Pharmacokinetics of the novel anticonvulsant HEPP after single intravenous administration of three different doses in dogs.

HEPP (D, L-3-hydroxy-3-ethyl-3-phenylpropanamide) is a novel compound with a wide spectrum of anticonvulsant activity and relatively low toxicity. The aim of this investigation was to study the pharmacokinetics of HEPP in mongrel dogs and to assess its linearity after intravenous administration of 8, 15, and 30 mg kg-1. A biphasic disappearance pattern with a rapid distribution phase was observed in the plasma concentration versus time curve. The mean terminal half-life (t1/2 beta) was the same after the three doses (3.4 +/- 0.15 h) and the mean half-lives of the distribution phase (t1/2 alpha) were not significantly different after the three doses (0.09 +/- 0.02, 0.08 +/- 0.07, and 0.11 +/- 0.03 h for 8, 15, and 30 mg kg-1 respectively). The mean AUC0-infinity values were 44.1 +/- 10.8, 72.1 +/- 8.8, and 127.4 +/- 23.2 micrograms h mL-1, respectively, showing a linear increase. The individual values of AUC0-infinity corrected for the administered dose (AUC0-infinity/D) were 0.29 +/- 0.04, 0.23 +/- 0.05, and 0.22 +/- 0.06 h mL-1. These values were not statistically different. Neither the mean residence time (MRT = 4.55 +/- 1.50, 4.90 +/- 1.32, and 5.07 +/- 1.95 h), the steady state volume of distribution (Vss = 0.86 +/- 0.11, 1.01 +/- 0.17, and 1.20 +/- 0.40 L kg-1) nor the systemic clearance (Cl = 3.36 +/- 0.82, 3.53 +/- 0.44, and 4.02 +/- 0.68 mL min-1 kg-1) showed significant differences between doses. The values of Vss suggest that HEPP is distributed in the whole body fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

Disposition kinetics of HEPP in rats after intravenous, oral, and intraperitoneal administration. Correlation of plasma and brain levels with the anticonvulsant effect.

D, L-3-hydroxy-3-ethyl-3-phenylpropanamide (HEPP) is a synthetic drug with anticonvulsant effects in a variety of seizure models. HEPP pharmacokinetics was studied after single 50 mg kg-1 intravenous (i.v.), intraperitoneal (i.p.), and oral (PO) administration in male albino Wistar rats. The plasma concentration against time curves showed a biphasic decay pattern with a similar distribution phase and the same terminal rate constant (beta = 0.22 h-1) by all three routes. The apparent volume of distribution at steady state (Vss = 0.80 L kg-1) indicates that HEPP is extensively distributed in extracellular tissues. This finding agrees very well with its low binding to plasma protein (mean bound fraction = 19.3 +/- 1.1%). The systemic clearance (Cl) was very low (3.30 mL min-1 kg-1). The bioavailability after IP and PO administration was 0.80 and 0.60 respectively. In the pharmacokinetic-pharmacodynamic studies a direct relationship was found between the protective effect of HEPP against pentylenetetrazole (PTZ) induced seizures and its concentration in plasma and/or brain. The concentrations at half-maximal effect (EC50) with 95% confidence interval (Cl) were 70.6 (66-75.5) micrograms mL-1 in serum and 60.1 (55.4-65.1) micrograms g-1 in brain. There was a rapid uptake of HEPP into the brain, and after the distributive phase, the disappearances in plasma and brain were almost parallel [C(serum) = 109 e-0.25t, r2 = 0.95; C(brain) = 38 e-2.53t + 91 e-0.21t, r2 = 0.93], with a C(brain)/C(plasma) ratio of 1.1.

Plasma determination of the novel anticonvulsant D,L-3-hydroxy-3-ethyl-3-phenylpropionamide and preliminary pharmacokinetic studies in the rat.

A sensitive gas chromatographic method with flame ionization detection was developed for the analysis in plasma of the novel anticonvulsant D,L-3-hydroxy-3-ethyl-3-phenylpropionamide (HEPP), using D,L-2-hydroxy-2-ethyl-2-phenylacetamide as the internal standard. HEPP was extracted from alkalinized plasma into dichloromethane and quantified after derivatization with bis(trimethylsilyl)-trifluoroacetamide: Standard curves were linear from 0.5 to 50 and from 2 to 100 micrograms/ml of plasma, using 1.5 and 5 micrograms of the internal standard, respectively. The lower limit of detection at a signal-to-noise ratio of 3 standard deviations was 0.33 micrograms/ml of sample. The sensitivity, accuracy and reproducibility of the method were shown to be satisfactory for pharmacokinetic studies of HEPP. After intraperitoneal administration of 50 mg/kg to Wistar rats, the principal kinetic parameters were: absorption half-life = 0.04 h; volume of distribution = 1.32 l/kg; clearance = 4.40 ml/min; peak concentration = 50 micrograms/ml; peak time = 0.25 h; mean residence time = 4.55 h.

Partition coefficients of three new anticonvulsants.

The partition coefficients of three homologous anticonvulsant phenylalkylamides [racemic alpha-hydroxy-alpha-ethyl-alpha-phenylacetamide (HEPA); beta-hydroxy-beta-ethyl-beta-phenylpropionamide (HEPP); and gamma-hydroxy-gamma-ethyl-gamma-phenylbutyramide (HEPB)] were determined by reversed-phase high-performance liquid chromatography (RP-HPLC). The system was calibrated with a series of simple amines and amides, using their published log P values. The log kw values (methanol:water, extrapolated to 100% water) were 1.260 for HEPA, 1.670 for HEPP, and 1.852 for HEPB. From these results, the partition coefficients (log P) were calculated by regression as 1.20, 1.83, and 2.11, respectively. The log P values were essentially equal to those calculated by the Leo-Hansch fragmental method. Since the potency of the three anticonvulsants is approximately the same in a variety of tests, no dependence on lipophilicity could be established.

A Free-Wilson/Fujita-Ban analysis and prediction of the analgesic potency of some 3-hydroxy- and 3-methoxy-N-alkylmorphinan-6-one opioids.

Herein we describe a Free-Wilson/Fujita-Ban QSAR (quantitative structure-activity relationship) analysis of the analgesic potency of over 50 semisynthetic opioid narcotics. The 3-hydroxy- and 3-methoxy-N-alkylmorphinan-6-ones of B/C-cis and -trans stereochemistry include compounds exhibiting structural variation at five positions [N-methyl (C17), oxygen at C3, C4-C5 oxygen bridge, alkyl substituents at C7 and C8]. The pharmacological parameter correlated was the analgesic potency (-log ED50) exhibited on abdominal contractions produced by acetylcholine injection in mice. A satisfactory correlation was obtained only by assuming interdependent contributions of the substituents on C17 and O(C3), with which it was possible to explain 75% of the variance. Phenolic compounds (3-OH) behave somewhat differently from the methyl ethers (3-OCH3), and in both series the substituents on C8 have a size-dependent negative contribution, implying steric hindrance at their contact point on the receptor. With use of this correlation the potency of five further members of the series was predicted. Subsequent testing fully confirmed the validity of the correlation since the measured potencies were, within experimental error, equal to those calculated. In a further refinement, phenolic compounds were considered separately from the ethers, and it was found that the contribution of the substituents on C17, C7, and C8 remained similar in sign and magnitude but not that of the furan oxygen. This analysis allows us to conclude that if both phenolic and nonphenolic members of this series act on the same receptor they must bind at different subsites or in alternate modes, supporting an earlier proposal in the literature.

Quantitation of the criticality of chiral centers toward stereoselective recognition: epimeric eudismic analysis of 1,3-oxathiolane muscarinic agonists and antagonists.

Recently published data on the affinities of 14 pairs of chiral ligands, (1,3-oxathiolanes) for muscarinic receptors in three different tissues were subjected to eudismic analyses. The enantiomeric eudismic-affinity correlations (EACs) found by Gualtieri et al. were confirmed and extended to the submolecular level: (1) regressions of the eudismic index (log affinity ratio; EI) against eutomer potency of the average affinities were highly significant, indicating that the binding sites in all three tissues are identical; (2) for the five agonists the EAC was shifted to lower affinities and had a small slope (EAQ), in agreement with previous observations in other systems; (3) of the nine antagonists, six gave an excellent regression with unit slope, practically superimposable on that previously obtained for 10 structurally different oxotremorine derivatives, while two others (1,3-oxathiolanes) could be plotted on a separate line with the same EAQ, but shifted to higher affinities; (4) the aberrant low EI of the last antagonist could be explained in terms of its structure. Furthermore, an epimeric EAC (EEAC) revealed additional important information for quantitative stereo-structure-activity relationships (QSSAR): the 25 possible epimeric comparisons were found to group into 6 different EACs in accord with differences in their structure: (1) the agonists fell on three separate lines of nearly identical (unitary) slope, which grouped cleanly in terms of the center of epimerization (positions 2, 3, and 5); (2) the antagonists of lower affinity fell on three lines with a common X-intercept but with different slopes corresponding to epimerization at the different centers of chirality, indicating that these display quantitative differences in their criticality toward stereoselective recognition; (3) the remaining two antagonists of higher affinity fell on a separate line, again of unit slope.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute thallium intoxication: kinetic study of the relative efficacy of several antidotal treatments in rats.

Rats were administered a sublethal dose of thallium (12.35 mg/kg as aqueous thallous sulfate, Tl2SO4, equivalent to 10 mg Tl+/kg per os) on day 0. Urine and feces were collected separately every day for 8 days and analyzed by atomic absorption spectroscopy. Based on information in the literature, five antidotal treatments (dithizone, activated charcoal, furosemide, Prussian Blue, and a combination of Prussian Blue and furosemide) were compared with controls for their efficacy in reducing the total thallium body load. In the control group (C,n = 10) of an approximate administered dose of 2 mg, after 8 days 411 micrograms (21%) had been eliminated in the urine and 641 micrograms (32%) in the feces, making a total of 1,052 micrograms (53%). In the treated groups the effects were very significant and in accord with the mode of action of the antidotes: furosemide (a diuretic) only enhanced urinary elimination; activated charcoal and Prussian Blue (unabsorbed adsorbents) only increased fecal elimination; dithizone increased only urinary elimination, whereas combined treatment with Prussian Blue and furosemide increased elimination by both routes. At the end of 8 days the control group had only eliminated 53% of the dose; this was increased to 99% by dithizone, 93% by activated charcoal, 64% by furosemide, 82% by Prussian Blue and 92% by combining furosemide and Prussian Blue. In view of the inherent toxicity of dithizone, it is suggested that treatment with a combination of Prussian Blue-furosemide or with activated charcoal should be adequate.(ABSTRACT TRUNCATED AT 250 WORDS)

Parameters for the adsorption of thallium ions by activated charcoal and Prussian blue.

Activated charcoal and Prussian blue are effective antidotes in acute thallium (T1+) intoxication in rats. They act by trapping any metal present in or secreted into the gut by the gastro-intestinal epithelium. It was therefore of interest to determine the parameters of the Langmuir adsorption isotherms of T1+ ions for these two adsorbents. The data from equilibration experiments were analyzed by direct least-squares fitting to a hyperbola and with Langmuir's equation to give the following results: Activated charcoal: K1(-1) = 192 micrograms ml-1, K2 = 124 mg g-1 Prussian Blue: K1(-1) = 130 micrograms ml-1, K2 = 72 mg g-1. These high values provide in vitro confirmation of their in vivo antidotal efficacy and show that activated charcoal can replace Prussian blue when this latter drug is unobtainable.