Solute Absorption from the Airways of the Isolated Rat Lung. V. Charge Effects on the Absorption of Copolymers of N(2-hydroxyethyl)-DL-Aspartamide with DL-Aspartic Acid or Dimethylaminopropyl-DL-Aspartamide

Purpose. To determine the effects of ionized substituents upon the pulmonary absorption of 6-8 kDa synthetic, hydrophilic polypeptides. Methods. Fluorophore-labeled poly (hydroxyethylaspartamide), F-PHEA (neutral at pH 7.4) and its copolymer derivatives poly (hydroxyethylaspartamide-co-dimethylaminopropylaspartamide), F-P(HEA-DMAPA) (positive at pH 7.4) and poly (hydroxyethylaspartamide-co-aspartic acid), F-P(HEA-AA) (negative at pH 7.4) were synthesized and administered in different concentrations to the airways of the isolated rat lung preparation. The time and molecular weight dependencies of polypeptide absorption into perfusate were determined at intervals by gel permeation chromatography. Results. For all polypeptides, molecular weights in perfusate were about 1 kDa less than those which were administered, due to preferential absorption of smaller molecules. The absorption, up to 70% of the administered dose over 3 h, of the anionic F-P(HEA-AA), was significantly faster than that of the neutral F-PHEA or the polycationic F-P(HEA-DMAPA). The latter derivative produced greatest edema in the lung. Absorption showed both active [dose-dependent kinetics] and passive [diffusive] components for all three polymers. Conclusions. Pulmonary absorption of similarly sized macromolecular PHEA derivatives, either neutral, positively or negatively charged, occured via carrier-mediated and diffusive mechanisms. The highest rate of absorption was observed with the polyanionic derivative.     

Solute Absorption from the Airways of the Isolated Rat Lung. II. Effect of Surfactants on Absorption of Fluorescein

To determine the effects on the pulmonary barrier of several surface active agents, a series of metered dose inhalers (MDIs) was prepared and used to dose aerosolized surfactant to the airways of isolated perfused rat lungs. The MDIs contained a range of concentrations, from 0.1 to 5.0% (w/w), of either oleic acid, oleyl alcohol, or Span 85, which released 45 µg (0.1%, w/w) to 1660 µg (5.0%, w/w) of surfactant per actuation. The permeability of the pulmonary barrier was assessed by the rate of transfer of disodium fluorescein dosed as 100 µl of aqueous solution (1 mg/ml) after administering the surfactants. Some 12.1 ± 4.7% of the recovered surfactant, per dose, was assessed to reach the pulmonary regions of the lung. All surfactants tested caused an increase in fluorescein transfer rates. A single actuation from the MDI containing 5% (w/w) oleic acid produced gross edema in all lungs tested within 40 min and the first-order half-lives of absorption were reduced almost threefold, from 12.9 ± 2.5 min for controls to 4.5 ± 0.8 min. Differences in absorption were noted between the acid and the alcohol, which is consistent with the hypothesis that both the hydrocarbon chain and the polar head group have roles in the altered permeability to fluorescein. The absorption of fluorescein when dosed from the MDI containing 5% (w/w) Span 85 was increased but all surfactants dosed from the lowest concentration MDI of 0.1% (w/w) did not alter absorption rates of the dye relative to those of controls. Results are discussed in light of current interest in absorption enhancement and the presence of surfactants in currently marketed MDIs.     

Solute Absorption from the Airways of the Isolated Rat Lung. I. The Use of Absorption Data to Quantify Drug Dissolution or Release in the Respiratory Tract

Coprecipitates of fluorescein and magnesium hydroxide demonstrate delayed absorption relative to fluorescein solutions when administered to the airways of the isolated perfused rat lung (IPRL). Perfusate concentration vs time profiles showed that dissolution and not epithelial permeability was the rate-controlling factor in the airway-to-perfusate transfer process. A simple data deconvolution method was developed to determine the fluorescein release from the microparticulate coprecipitates in the airways. The deconvolution technique is generally applicable and provides values for undissolved solute remaining in the airways as a function of time provided that (a) significant binding and/or metabolism does not occur, (b) absorption from solution is apparent first order, and (c) all solid or dissolved material reaching perfused regions is absorbed within the lifetime of the preparation. Increased release rates of fluorescein occurred from precipitates containing greater starting concentrations of the dye. Dissolution profiles were similar to those that occur for log-normally distributed powders. The analysis of two unusual time profiles implied that the regional distribution of solid and dissolved material, between perfused areas and nonperfused areas, could be nonhomogeneous despite the use of a standardized dosing technique. The studies describe a method of using the IPRL with the potential to screen aerosol formulations for extended dissolution in the respiratory tract.     

Peptidoleukotriene (PLT) Release and Absorption from the Airways of the Isolated Perfused Guinea Pig Lung Following Chemical and Antigenic Challenge

Purpose. To study the release and absorption of peptidoleukotrienes (PLTs) from the airways of the guinea pig lung following calcium ionophore A23187 (CI), benzalkonium chloride (BAC), ethylene diamine tetra-acetic acid (EDTA) or ovalbumin (OA) challenge. Methods. PLT C4/D4/E4 were quantified in the perfusate of the isolated perfused guinea pig lung (IPGPL) following intratracheal administration of CI, BAC, EDTA or OA in different doses. The formation and airway-to-perfusate transfer kinetics of PLTs were analyzed by fitting mean data for cumulative PLT in perfusate vs. time to an A B C first-order release and transfer model, with dose-dependent transfer rate constants. Results. CI induced apparent first order release of PLTs with a t 1.2 minutes. The amount of PLT released was CI dose-dependent, as was the airway-to-perfusate transfer rate constant. These reached maxima of 0.254 g and 0.0557 min.^–1, respectively, around a CI dose of 100 g. In OA-sensitized IPGPL preparations, OA induced a similar dose-dependent release of PLTs, although the rates of PLT release were much greater and more variable than those seen with CI. In OA sensitized IPGPL preparations, at an OA dose of 1000 g, the maximum amount of PLT released was 0.289 g and the maximal airway-to-perfusate transfer rate constant was 0.0229 min^–1. BAC and EDTA failed to induce quantifiable PLT release from the airways. Conclusions. Rapid release of the inflammatory mediators, PLT C4/ D4/E4, could be induced in the unsensitized IPGPL by CI, and in the sensitized IPGPL by OA. Transfer into perfusate occurred in both cases with dose-dependent t ranging from 12.4 through 57.8 minutes.     

Insulin Self-association: Effects on Lung Disposition Kinetics in the Airways of the Isolated Perfused Rat Lung (IPRL)

Purpose To characterize the kinetic dependence of pulmonary absorption and metabolism of insulin and lispro on the magnitude of their hexameric association. Methods Hexamer content by weight percent (%Hex) in various insulin-zinc and lispro-zinc solutions were determined by quantitative centrifugal ultrafiltration and zinc titration with terpyridine (QCUF-ZTT). Each of the solutions (0.1 ml) was then administered into the airways of the IPRL of normal and experimental diabetic animals. Rate constants were determined for lung absorption (k _a) and non-absorptive loss (k _nal; comprising mucociliary clearance and metabolism). Results %Hex in administered solutions ranged from 3.3 to 94.4%. Data analysis showed excellent correlations between the values for k _a or k _nal and %Hex, irrespective of insulin type, concentration, solution pH or ionic strength. The values for k _a decreased (0.22 → 0.05 h⁻¹) with increasing %Hex, as did values for k _nal. At %Hex in administered solutions ≥50%, values for k _nal approached estimates for the rate constant for mucociliary clearance, implying that lung metabolism occurred primarily with monomeric insulin. There were no differences in insulin disposition kinetics between lungs taken from experimental diabetic and sham-control animals. Conclusions The kinetics of pulmonary insulin disposition depended on the magnitude of molecular self-association. Dissociated forms of insulin (dimers or monomers) in the dosing solution showed higher rates than hexamers for both lung absorption and metabolism.     

Nasal Absorption in the Rat. III. Effect of Lysophospholipids on Insulin Absorption and Nasal Histology

The intranasal absorption enhancing and histological effects of a range of lysophospholipids has been investigated in the rat. Blood glucose levels fell rapidly following the administration of insulin (8 IU/kg) in combination with lysophosphatidylcholines (LPC; 0.625% w/v) which had ten or more carbon groups in their fatty acid chain. The effect of the LPC-caproyl (C6) was comparable to that of an unenhanced insulin formulation; the enhancing effect of LPC-decanoyl (C10) was similar to that of an LPC-palmitoyl/stearoyl (C16/C18) for similar concentrations. The effect of LPC-decanoyl was reduced with concentration but was still significant at 0.2% w/v (5mM). Lysophosphatidylglycerol (LPG) had a marked insulin absorption enhancing effect even at 0.0625% w/v. The histological effects of LPC-caproyl were similar to those of an unenhanced insulin formulation, while co-administration of LPC-decanoyl resulted in evidence of epithelial interaction. LPG (0.5% w/v) resulted in similar histological changes as LPC (0.625% w/v) (1), but at 0.0625% w/v no significant changes in epithelial integrity were observed. The length of the fatty acid residue of lysophospholipids was identified as an important factor for intranasal absorption enhancing activity. The nature of the polar head group may also have an influence. Increased insulin absorption was not necessarily accompanied by severe disruption of the nasal epithelium. Careful selection of lysophospholipid type and concentration may enable therapeutic drug levels to be achieved via the nasal route without prohibitive toxic effects.     

Intestinal Absorption of (–)-Carbovir in the Rat

(–)-Carbovir (CBV) is a carbocyclic nucleoside analogue with in vitro activity against the human immunodeficiency virus. The sites and mechanism of absorption of (–)-CBV from the rat small intestine were studied in the anesthetized male Sprague–Dawley rat. (–)-CBV was perfused through either duodenal, jejunal, or ileal segments at three concentration levels ranging from 1 to 500 µg/mL. The fraction remaining to be absorbed at steady-state and the absorptive clearance were calculated for each experiment. The effect of solvent drag on the absorptive clearance was also investigated. Two-way ANOVA for the absorptive clearance per unit length was not significant for either (–)-CBV concentration or site of perfusion. The fraction remaining to be absorbed at steady-state was found to be 0.804 ± 0.091 (n = 30). A strong correlation was found between the absorptive clearance and the net water absorptive flux. The mechanism of (–)-CBV absorption across the rat small intestine apparently consists of both passive diffusion and convection.     

The Influence of Drugs and Other Factors on Inactivation of Prostaglandin E2 by the Rat Isolated Perfused Lung

1. The mechanisms responsible for inactivating prostaglandin E₂ (PGE₂) in the rat isolated lung were saturated by high rates of arterial presentation of the prostaglandin. 2. Lungs from normotensive females, and from males of the New Zealand hypertensive strain, inactivated PGE₂ less readily than did those from normotensive males. 3. Increasing the perfusion rate or pre-treating animals with probenecid or cycloheximide reduced inactivation of PGE₂. Treatment with cycloheximide plus probenecid did not however reduce inactivation to a greater extent than did cycloheximide alone. 4. Pregnancy or administration of hydrocortisone increased pulmonary removal of PGE₂ whereas adrenalectomy reduced it. 5. Thus the rate of inactivation of PGE₂ in this species may depend both on the activity of an initial active transport process and also on the levels of catabolising enzymes. The latter may be of greatest importance when pulmonary artery concentrations of PGE₂ are low with the transport mechanism assuming greater significance when they are high. The rate of removal is also dependent on sex, genotype, steroidal status, pregnancy and pulmonary flow.     

Intestinal Absorption of Drugs. III. The Influence of Taurocholate on the Disappearance Kinetics of Hydrophilic and Lipophilic Drugs from the Small Intestine of the Rat

The influence of sodium taurocholate (TC) on the intestinal absorption of drugs was studied in vivo in a chronically isolated internal loop in the rat. The hydrophilic drugs paracetamol (PA) and theophylline (TP) and the lipophilic drugs griseofulvin (GF) and ketoconazole (KE) were used as model drugs. The drug concentrations were kept below the saturation concentration. Absorption kinetics of the drugs were evaluated on the basis of disappearance rates of the drug from luminal solutions in the intestinal loop. Concentrations of TC above the critical micelle concentration (CMC) did not affect the absorption rate of the hydrophilic drugs PA and TP; the barrier function of the intestinal wall for PA and TP was not altered in the presence of taurocholate. The addition of concentrations of TC above the CMC in the perfusion solution resulted in a reduction of the absorption rate of GF and KE. The reduction in the absorption kinetics of GF in the presence of TC correlated well with the reduction of the drug-free fraction in solution due to micellar solubilization. For KE this relation was less clear. It was not possible to determine, on the basis of the phase-separation model, to what extent the fraction of the drug incorporated in TC micelles contributes to the overall diffusion of GF and KE across the preepithelial diffusion barrier. It was concluded that TC exhibits only a minor, if not negligible, effect on the barrier function of the aqueous diffusion barrier adjacent to the intestinal wall.     

Dose-Dependent Intestinal Absorption and Significant Intestinal Excretion (Exsorption) of the β-Blocker Pafenolol in the Rat

The elimination of [³H]pafenolol and metabolites was investigated in fasted and fed rats. Separate groups received intravenous doses (0.3 and 3.0 µmol/kg) and oral doses (1 and 25 µmol/kg). After iv administration of pafenolol, the excretion of unchanged drug into urine and feces was about 50 and 25–30% of the given dose, respectively. The predominating mechanism for the excretion of pafenolol into feces was intestinal excretion (exsorption) directly from blood into gut lumen, since only about 3% of a given iv dose was recovered as pafenolol in the bile. When the oral dose was raised from 1 to 25 µmol/kg, the mean (±SD) bioavailability, calculated from urine data, increased from 14 ± 9 to 30 ± 11% (P < 0.05) in the starved rats and from 14 ± 3 to 16 ± 3% in the fed animals. In parallel, the fraction absorbed from the gut (f _a) increased from 19 ± 9 to 31 ± 10% in the starved rats and from 16 ± 4 to 19 ± 5% in the fed animals, respectively. This indicates that the low bioavailability is due primarily to poor intestinal uptake.     

Oral Absorption of Peptides Through the Cobalamin (Vitamin B12) Pathway in the Rat Intestine

Purpose. This study was aimed at examining the extent and mechanismof uptake of cobalamin (Cbl)-conjugated peptides in vitro and in vivo. Methods. To enable acquisition of quantitative absorption data ofCbl-peptides, metabolically stable octapeptides (DP3), with (Cbl-Hex-DP3)or without a hexyl spacer (Cbl-DP3), were coupled to Cbl andradiolabeled. For comparison, LHRH coupled to Cbl was used as metabolicallysusceptible peptide. Biological recognition of Cbl-peptides was studiedin the physiological order: binding by Intrinsic Factor (IF), recognitionand transport of the IF-complexes by IF-Cbl receptors (IFCR) onCaco-2 monolayers and oral absorption of the Cbl-conjugates in the rat. Results. All Cbl-peptides bound to IF and the IF-complexes wererecognized by IFCR receptors on Caco-2 monolayers. Binding wassaturable and could be inhibited by a 20-fold excess of IF-Cbl, but notof Non-intrinsic Factor (NIF)-Cbl. Oral administration of these ligandsto rats resulted in absorption of 53%, 45%, 42%, and 23% of theapplied radioactivity for Cbl, Cbl-LHRH, Cbl-Hex-DP3, and Cbl-DP3,respectively. Simultaneous administration of a >10⁵-fold excess ofunlabeled Cbl reduced uptake of all compounds to <4%. Tissuedistribution and elimination of the metabolically stable Cbl-conjugates werecomparable to Cbl. Conclusions. The endogenous Cbl uptake pathway can be exploitedfor oral peptide delivery as indicated by the specific and high (40–45%)uptake of metabolically stable Cbl-coupled octapeptides.Deceased     

Pulmonary Absorption of Recombinant Methionyl Human Granulocyte Colony Stimulating Factor (r-huG-CSF) After Intratracheal Instillation to the Hamster

Recombinant methionyl human granulocyte colony stimulating factor (G-CSF), a molecule of 18.8 kDa, has been shown to induce a systemic response after delivery by aerosol. In this work, rate and extent of absorption as well as the response were determined after bolus administration of solutions by intratracheal instillation (IT). The protein was quantified using a specific ELISA and the biological response was assessed by monitoring the increase in numbers of circulating white blood cells (WBC). A dose–response curve was obtained after IT, subcutaneous injection (SC), and intracardiac injection (IC) of 100 µL of a nominal dose ranging from 1 to 1000 µg/kg G-CSF (n = 5). WBC numbers were determined 24 hr postadministration. Absorption and clearance kinetics were determined after IT and IC of 500 µg/kg protein over a 24-hr time period (n = 5). The response of the lung to G-CSF was monitored by WBC counts and differentials in lung lavage fluid. 73.6 ± 10.5% (n = 7) of the IT dose reached the lung lobes. The response to single doses of G-CSF by IT or SC was similar, with WBC numbers increasing over 4× baseline at the higher doses. Absorption from the lung was rapid and did not follow first-order kinetics. Clearance after the IC dose was described by a biexponential equation ( = 1.41, = 0.24 hr^–1). Peak serum levels were obtained 1–2 hr after IT. The bioavailability was 45.9% of the administered dose and 62.0% of the dose reaching the lung lobes. These results indicate that G-CSF is rapidly absorbed from the lung. Pulmonary delivery via the airways has promise as an alternative to parenteral injection.     

Absorption,Metabolism, and Excretion of 2,3:4,5-Bis(2-Butylene) Tetrahydro-2 Furaldehyde (Mgk R11)in the Rat

Abstract

Experiments were conducted in four groups of rats to determine the absorption, distribution, metabolism, and excretion (ADME) patterns following oral administration of [formyl-¹⁴C] 2,3:4,5-bis(2-butylene) tetrahydro-2 furaldehyde (MGK R11).

Ten rats (five males and five females) were used in each of the four experiments. Fasted rats were administered [for-myl-¹⁴C] MGK R11 at a single oral dosage of 65 mg/kg, at a single oral dosage of 1000 mg/kg, and at a daily oral dosage of 65 mg/kg of nonradiolabeled compound for 14 days followed by a single dose of ¹⁴C-labeled compound at 65 mg/kg. Rat blood kinetics were determined in the fourth group following a single oral dose of 65 mg/ kg. Each animal was administered approximately 12–14 μCi of radioactivity.

Urine and feces were collected from 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 30 min in both the males and females, indicating very rapid absorption. The decline of radioactivity from blood followed a biphasic elimination pattern. The first half-life was 1.36 h for males and 1.18 h for females. In the second phase, the half-life was 21 h for males and 26 h for females.

Female rats excreted 67.21-86.85% of the radioactivity in urine and 13.99–28.08% in feces, whereas male rats excreted 50.19–64.37% of the administered radioactivity in urine and 31.43–40.94% in feces. Tissue residues of ¹⁴C ranged between 0.47% and 1.09% of the administered dose. The total mean recovered radioactivity of the administered dose in the four definitive studies ranged between 92% and 101%. No parent compound was detected in the urine.

Three major and one minor metabolite was isolated by high-performance liquid chromatography (HPLC) and identified by gas chromatography/mass spectrometry (GC/MS). One major metabolite was formed by oxidation of the aldehyde moiety to the carboxylic acid. A second metabolite was the glucuronic acid conjugate of the carboxylic acid and the third was formed by reduction of the aldehyde moiety of MGK R11 to an alcohol followed by glucuronic acid conjugation. The minor metabolite was the unconjugated alcohol derivative of MGK R11.

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.     

Improvement of the Pulmonary Absorption of (Asu1,7)-Eel Calcitonin by Various Protease Inhibitors in Rats

The effects of protease inhibitors, Na-glycocholate, bacitracin, bestatin, nafamostat mesilate and soybean trypsin inhibitor (STI) on the pulmonary absorption of (Asu^1,7)-eel calcitonin (ECT, molecular weight 3363) were investigated in rats. The pulmonary absorption of ECT was estimated by measuring its hypocalcemic effect. When ECT alone was administered into the lung, the pharmacological availability of ECT was 2.7%. Co-administration with STI or bestatin did not change the pharmacological effect of ECT. However, Na-glycocholate, bacitracin and nafamostat mesilate caused a significant hypocalcemic effect following the pulmonary absorption of ECT and a maximal effect was noted in the presence of 20 mM bacitracin, approaching the effect after intravenous administration of ECT. Bacitracin and Na-glycocholate reduced the degradation of ¹¹¹In-ECT in rat lung homogenate. Therefore, protease inhibitors effectively improved the pulmonary absorption of ECT.     

Heparin Absorption Across the Intestine: Effects of Sodium N-[8-(2-Hydroxybenzoyl)Amino]Caprylate in Rat In Situ Intestinal Instillations and in Caco-2 Monolayers

Purpose. The effects of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) on heparin intestinal absorption were studied using rat in situ ileal and colonic instillations and Caco-2 monolayers. Methods. The flux of heparin was tested in the following groups: i) heparin alone, ii) heparin in the presence of SNAC, iii) heparin in the presence of propylene glycol (PG), and iv) heparin in the presence of SNAC and PG. Heparin absorption was measured by the APTT assay in the in situ models and by the anti-Factor Xa assay in Caco-2. SNAC and [³H]-SNAC fluxes were assessed by HPLC and by scintillation counting respectively. Results. In the rat ileal and colonic in situ instillations SNAC (17–35mg) promoted heparin absorption in the presence and absence of PG without damaging the tissue. PG alone did not alter heparin absorption in situ, but it amplified the effect of SNAC. In Caco-2, enhanced heparin fluxes were variable in the presence of non-cytotoxic concentrations of SNAC (< l0mg/ml) and these effects could not be discriminated from those of PG. Papp values for SNAC alone were 2.2 × 10^–5 cm/s and 2.0 × 10^–5 cm/s in the mucosal-to-serosal and serosal-to-mucosal directions respectively, suggesting a substantial passive transcellular flux. Transport of SNAC was significantly reduced in the presence of heparin and/or PG, perhaps indicating physical association between the agents. Conclusions. SNAC augmented heparin absorption alone and in combination with PG in the rat in situ models without causing toxicity. Caco-2 had limitations for testing increased heparin absorption due to cytotoxic effects of high concentrations of SNAC and PG. However, SNAC itself was well absorbed across Caco-2 and its mechanism of permeation was determined.     

Requirement of Pretone by Thromboxane A(2) for Hypoxic Pulmonary Vasoconstriction in Precision-cut Lung Slices of Rat

Hypoxic pulmonary vasoconstriction (HPV) is physiologically important response for preventing mismatching between ventilation and perfusion in lungs. The HPV of isolated pulmonary arteries (HPV-PA) usually require a partial pretone by thromboxane agonist (U46619). Because the HPV of ventilated/perfused lungs (HPV-lung) can be triggered without pretone conditioning, we suspected that a putative tissue factor might be responsible for the pretone of HPV. Here we investigated whether HPV can be also observed in precision-cut lung slices (PCLS) from rats. The HPV in PCLS also required partial contraction by U46619. In addition, K(+) channel blockers (4AP and TEA) required U46619-pretone to induce significant contraction of PA in PCLS. In contrast, the airways in PCLS showed reversible contraction in response to the K(+) channel blockers without pretone conditioning. Also, the airways showed no hypoxic constriction but a relaxation under the partial pretone by U46619. The airways in PCLS showed reliable, concentration-dependent contraction by metacholine (EC(50), ~210 nM). In summary, the HPV in PCLS is more similar to isolated PA than V/P lungs. The metacholine-induced constriction of bronchioles suggested that the PLCS might be also useful for studying airway physiology in situ.     

Contribution of Monoamine Oxidase(MAO) to the Binding of Tertiary Basic Drugs in Isolated Perfused Rat Lung

The effect of tertiary basic drugs on mitochondrial MAO activity and the effect of MAO inhibitors (MAOIs) on basic drug accumulation in the isolated perfused rat lung were studied to clarify the role of MAO in drug binding to lung tissue. In the perfused lung preparation, the inhibition of MAO by basic drugs correlated well with their lipid solubilities and followed competitive kinetics. The inhibitory rank order (imipramine diphenhydramine > quinine > metoclopramide > procainamide) also correlated with their accumulation in the perfused lung. Moreover, MAOI treatment decreased the accumulation of basic drugs in the lung, and the potency of MAOIs to inhibit drug accumulation in the lung correlated with their MAO inhibitory activity. These results indicate that lung MAO has specific binding sites for basic drugs and may function as a drug reservoir.     

Absorption,metabolism and excretion of 4-chloro-2-methylphenoxyacetic acid (MCPA) in rat and dog

1. The oral no overall adverse effect level (NOAEL) for chronic toxicity of 4-chloro-2-methylphenoxyacetic acid (MCPA) in rat is ~1.3?mg kg^-1 and in dog is 0.2 mgkg^-1. In an attempt to explain the difference in toxicology between these species, rats and dogs were orally dosed with (¹⁴C)-MCPA at 5 or 100?mg kg^-1 and plasma toxicokinetics, rates and routes of excretion and biotransformation were investigated. 2. Elimination of radioactivity in rat plasma was biphasic and in dog was monophasic. Rat eliminated radioactivity from plasma significantly faster than dog (approximate values based on total radioactivity: 5 mgkg^-1 rat: t_½dist 3.5 h, t_½elim 17.2-36.2 h, AUC_(0-∞) 230 µg equiv h g^-1; 5 mgkg^-1 dog: t_½47 h, AUC_(0-∞) 2500 µg equiv h g^-1; 100mg kg^-1 rat: t_½dist 10 h, t_½elim 10.27-25.4 h, AUC_(0-∞) 5400 µg equiv h g^-1; 100?mg kg^-1 dog: t_½41 h, AUC_(0-∞) 20 500µg equiv h g^-1). 3. For both species, the principal route of excretion was in urine but renal elimination was notably more rapid and more extensive in rat. 4. In both rat and dog, excretion of radioactivity was mainly as MCPA and its hydroxylated metabolite hydroxymethylphenoxyacetic acid (HMCPA). In rat, both were mainly excreted as the free acids although a small proportion was conjugated. In dog, the proportion of HMCPA was increased and the majority of both species was excreted as glycine or taurine conjugates. 5. These data, along with previously published accounts, indicate that renal elimination of MCPA in dog is substantially slower than in rat resulting in disproportionate elevation of AUC (based on total radioactivity) in dog compared with rat.     

A New Method for Estimating Dermal Absorption from Chemical Exposure: 2. Effect of Molecular Weight and Octanol-Water Partitioning

A new method for estimating dermal absorption including the effects of exposure time and chemistry is described generally in Part 1 of this series. This method accounts for the larger absorption rates during the initial exposure period as well as the hydrophilic barrier which the viable epidermis presents to lipophilic chemicals. A key parameter in this procedure, the ratio of the stratum corneum and epidermis permeabilities (B) depends on molecular weight and octanol-water partitioning. Several approaches for approximating B and its affect on the dermal absorption prediction are discussed here. Generally, the parameter B is only important for highly lipophilic chemicals which also have relatively small molecular weights. When B is important, the recommended prediction for B is based on the Potts and Guy correlation for human stratum corneum permeability.     

Comparison between the Absorption of Nicotinic Acid and Pentaerythritol Tetranicotinate (Perycit®) from Ordinary and Enterocoated Tablets

Nicotinic acid was shown to be rapidly absorbed from the gastrointestinal tract but also rapidly eliminated from the blood stream. Administration of nicotinic acid was therefore associated with large fluctuations of nicotinic acid concentration in the plasma. Two alternative ways of maintaining a moderate but more constant increase of the nicotinic acid concentration in the blood were studied. One way was to give nicotinic acid as a “sustained release” preparation. Nicotinic acid in enterocoated tablets with dissolution times of 2 hrs (in simulated intestinal juice), induced only an irregular and transitory increase of the plasma nicotinic acid concentration after 5 hrs and in some subjects only a reduction in plasma FFA. Enterocoated tablets with a dissolution time of 4 hrs were ineffective. Nicotinic acid is a weak acid and as such is poorly absorbed from the more distal parts of the digestive tract. Therefore the biological prerequisites for this alternative method were not so good. The second alternative method studied was to give a nicotinic acid ester which would continuously release nicotinic acid in the body. The nicotinic acid ester used (pentaerythritol tetranicotinate, perycit®, Bofors) given in an oral dose of 1 g, was found to give a moderate but consistent and prolonged increase in the free nicotinic acid concentration and a consistent decrease in the FFA-level of plasma with a moderate flush. Nicotinic acid in ordinary tablets and in an equivalent dose induced a considerably more pronounced flush and a somewhat larger reduction in plasma FFA which however was of shorter duration. The decrease was accompanied by a secondary and prolonged elevation of the plasma FFA concentration. This secondary increase was not observed in the experiments with pentaerythritol tetranicotinate. The possible importance of these differences from a pharmacotherapeutical point of view is discussed.