介绍物理化学方法研究药物吸收、分布、代谢和排泄

目的介绍用于研究药物吸收、分布、代谢和排泄的物理化学方法。方法总结了药物溶解度、解离常数和亲脂性的各种测定方法。结果与结论药物的物理化学性质在药物代谢和药物动力学的研究中起着非常关键的作用。     

Absorption and Mass Balance of Mgk R11 and Mgk R11 Formulated with Deet,Mgk 264, and Mgk 326 Following an 8 Hour Dermal Exposure in Human Volunteers

Abstract

Dermal absorption and excretion of MGK R11 [2,3:4,5-bis(2-butylene) tetrahydro-2 furaldehyde, McLaughlin Gormley King Company, Minneapolis, MN] was studied using [¹⁴C]MGK R11 either by itself or formulated with DEET (N,N-diethyl-m-toluamide), MGK 264 (N-octylbicycloheptene dicarboximide), and MGK 326 (di-n-propyl-isocinchomeronate). Each of these two formulations was tested on four young, healthy male volunteers, using a single topical application on the forearm under nonocclusive conditions for an 8 h period. Blood from the ipsilateral and contralateral arms, urine, and feces were collected at selected intervals during the 8 h application and through a 120 h postapplication period. The application area was also tape-stripped to determine if any of the test material accumulated in the stratum corneum. These samples provided data that permitted some insight into the kinetics of penetration and elimination processes of MGK R11. Urine samples, swabs, and skin rinse samples were analyzed by high-performance liquid chromatography (HPLC) to characterize the metabolic profile, identify the major metabolites, and determine the metabolic pathway.

MGK R11, either by itself or formulated, was poorly absorbed through the skin as shown by the amount of radioactivity excreted in the urine and the very low plasma radioactivity level in the ipsilateral plasma. When dosed by itself, approximately 8% of the dose was excreted in the urine. In contrast, only 3% of the formulated MGK R11 was excreted in the urine. Approximately 0.3% of the dose was excreted in the feces. There was no evidence of accumulation of MGK R11 in the skin, as evidenced by low amounts of radioactivity in the tape strippings. A significant portion of the dosed radioactivity was recovered from the dome covering the dosing site amounting to 67% of the compound by itself or 27% of the formulated product, indicating a difference of volatility depending on the formulation. The rest of the external radioactivity was present in the swabs. Total recovery of the applied radioactivity was 89.9% and 99.5% for MGK R11 and the formulated product, respectively. Radiochemical analyses of the swab composites indicated a 30% degradation of parent compound in the one-component swabs and no degradation in the four-component swabs. Absorbed MGK R11 was completely metabolized prior to its excretion in the urine to two metabolites that accounted for 95% of the urinary metabolites. The major metabolic pathway is by oxidation of the aldehyde to the corresponding acid or reduction of the aldehyde to the corresponding alcohol followed by conjugation to produce the glucuronide.     

Reproductive and Developmental Toxicity of N,N-Diethyl-m-toluamide in Rats

N,N-Diethyl-m-toluamide (mDET, DEET) is widely used as a topicalinsect repellent. It is the active ingredient in many consumerformulations, which usually contain 10–25% mDET in analcohol base. More concentrated consumer products are also available,including some that are pure technical grade mDET. Persons livingor employed in mosquito-infested areas may have very high seasonalexposures to mDET. Because contradictory reports had been publishedon the reproductive and developmental toxicity of mDET, a seriesof studies was conducted in male and female Sprague-Dawley rats.All treatments were administered by daily subcutaneous injectionsof undiluted mDET. A dose finding study was done using 12 time-matedfemales per group treated on Gestational Days (GD) 6–15with 0.50, 0.62, 0.78, 0.92, or 1.2 ml mDET /kg/day. No femalessurvived 10 days of mDET dosing with 1.2 ml/kg/day. Deaths occurredin all other groups except the low dose (0.50 ml/kg/ day). Pregnantfemales treated on GD 6–15 with 0 or 0.30 ml/ kg/day wereused for the teratology study. Half of each group was euthanizedon GD 20: the second half was singly housed in nesting boxesand allowed to deliver litters. Live pups were counted and weighedsoon after birth on Postnatal Day (PD) 0 and again on PD 3,9, and 14. Proven fertile males were treated 5 days/week for9 weeks with 0, 0.30, 0.73, 1.15, or 1.80 ml mDET /kg/day fora male dose-finding study. Each group consisted of 20 males.No males survived the 1.80 ml/kg/day. Deaths occurred in allremaining dose groups except the 0.30 ml/kg/ day and controlgroup. Immediately following the final treatment of the maledose study, 11 males were randomly selected from the 0.30 and0.73 ml/kg/day groups. They were cohabited for 7 days with 4females per male during post-treatment Weeks 1 and 2. Half ofthe females were euthanized 12–14 days after the lastday of cohabitation for a dominant lethal study; the remainingfemales were singly housed in nesting boxes and allowed to deliverlitters. Live pups were counted and weighed on PD 0 and 3. Therewas no evidence of reproductive or developmental toxicity inany of these assays, but there were signs of neuro-toxicityin treated adult male and female rats, which may relate to reportsof neurotoxicity in humans heavily exposed to mDET -containinginsect repellents, o 1992 society of Toxicology.     

Absorption,Metabolism and Excretion of N,N-Bis(phenylcarbamoylmethyl)dimethylammonium Chloride (QX-572) in the Rat

The gastro-intestinal absorption and metabolic fate, after intravenous and intraperitoneal administration, of [³H]N, N-bis(phenylcarbamoylmethyl)dimethylammonium chloride (QX-572), a lidocaine derivative with anti-arrhythmic activity, has been investigated in the rat.

Only about one-third of the dose is absorbed after oral administration to fasted animals. Pre-feeding of rats markedly diminishes the apparent availability of the drug. Co-administration of salicylate results in about 50% increase in the absorption of QX-572.

After intravenous administration of [³H]QX-572 to normal rats, urinary excretion of ³H is 60% greater than after intraperitoneal administration. Total urinary recovery of ³H is similar after intravenous or intraperitoneal administration to rats with ligated bile ducts, although much higher than that observed in non-ligated rats.

Urinary excretion data suggest that in normal rats apparent QX-572 is excreted in bile to a much greater extent after intraperitoneal than after intravenous administration. The total cumulative ³H recovered from rat bile 24 h after administration of [³H]QX-572 was about 65% greater after intraperitoneal than after intravenous administration.

One metabolite, possibly a carboxylic acid, was excreted in the urine along with unchanged drug. Irrespective of the route of administration about 70% of the total ³H in the urine represented unchanged drug and the metabolite accounted for the balance. Essentially, no intact drug was found in the bile. The same metabolite as identified in the urine accounted for about 80% of total ³H in the bile.

In the rat QX-572 undergoes significant first-pass metabolism and the metabolite is rapidly cleared from liver to bile.     

Challenges and Opportunities in Absorption, Distribution, Metabolism, and Excretion Studies of Therapeutic Biologics

With the advancement of biotechnology in the last two decades, optimized and novel modalities and platforms of biologic moieties have emerged rapidly in drug discovery pipelines. In addition, new technologies for delivering therapeutic biologics (e.g., needle-free devices, nanoparticle complexes), as well as novel approaches for disease treatments (e.g., stem cell therapy, individualized medicine), continue to be developed. While pharmacokinetic studies are routinely carried out for therapeutic biologics, experiments that elucidate underlying mechanisms for clearance and biodistribution or identify key factors that govern absorption, distribution, metabolism, and excretion (ADME) of biologics often are not thoroughly conducted. Realizing the importance of biologics as therapeutic agents, pharmaceutical industry has recently begun to move the research focus from small molecules only to a blended portfolio consisting of both small molecules and biologics. This trend brings many opportunities for scientists working in the drug disposition research field. In anticipation of these opportunities and associated challenges, this review highlights impact of ADME studies on clinical and commercial success of biologics, with a particular focus on emerging applications and technologies and linkage with mechanistic pharmacokinetic/pharmacodynamic modeling and biomarker research.     

Absorption,Distribution, Metabolism,and Excretion of N-Octylbicycloheptene Dicarboximide (MGK 264) Administered Orally to Rats

Abstract

Experiments were conducted in four groups of rats to determine the absorption, distribution, metabolism, and excretion (ADME) patterns following oral administration of [hexyl-1-¹⁴C] N-octylbicycloheptene dicarboximide (MGK 264).

Ten rats (five males and five females) were used in each of the four experiments. Fasted rats were administered fhexyl-1-¹⁴C] MGK 264 at a single oral dose of 100 mg/kg, at a single oral dose of 1000 mg/kg, and at a daily oral dose of 100 mg/kg of nonradiolabeled compound for 14 days followed by a single dose of ¹⁴C-labeled compound at 100 mg/kg. Rat blood kinetics were determined in the fourth group following a single oral dose of 100 mg/kg. Each animal was administered 18-30 μCi radioactivity.

Urine and feces were collected for all groups at predetermined time intervals. Seven days after dose administration, the rats were euthanized and selected tissues and organs were harvested. Samples of urine, feces, and tissues were subsequently analyzed for ¹⁴C content.

In the blood kinetics study, radioactivity peaked at approximately 4 h for the males and 6 h for the females. The decline of radioactivity from blood followed a monophasic elimination pattern. The half-life of blood radioactivity was approximately 8 h for males and 6 h for females.

Female rats excreted 71.45-73.05% of the radioactivity in urine and 20.87-25.28% in feces, whereas male rats excreted 49.49-63.49% of the administered radioactivity in urine and 31.76-46.67% in feces. Total tissue residues of radioactivity at 7 days ranged from 0.13 to 0.43% of the administered dose for all dosage regimens. The only tissues with ¹⁴C residues consistently higher than that of plasma were the liver, stomach, intestines, and carcass. The total mean recovered radioactivity of the administered dose in the studies ranged between 93.1 and 97.4%. No parent compound was detected in the urine.

Four major metabolites and one minor metabolite were isolated from the urine by high-performance liquid chromatography (HPLC) and identified by gas chromatography/mass spectometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS). The four major metabolites were shown to be carboxylic acids produced by either ω-1 oxidation or β-oxidation of the side chain and oxidation of the norbornene ring double bond. The minor metabolite was the carboxylic acid of the intact norbornene ring.

The gender of the animals affected the rate, route of excretion, and metabolic profile. The urinary excretion rate was faster in females than in males and the amount excreted was also greater in female rats.     

The Acquisition and Application of Absorption,Distribution, Metabolism,and Excretion (ADME) Data in Agricultural Chemical Safety Assessments

A proposal has been developed by the Agricultural Chemical Safety Assessment (ACSA) Technical Committee of the ILSI Health and Environmental Sciences Institute (HESI) for an improved approach to assessing the safety of crop protection chemicals. The goal is to ensure that studies are scientifically appropriate and necessary without being redundant, and that tests emphasize toxicological endpoints and exposure durations that are relevant for risk assessment. Incorporation of pharmacokinetic studies describing absorption, distribution, metabolism, and excretion is an essential tool for improving the design and interpretation of toxicity studies and their application for safety assessment. A tiered approach is described in which basic pharmacokinetic studies, similar to those for pharmaceuticals, are conducted for regulatory submission. Subsequent tiers provide additional information in an iterative manner, depending on pharmacokinetic properties, toxicity study results, and the intended uses of the compound.     

Absorption,Metabolism, and Disposition of [14C]SDZ ENA 713, an Acetylcholinesterase Inhibitor,in Minipigs Following Oral,Intravenous, and Dermal Administration

Purpose. SDZ ENA 713 (rivastigmine) is an acetylcholinesterase inhibitor intended for therapeutic use in Alzheimer's disease. The present study compared the pharmacokinetics of [¹⁴C]SDZ ENA 713 after intravenous, oral, and dermal administration to male minipigs, and also examined the effects of dose level and skin abrasion on transdermal absorption. Methods. Four groups of 3 minipigs each received a single intravenous (0.1 mg/kg), single oral (1.0 mg/kg), or topical doses of 18 mg or 54 mg of [¹⁴C]SDZ ENA 713. Topical doses were administered as dermal patches on two occasions 10 days apart. On Study Day 1, test patches were applied to a virgin skin site. Placebo patches were applied to a separate skin site and were replaced daily during Days 1–10. On Study Day 11, test patches were applied to the site on which the placebo patches had been previously applied. After each dose, serial blood and quantitative urine and feces were collected at designated intervals for 7 days. Concentrations of radioactivity, parent drug, and metabolite ZNS 114–666 were measured in whole blood. Radioactivity was also determined in excreta, skin application sites (at study termination), and on used dermal patches (at 24 hr after application). Results. Oral doses of [¹⁴C]SDZ ENA 713 were rapidly (t_max = 0.83 hr) and efficiently (ca. 93%) absorbed, although the bioavailability of the parent drug was low, ca. 0.5%, apparently due to extensive first-pass metabolism. Radioactivity was excreted mainly in the urine (90%) with a half-life of 56 hr, slightly longer than that observed after an intravenous dose, 46 hr. After dermal administration of [¹⁴C]SDZ ENA 713 to a virgin skin site, absorption was 8% at both dose levels investigated. Following daily application of placebo patches for 10 days, absorption from a [¹⁴C]SDZ ENA 713 dermal patch increased by approximately twofold, 17% and 19% of the 18 mg and 54 mg doses, respectively. The increase is possibly due to hydration or abrasion of the skin as a result of repeated application and removal of the adhesive patches. Whereas total absorption from the dermal dose was smaller than that from the oral dose, essentially all of the absorbed drug via the dermal route reached the systemic circulation intact, thus yielding a SDZ ENA 713 bioavailability 20–40 times greater than that of the oral dose. Metabolite ZNS 114–666 was rapidly formed and accounted for <4% of total drug-related material in the systemic circulation. Conclusions. Dermal administration in minipigs provided a markedly greater bioavailability of SDZ ENA 713 than the oral route. The extent of absorption was independent of dose within the range tested, and appeared to be enhanced by hydration or abrasion of the skin application site.     

Absorption, Distribution, Metabolism, and Excretion of 1,3-Diphenylguanidine in the Male F344 Rat

Absorption, Distribution, Metabolism, and Excretion of 1,3-Diphenylguanidinein the Male F344 Rat IOANNOU, Y. M., AND MATTHEWS, H. B. (1984).Fundam. Appl. Toxicol. 4, 22-29. 1,3-Diphenylguanidine (DPG),a rubber accelerator, was readily absorbed from the gastrointestinaltract of the male Fischer rat and rapidly distributed throughoutthe body tissues. Absorption and disposition of DPG were notsignificantly affected by the route of administration or bythe dose in the dose range studied, 1.5 to 150 µmol/kg.Most of the dose of DPG was excreted in the urine and fecesat approximately equal amounts within 24 hr after oral or ivadministration. Greater than 99% of the DPG dose was clearedinto the urine and feces within 3 days after administration.Approximately 30% of the DPG-derived radioactivity excretedin urine was the parent compound, DPG, while the remainder waspresent in the form of two major and one minor metabolite. Closeto 95% of the radioactivity excreted in bile was in the formof a single major metabolite. Administration of multiple dosesresulted in a proportional increase of DPG-derived radioactivityin the liver as the number of doses increased. DPG-derived radioactivitydid not increase in other tissues following multiple doses.     

Absorption,Excretion and Metabolism of a New Dihydropyridine Diester Cerebral Vasodilator in Rats and Dogs

1. After oral administration of [¹⁴C]dihydropyridine diester, the plasma concn. of radioactivity was similar in rats and dogs, reaching a maximum at 0·5 to 1?h and decreasing with a half life of about 3·5 h. The plasma concn. of unmetabolized drug in dogs was 10 times higher than in rats. Radioactivity in rat tissue was high in liver, kidney and lung after both oral and intravenous administration.

2. In both species, 66–72% of radioactivity was excreted in faeces and 23–29% in urine in 48?h, regardless of the route of administration. Biliary excretion in rats after oral dosage amounted to 65%.

3. Eight metabolites were identified from urine of dogs and rats. They were derived from one or several of the following pathways: I, debenzylation of the N-benzyl-N-methylaminoethyl side chain; II, reduction of the 3-nitro group on the phenyl substituent; III, oxidation of the 1,4-dihydropyridine ring to the corresponding pyridine; IV, oxidative removal of the N-benzyl-N-methylamino group yielding a carboxylic acid; V, hydrolysis of the N-benzyl-N-methylamino-ethyl ester to the corresponding carboxylic acid; VI, hydroxylation of the 2-methyl group of the 1,4-dihydropyridine ring to hydroxymethyl.     

Teratologic Evaluations of N,N-Diethyl-m-toluamide (DEET) in Rats and Rabbits

The potential for DEET to produce developmental toxicity wasevaluated in Charles River CD rats and New Zealand White rabbits.Rats were administered undiluted DEET by gavage on GestationalDays (gd) 6–15 at dosage levels of 0, 125, 250, and 750mg/kg/day. Rabbits were administered undiluted DEET by gavageon gd 6–18 at dosage levels of 0, 30, 100, and 325 mg/kg/day.Group sizes were 25 females per group for rats and 16 femalesper group for rabbits. Control rats and rabbits were ad ministeredcorn oil at the same dosage volumes administered in the high-doseDEET groups. In rats, maternal toxicity in the form of clinicalsigns including two deaths and depressed body weight and foodconsumption was observed at the high-dose level of 750 mg/kg/day.Rat fetal body weights per litter also were reduced at 750 mg/kg/day.In rabbits, maternal toxicity in the form of depressed bodyweight and food consumption was observed at the high-dose levelof 325 mg/kg/day. No maternal toxicity was observed at the low-or mid-dose groups for rats or rabbits. With the exception ofthe reduced fetal weights in rats at 750 mg/kg, there was noevidence of fetal toxicity, no effects on any of the gestationalparameters, nor were there any treat ment-related increasesin external, visceral, or skeletal variations or malformationsin the offspring from the rats and rabbits from these studies.1994 Society of Toxicology.     

Neurotoxicity Evaluation of N,N-Diethyl-m-toluamide (DEET) in Rats

The neurotoxic potential of N,N-diethyl-m-toluamide (DEET) wasevaluated following acute oral administration or following multigenerationplus chronic dietary administration to the rat. For the acutestudy, rats were administered undiluted DEET at dose levelsof 50, 200, or 500 mg/kg by gavage. A dose level of 500 mg/kgwas considered to be the highest practical dose that could beevaluated in this study based upon observations of overt toxicityat 500 mg/kg and mortality at 1000 mg/ kg in a dose range-findingstudy. The two measures of neurotoxicity evaluated in the acutestudy were functional observational battery (FOB) and motoractivity measurements. An apparent treatment-related effectin thermal response time (increased) was noted for both sexes1 hr after dosing at the 500 mg/kg dose level. A questionableeffect on rearing activity (decreased) also was noted at thesame dose level. For the multigeneration plus chronic dietaryadministration study, rats were administered DEET at dietaryconcentrations of 0, 500, 2000, or 5000 ppm continuously overtwo generations and then chronically for 9 months. A dietaryconcentration of 5000 ppm meets the criteria for a maximum tolerateddose (MTD) based on traditional chronic toxicology assessments.Evaluations included FOB, motor activity, discriminative acquisitionand reversal in an Mmaze, acoustic startle habituation, passiveavoidance acquisition and retention, and microscopic examinationof central and peripheral nervous tissue. The only effect thatwas considered to be possibly treatment-related was a slightincrease in exploratory locomotor activity at the 5000 ppm doselevel. Based on the results of these studies, the nervous systemdoes not appear to be a selective target when DEET is administeredto rats either as a single oral dose at high dose levels orchronically at the MTD.     

Absorption, Distribution, Metabolism, and Excretion (ADME) Studies of Biotherapeutics for Autoimmune and Inflammatory Conditions

Biotherapeutics are becoming an increasingly common drug class used to treat autoimmune and other inflammatory conditions. Optimization of absorption, distribution, metabolism, and excretion (ADME) profiles of biotherapeutics is crucial for clinical, as well as commercial, success of these drugs. This review focuses on the common questions and challenges in ADME optimization of biotherapeutics for inflammatory conditions. For these immunomodulatory and/or immunosuppressive biotherapeutics, special consideration should be given to the assessment of the interdependency of ADME profiles, pharmacokinetic/pharmacodynamic (PK/PD) relationships, and immunogenicity profiles across various preclinical species and humans, including the interdependencies both in biology and in assay readouts. The context of usage, such as dosing regimens, extent of disease, concomitant medications, and drug product characteristics may have a direct or indirect (via modulation of immunogenicity) impact on ADME profiles of biotherapeutics. Along these lines, emerging topics include assessments of preexisting reactivity to a biotherapeutic agent, impact of immunogenicity on tissue exposure, and analysis of penetration to normal versus inflamed tissues. Because of the above complexities and interdependences, it is essential to interpret PK, PD, and anti-drug antibody results in an integrated manner. In addition, because of the competitive landscape in autoimmune and inflammatory markets, many pioneering ADME-centric protein engineering and subsequent in vivo testing (such as optimization of novel modalities to extend serum and tissue exposures and to improve bioavailability) are being conducted with biotherapeutics in this therapeutic area. However, the ultimate challenge is demonstration of the clinical relevance (or lack thereof) of modified ADME and immunogenicity profiles.     

Pre‐clinical Characterization of Absorption,Distribution, Metabolism and Excretion Properties of TAK‐063

TAK‐063 is currently being developed to treat schizophrenia. In this study, we investigated the absorption, distribution, metabolism and excretion (ADME) properties of TAK‐063 using several paradigms. Following oral administration of TAK‐063 at 0.3 mg/kg, bioavailability of TAK‐063 was 27.4% in rats and 49.5% in dogs with elimination half‐lives of 3.1 hr in rats and 3.7 hr in dogs. TAK‐063 is a highly permeable compound without P‐glycoprotein (P‐gp) or breast cancer resistance protein substrate liability and can be readily absorbed into systemic circulation via the intestine. TAK‐063 can also cross the blood–brain barrier. TAK‐063 was metabolized mainly by CYP2C8 and CYP3A4/5, while incubation with human liver microsomes produced the major human metabolite, M‐I as well as several unknown minor metabolites. Metabolism of TAK‐063 to M‐I occurs through hydroxylation of the mono‐substituted pyrazole moiety. In vitro, TAK‐063 was observed to inhibit CYP2C8, CYP2C19 and P‐gp with IC₅₀ values of 8.4, 12 and 7.13 μM, respectively. TAK‐063 was primarily excreted in the faeces in rats and dogs with M‐I as a predominant component. The pre‐clinical data from these ADME studies demonstrate a favourable pharmacokinetic profile for TAK‐063 with good brain distribution supporting the feasibility of targeting central nervous system regions involved in schizophrenia pathophysiology. TAK‐063 has recently been investigated in a phase 2 clinical trial (NCT02477020).     

In Vivo Bioavailability and Metabolism of Topical Diclofenac Lotion in Human Volunteers

Purpose. The primary objective of this study was to determine the rate and extent of transdermal absorption for systemic delivery of diclofenac from Pennsaid (Dimethaid Research, Inc.) topical lotion into the systemic circulation after the lotion was applied to human volunteers, in an open treatment, non-blinded, non-vehicle controlled study. In addition, the in vivo metabolism of this topical diclofenac lotion has also been studied. Methods. Human volunteers were dosed with topical [¹⁴C]-diclofenac sodium 1.5% lotion on the knee for 24 h. Sequential time blood and urine samples were taken to determine pharmacokinetics, bioavailability and metabolism. Results. Topical absorption was 6.6% of applied dose. Peak plasma ¹⁴C occurred at 30 h after dosing, and peak urinary ¹⁴C excretion was at 24–48 h. The urinary ¹⁴C excretion pattern exhibits more elimination towards 24 h and beyond, as opposed to early urinary ¹⁴C excretion. This suggests a continuous delivery of [¹⁴C]-diclofenac sodium from the lotion into and through skin which only ceased when the dosing site was washed. Skin surface residue at 24 h was 26 ± 9.5% dose (remainder assumed lost to clothing and bedding). Extraction of metabolites from urine amounted to 7.4–22.7% in untreated urine, suggesting substantial diclofenac metabolism to more water soluble metabolites, probably conjugates, which could not be extracted by the method employed. Two Dimensional TLC analysis of untreated urine showed minimal or no diclofenac, again emphasizing the extensive in vivo metabolism of this drug. Treatment of the same urine samples with the enzymes sulfatase and (-glucuronidase showed a substantial increase in the extractable material. Three spots were consistently present in each sample run, namely diclofenac, 3hydroxy diclofenac and an intermediate polar metabolite (probably a hydroxylated metabolite). Therefore, there was significant sulfation and glucuronidation of both diclofenac and numerous hydroxy metabolites of diclofenac, but many of the metabolites/conjugates remain unidentified. Conclusions. There was a continuous delivery of diclofenac sodium from the lotion into and through the skin, which ceased after the dosing site was washed. The majority of the material excreted in the urine were conjugates of hydroxylated metabolites, and not the parent chemical, although further identification is required.     

Preliminary Studies on the Absorption,Distribution, Metabolism,and Excretion of THIP in Animal and Man using 14C-labelled Compound

Abstract: Distribution of radioactivity in rats, serum levels in human volunteers and rats and elimination of radioactivity in volunteers, rats, and mice following oral administration of ¹⁴C-labelled THIP have been investigated. Peak values of radioactivity in the organs and in serum were seen half an hour after administration, indicating a rapid absorption. Highest concentrations of radioactivity were found in the kidneys, but radioactivity was seen in all investigated tissues including the brain. The radioactivity was mainly excreted with urine (84–93%). Thin-layer chromatography of urine from volunteers, rats, and mice showed that most of the excreted radioactivity corresponds to unchanged THIP. Three metabolites were found in urine from rats each in amounts of 2–7% of the total dose given. Two of these metabolites were also found in urine from the volunteers in amounts of 30–35% and <2%, respectively, and in urine from mice in amounts of 21% and 6% of the total dose, respectively. No radioactivity corresponding to unchanged THIP was found in faeces indicating complete absorption of THIP following oral administration. One of the metabolites, the main one in man and mouse, seemed to be a glucuronic acid conjugate of THIP, but the chemical structure of the metabolites has not yet been established.     

Metabolism of Linoleamides: II. Absorption,Distribution, Excretion and Metabolism of N-[α-Phenyl-β-(p-tolyl)ethyl] linoleamide

1. Absorption, distribution, excretion and metabolism of (-)N-[α-phenyl-β-(p-tolyl)ethyl][¹⁴C]linoleamide (¹⁴C-PTLA) were studied in rats and dogs. Faecal excretion of PTLA was studied in dogs and men by g.l.c.

2. ¹⁴C-PTLA (10 mg/kg) given orally to rats resulted in urinary and faecal excretion of radioactivity of 2 and 93 %, respectively, by male rats and 8 and 87% by female rats in 48 h. Faecal excretion of PTLA in men was similar to that in rats.

3. Distribution of radioactivity in rats and dogs after oral administration of ¹⁴C-PTLA showed that a major part of the dose was not absorbed.

4. N-[α-Phenyl-β-(p-tolyl)ethyl]succinic acid monoamide and N-[α-phenyl-β-(p-tolyl)ethyl]glutaric acid monoamide were detected in the urine of rats dosed orally with ¹⁴C-PTLA.     

A Comparison of the Acute Toxicity, Neuropathology, and Electrophysiology of N,N-Diethyl-m-toluamide and N,N-Dimethyl-2,2-diphenylacetamide in Rats

The insect repellent DEET and the structurally related herbicidediphenamid both cause ataxia associated with a spongiform myelinopathylargely confined to the cerebellar roof nuclei. This local myelinopathywas accompanied by the formation of neuronal cytoplasmic cleftsand was produced by a single dose of 1 to 3 g/kg N,N-diethyl-m-toluamide(DEET). These dose levels also produced a severe and often fatalprostration and clear electrophysiological signs of prolongedsuppressed seizure activity. Diphenamid produced an identicalmyelinopathy after doses of 0.8 to 1.5 g/kg but without thesevere prostration, suppressed seizures, or neuronal clefts.The effects of diphenamid were shown to be reversible over 3to 7 days by neuropathological, motor, and auditory evoked responseindices. Both compounds caused characteristic changes in auditoryevoked response which may be useful in clinical diagnosis. Sixother alkyl amides, two of which produce signs of CNS excitation,failed to produce myelinopathy at the maximum tolerated doses.Our findings show close parallels with a number of human casesof DEET poisoning and indicate that other amides, like diphenamid,also pose a potential hazard.