentation of the response to allyl alcohol. These data indicate that LPS markedly enhances the hepatotoxic response to allyl alcohol. Furthermore, the results suggest that the LPS-induced enhancement of allyl alcohol hepatotoxicity occurs through a Kupffer cell-dependent mechanism.

[Acute oral poisoning with isopropyl alcohol in alcoholics]. / Ostre doustne zatrucie alkoholem izopropylowym u osoby uzaleznionej od alkoholu etylowego.

The symptoms and clinical course of repeated poisonings with isopropyl alcohol in ethanol addicted 43-years old man is presented in the study. The blood and urine concentrations of isopropanol and acetone and also the blood ethanol concentration are given. The biological half-life of isopropanol calculated for the first 12 hours from admission to the Clinic was 6.9 hours. The biological half-life of acetone in the first 6 hours of hospitalisation was 5 hours, and then a considerable slowing down up to 29 hours was noted. The clinical symptoms, similar to ethanol poisoning, including strongly manifested catatonia and ketonuria without metabolic acidosis indicate the isopropanol intoxication. Hypokalemia should to be taken into consideration in treatment of isopropanol poisoning. An intravenous bicarbonates should be administered carefully e.g. when rhabdomyolysis occur.

New ways to use biochemical indicators of alcohol abuse to regrant licences in a fairer manner after drunken driving in Germany.

The failure of medical-psychological examination to provide convincing recommendations concerning the regranting of licences in a significant number of cases illustrates the need for objective laboratory testing. Experience in Germany shows that blood-alcohol concentration alone could lead to misleading recommendations, and suggests that laboratory testing is best done on samples taken at the time of the offence, rather than subsequently at medical-psychological investigation.

Isopropanol: summary of TSCA test rule studies and relevance to hazard identification.

The toxicity of isopropanol (IPA) has been extensively studied as a result of a Test Rule under Section 4 of the Toxic Substances Control Act. In general, the data showed that IPA has a low order of acute and chronic toxicity; does not produce adverse effects on reproduction; is neither a teratogen, a selective developmental toxicant, nor a developmental neurotoxicant; and is not genotoxic or an animal carcinogen. IPA is, however, a potential hazard for transient central nervous system depression at high exposure levels. In addition, IPA produced effects to several rodent toxicity endpoints at high dose levels (i.e., motor activity, male mating index, and exacerbated renal disease) which are of unclear relevance to human health. The data generated by these studies confirmed that IPA acts as a typical short-chain alcohol in mammalian biological systems. It produces a significant narcotic effect upon exposure at high levels for extended periods of time, with no irreversible effects even after repeated exposure, which is consistent with other short-chain alcohols. The metabolism of IPA appears equivalent across species with rapid conversion to acetone and carbon dioxide. Overall, these studies demonstrate IPA exposure is a low potential hazard to human health. This information will allow for an improved assessment of the human health risks from IPA exposure.

[Formation of so-called byproducts (propanols, butanols et al.) from ethanol by microorganisms]. / Zur Bildung sogenannter Begleitstoffe (Propanole, Butanole u. a.) aus Ethanol durch Mikroorganismen.

Microbiological literature implies and furnishes evidence that aliphatic alcohols and the corresponding carboxylates as well as acetone can be produced from ethanol during microbial metabolic processes. Propionate/propanol-1 followed by butyrate can be obtained by means of step-by-step reductive carboxylation of acetyl-CoA. Both butyrate/butanol-1 and caproate/hexanol-1 are typical fermentation products of Clostridium kluyvery. In cases where butyrate decomposition is disrupted up to 50% of butyrate is isomerised to isobutyrate. In addition to ethanol, butyrate and butanol-1, isopropanol and acetone are characteristic products of commercially used Clostridia. One would expect that saccharolytic organisms producing ethanol in addition to other "solvents" (butanol-1, acetone, isopropanol) can also synthesise the solvents if the substrate is changed (ethanol instead of carbohydrate). Under carbon monoxide, formiate and hydrogen, some CODH-active Clostridia can, very efficiently, convert various carboxylates into the corresponding alcohols. There are several groups of organisms present in human intestinal tract that can utilise ethanol and other alcohols.

Clinical sevoflurane metabolism and disposition. I. Sevoflurane and metabolite pharmacokinetics.

BACKGROUND: Sevoflurane has low blood and tissue solubility and is metabolized to free fluoride and hexafluoroisopropanol (HFIP). Although sevoflurane uptake and distribution and fluoride formation have been described, the pharmacokinetics of HFIP formation and elimination are incompletely understood. This investigation comprehensively characterized the simultaneous disposition of sevoflurane, fluoride, and HFIP. METHODS: Ten patients within 30% of ideal body weight who provided institutional review board-approved informed consent received sevoflurane (2.7% end-tidal, 1.3 MAC) in oxygen for 3 h after propofol induction, after which anesthesia was maintained with propofol, fentanyl, and nitrous oxide. Sevoflurane and unconjugated and total HFIP concentrations in blood were determined during anesthesia and for 8 h thereafter. Plasma and urine fluoride and total HFIP concentrations were measured during and through 96 h after anesthetic administration. Fluoride and HFIP were quantitated using an ion-selective electrode and by gas chromatography, respectively. RESULTS: The total sevoflurane dose, calculated from the pulmonary uptake rate, was 88.8 +/- 9.1 mmol. Sevoflurane was rapidly metabolized to the primary metabolites fluoride and HFIP, which were eliminated in urine. HFIP circulated in blood primarily as a glucuronide conjugate, with unconjugated HFIP < or = 15% of total HFIP concentrations. In blood, peak unconjugated HFIP concentrations were less than 1% of peak sevoflurane concentrations. Apparent renal fluoride and HFIP clearances (mean +/- SE) were 51.8 +/- 4.5 and 52.6 +/- 6.1 ml/min, and apparent elimination half-lives were 21.4 +/- 2.8 and 20.1 +/- 2.6 h, respectively. Renal HFIP and net fluoride excretion were 4,300 +/- 540 and 3,300 +/- 540 mumol. Compared with the estimated sevoflurane uptake, 4.9 +/- 0.5% of the dose taken up was eliminated in the urine as HFIP. For fluoride, 3.7 +/- 0.4% of the sevoflurane dose taken up was eliminated in the urine, which, because a portion of fluoride is sequestered in bone, corresponded to approximately 5.6% of the sevoflurane dose metabolized to fluoride. CONCLUSIONS: Sevoflurane was rapidly metabolized to fluoride and HFIP, which was rapidly glucuronidated and eliminated in the urine. The overall extent of sevoflurane metabolism was approximately 5%.

Low-level hyperbaric exposure antagonizes locomotor effects of ethanol and n-propanol but not morphine in C57BL mice.

Low-level hyperbaric exposure antagonizes a broad range of behavioral effects of ethanol in a direct, reversible, and competitive manner. This study investigates the selectivity of the antagonism across other drugs. C57BL/6 mice were injected with saline, ethanol, n-propanol, or morphine sulfate, and then were exposed to 1 atmosphere absolute (ATA) air, 1 ATA helium-oxygen gas mixture (heliox), or 12 ATA heliox. Locomotor activity was measured from 10 to 40 min following injection. N-propanol produced a dose-dependent depression of locomotor activity from 1.0 g/kg. Morphine produced a dose-dependent stimulation of locomotor activity at doses of 3.75-12.0 mg/kg. Exposure to 12 ATA heliox significantly antagonized the locomotor depressant effects of 1.0 g/kg n-propanol and 2.5 g/kg ethanol, without significantly affecting blood concentrations of these drugs measured at 40 min postinjection. Exposure to 12 ATA heliox did not significantly antagonize the locomotor-stimulating effects of the two morphine doses tested (3.75 and 7.5 mg/kg). These findings suggest that exposure to 12 ATA heliox antagonizes the behavioral effects of intoxicant-anesthetic drugs like ethanol and n-propanol, which are believed to act via perturbation or allosteric modulation of functional proteins, but does not antagonize the effects of drugs like morphine, which act via more direct mechanisms. This demonstration of selective antagonism adds important support for the hypothesis that low-level hyperbaric exposure is a direct mechanistic ethanol antagonist, with characteristics similar to a competitive pharmacological antagonist.

Comparative disposition of 2,3-epoxy-1-propanol (glycidol) in rats following oral and intravenous administration.

Glycidol (2,3-epoxy-1-propanol), an industrial chemical, has been shown to be a reproductive toxicant in short-term studies and a carcinogen in rats and mice in oncogenicity studies. The reproductive toxicity of glycidol was believed to result from its conversion to alpha-chlorohydrin by the action of HCl in the stomach. The comparative disposition of glycidol was investigated in rats following oral (po) or intravenous (iv) administration at doses of 37.5 and 75 mg/kg. These were the doses used in the National Toxicology Program (NTP) oncogenicity study with glycidol. Approximately 87-92% of the dose was absorbed from the gastrointestinal tract of the rat. [14C]Glycidol equivalents were eliminated in urine (40-48% of dose in 72 h), feces (5-12%), and exhaled as CO2 (26-32%). At both doses, 9-12% and 7-8% (estimated) of the dose remained in tissues at 24 and 72 h following dosing, respectively. In general, the concentrations of glycidol equivalents in tissues were proportional to the dose. The highest concentrations of radioactivity were observed in blood cells, thyroid, liver, kidney, and spleen, and the lowest in adipose tissue, skeletal muscle, and plasma. The pattern of distribution of radioactivity in tissues was similar for both the iv and po routes. The total recovery of radioactivity ranged from 87 to 91% of dose. Urinary radioactivity was resolved by high-performance liquid chromatography (HPLC) analysis into 15 metabolites. There were one major (14-21% of the dose) and four lesser metabolites (each representing 2-8%); the others were minor, each representing 1% or less of the dose. In general, the urinary metabolic profile was similar following either iv or po administration at the two doses studied. Previous studies by other investigators suggested that alpha-chlorohydrin, which was presumably formed from glycidol by the HCl in the stomach, was metabolized and excreted in urine as beta-chlorolactic acid. The results of the present study show that very little, if any, urinary radioactivity coeluted with authentic beta-chlorolactic acid following either iv or po administration. Therefore, it is concluded that the conversion of glycidol to alpha-chlorohydrin is quantitatively insignificant. However, it may be significant with regard to glycidol reproductive toxicity. Also, the NTP oncogenicity study with glycidol was carried out within the dose range in which its disposition characteristics were linear.

Measurement of serum isopropanol and the acetone metabolite by proton nuclear magnetic resonance: application to pharmacokinetic evaluation in a simulated overdose model.

The purpose of this investigation was to 1) compare the performance of proton nuclear magnetic resonance spectroscopy to gas chromatography head-space analysis in the measurement of serum isopropanol and its metabolite, acetone, obtained during a simulated overdose, and 2) compare pharmacokinetic parameters obtained using the two analytical techniques. Three healthy volunteers ingested 0.6 mL/kg of 70% isopropanol and blood samples were obtained at baseline, 0.16, 0.33, 0.66, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, and 24.0 hours post-ingestion. Resulting sera were analyzed by gas chromatography head-space analysis and proton nuclear magnetic resonance spectroscopy for determination of isopropanol and acetone concentrations. A correlation between concentrations quantitated by gas chromatography head-space analysis versus proton nuclear magnetic resonance spectroscopy was determined using linear regression. Pharmacokinetic disposition parameters were determined from serum concentration-time data and compared using analysis of variance. For isopropanol, the linear regression equation which describes the relationship between gas chromatography head-space analysis and proton nuclear magnetic resonance spectroscopy was y = 1.041x - 2.180 (r2 = 0.995, p < 0.0001); for acetone, y = 1.022x - 0.946 (r2 = 0.984, p < 0.0001). Pharmacokinetic disposition parameters derived from the two analytical methods were comparable. Proton nuclear magnetic resonance spectroscopy can be used to rapidly quantitate serum isopropanol and acetone concentrations in the same sample when gas chromatography head-space analysis is unavailable. Also, proton nuclear magnetic resonance spectroscopy can be used to follow serial serum concentrations during an ingestion for the purpose of pharmacokinetic analysis.

Kinetics of a new iodolabeled MAO-B inhibitor in the rat brain and in cultured astrocytes.

3-Bromobenzyloxy phenyloxy hydroxymethyl propanol was labelled with iodine-125. Labeling yield was approximately 92%. Using HPLC and an RP18 column, Iodo*MD (MW = 412) was obtained at no-carrier-added conditions (specific activity 125 Ci/mmole). Biochemical experiments were carried out in vitro and showed a Ki for MAO-B of 5.4 nM and of 5000 for MAO-A (RA/B = 926). Using ex vivo kinetic inhibition in rat (dose: 5 mg/kg p.o.), the results demonstrated a strong similarity of action with BromoMD and IodoMD, with an inhibition percentage that decreased with time (91% at 1 hour, 48% at 8 hours, 2% at 24 hours). The rat brain Iodo*MD concentration was maximal after the first pass and inhibition decreased slowly with time (T1/2 = 1.8 hours). Uptake and wash-out of Iodo*MD was studied on two-day-old rat astrocytes in culture. Half-times of uptake and efflux were respectively 2.5 minutes and 7.5 minutes. The use of metabolic inhibitors (KCN and Digoxin) suggested the absence of any active transport. Binding studies with various concentration of cold MD 360194 showed that at 10(-8) M the uptake decreased significantly. Rats were dissected at different times post i.v. injection (0-2 hours), and the principal organs and brain were obtained (the brain was separated into 7 pieces). Radioactivity was concentrated mainly in the liver (24.6 +/- 4%), fat (12.4 +/- 3.4%) and muscles (18.4 +/- 3%). In the brain the concentration was approximately 1.2 +/- 0.3% within 30 minutes post i.v. injection and 0.84 +/- 0.15% thereafter. The hypothalamus and striatum were two-fold more active than the cortex.(ABSTRACT TRUNCATED AT 250 WORDS)