Arlington A. Forist

Metabolism of antidiabetic sulfonylureas in man: I. Biological half-lives of the p-acetylbenzenesulfonylureas, U-18536 and acetohexamide and their metabolites

Abstract The p -acetylbenzenesulfonylureas, 1-( p -acetylbenzenesulfonyl)-3-(hexahydro-1H-azepin-1-yl)-urea (U-18536) and 1-( p -acetylbenzenesulfonyl)-3-cyclohexylurea (acetohexamide), are rapidly absorbed and rapidly metabolized in man by reduction to their corresponding p -α-hydroxyethyl derivatives. After oral administration of 500 mg. of each drug to human subjects, serum concentrations of the drugs and their p -α-hydroxyethyl metabolites were determined at intervals for 15 hours. The average biological half-life of U-18536 in 8 nondiabetic male subjects was found to be 2.1 ± 0.2 (S.E.M.) hours, whereas the average half-life of its metabolite was found to be 3.0 ± 0.2 hours. The average biological half-lives of acetohexamide and its p -α-hydroxyethyl metabolite were found to be 1.3 ± 0.1 hours and 4.6 ± 0.9 hours, respectively. For both U-18536 and acetohexamide, the aparent half-life of disappearance of total sulfonylureas (drug plus metabolite) from the serum is essentially equal to that of their metabolites. Duration of hypoglycemic effect correlates best with total sulfonylureas in the serum, which is in agreement with the observation that the p -α-hydroxyethyl metabolites have hypoglycemic activity. Based on the biological half-lives of total sulfonylureas, intact drug or metabolite, neither U-18536 nor acetohexamide has a duration advantage over tolbutamide.

Determination of plasma levels of tolbutamide (1-butyl-3-p-tolylsulfonylurea, orinase).

Summary A procedure is presented for determination of Tolbutamide in plasma. The method consists of a chloroform extraction of weakly acidified plasma, concentration of the extract to dryness, dissolution of the residue in a measured volume of ethanol, treatment of the resulting solution with Darco G-60, and measurement of the absorbance of the resulting charcoal filtrate at 228 mμ. Recoveries of Tolbutamide from human and dog plasmas have been satisfactory and plasma levels determined by this procedure have correlated well with the hypoglycemic response elicited by the drug.

Clindamycin bioavailability from clindamycin-2-palmitate and clindamycin-2-hexadecylcarbonate in man

To determine the bioavailability of clindamycin from the microbiologically inactive clindamycin-2-palmitate and clindamycin-2-hexadecylcarbonate in man, a three-way crossover study was conducted with oral administration of the two esters and clindamycin hydrochloride. In each case, serum clindamycin bioactivity concentrations were fitted to a one-compartment open model with an initial lag time. Analysis of variance of measured quantities (serum concentrations and urinary excretion) and of derived pharmacokinetic parameters showed that for every comparison except maximum serum concentrations clindamycin-2-palmitate was not significantly different (at p=0.05) from clindamycin hydrochloride. Clindamycin-2-hexadecylcarbonate gave significantly different values from those for the hydrochloride in all cases except the rate constant and half-life for elimination from the serum. The palmitate was the superior ester and was bioequivalent to the hydrochloride in man.

Delta1-Hydrocortisone and hydrocortisone: plasma 17-hydroxycorticosteroid concentrations in the dog following oral and intravenous administration.

SummaryThe effects of orally and intravenously administered Δ1-hydrocortisone and hydrocortisone on plasma 17-OHCS concentrations in the dog have been studied. Δ1-Hydrocortisone produced higher and more prolonged plasma 17-OHCS elevations than did equivalent doses of hydrocortisone administered orally. The half-life of Δ1-hydrocortisone was found to be 1.37 times that of hydrocortisone. Intravenous administration of these steroids as the hemisuccinates gave lower but somewhat more prolonged elevations in plasma 17-OHCS concentrations than the corresponding free alcohols. It was concluded that Δ1-hydrocortisone was metabolized more slowly than hydrocortisone and suggested that this may explain, at least in part, the enhanced potency of the Δ1-steroid.Summary The effects of orally and intravenously administered Δ1-hydrocortisone and hydrocortisone on plasma 17-OHCS concentrations in the dog have been studied. Δ1-Hydrocortisone produced higher and more prolonged plasma 17-OHCS elevations than did equivalent doses of hydrocortisone administered orally. The half-life of Δ1-hydrocortisone was found to be 1.37 times that of hydrocortisone. Intravenous administration of these steroids as the hemisuccinates gave lower but somewhat more prolonged elevations in plasma 17-OHCS concentrations than the corresponding free alcohols. It was concluded that Δ1-hydrocortisone was metabolized more slowly than hydrocortisone and suggested that this may explain, at least in part, the enhanced potency of the Δ1-steroid.

Determination of metahexamide in human plasma.

Metahexamide [1-(3-amino-p-tolylsulfonyl)-3-cyclohexylurea] is a highly potent, orally active, antidiabetic agent belonging to the class of arylsulfonylureas. Correlation of plasma levels of metahexamide with reduction in blood sugar concentrations requires a suitable analytic procedure. Several methods have been reported previously for the determination of antidiabetic arylsulfonylureas. Spingler and Kaiser,l Forist et at?.: and Bladh and NordCn3 have described methods for the determination of tolbutamide (1-butyl-3-9-tolylsulfonylurea) based on the intense absorption by this compound a t 228 mp. The procedure of Toolan and Wagnel.4 for chlorpropamide [1-(p-chlorobenzenesulfonyl)-3-propylurea] similarly is based on ultraviolet spectroscopy. Visible spectrophotometric methods for tolbutamide determination have been reported by Spingler,6 by McDonald and Sawinski,6 and by Chulski? Carbutamide (1-butyl-3-sulfanilylurea) has been determined colorimetrically by diazotization of the aromatic amino group, followed by coupling with thiocol.8 Metahexamide also contains an aromatic amino group capable of diazotization and coupling. However, in this case the amino group is in the meta position relative to the sulfonamide group instead of the para position as is true in carbutamide and in the sulfa drugs. Moreover, in metahexamide a methyl group is also present ortho to the amino group. Because of these structural differences, the behavior of metahexamide in a modification of the Bratton-Marshall procedureg has been critically examined and is reported herein.

Pharmacokinetics of 4,5‐bis(p‐methoxyphenyl)‐2‐phenylpyrrole‐3‐acetonitrile in normal and polyarthritic rats

4,5-Bis(p-methoxyphenyl)-2-phenylpyrrole-3-aceton~trile (U-24,568, I) is a potent, orally-active anti-inflammatory agent in the adjuvant-induced polyarthritic rat (Kaiser & Glenn, 1972) and is more active than aspirin or ibuprofen in the treatment of rheumatoid arthritis, but also more toxic (Brooks, Schmid & others, 1970). Kaiser & Glenn (1972) developed a fluorometric method for the determination of I in biological materials and reported that: (a) plasma concentrations in the polyarthritic rat were linearly related to oral dose; (b) anti-inflammatory activity was linearly related to the logarithm of the average plasma concentration in a dosage interval at the equilibrium state; and (c) disappearance of I from circulation in normal rats was slow (half-life, -1 1.4 h).

Spectrophotometric Determination of Steroid Oximes

Abstract A spectrophotometric procedure for the determination of steroid oximes is described utilizing 11β-hydroxy-iia-methyl-5β-pregnane -3, 20 -dione dioxime (I) and iia-hydroxy-progesterone dioxime (II) as models. The method is based on (a) acid hydrolysis to release hydroxylamine, (b) oxidation of hydroxylamine to nitrous acid with iodine, (c) diazotization of sulfanilic acid with the nitrous acid, (d) coupling of the diazonium compound with N-(i-naphthyl)-ethylenediamine dihydrochloride, and (e) measurement of the azo dye at 550 nm. A stoichiometric yield of hydroxylamine is obtained. Analyses of I and II have given typical recoveries (mean ± S. D.) of 99.5 ± 1.1% and 97.8 + 3.5%, respectively. The method is sensitive to ≥ 0.3 × 10−5 M dioxime.

Infrared identification of paper chromatographed compounds. II. Procedures for some acidic compounds

The isolation and identification of individual organic compounds, such as drugs and their metabolites, in biological systems is usually complicated by the presence of small quantities of the desired material and overwhelming amounts of many extraneous substances. Yermentation beers and complex organic reaction mixtures may present a similar problem. Paper chromatography has proved to be an excellent tool for the separation of minute amounts of material in crude mixtures,’ and techniques for the resolution of a wide variety of mixtures containing difficultly separable, similar compounds have been developed. Biological samples, in particular, have been very effectively handled by paper chromatographic methods. Unfortunately, the separatory powers of paper chromatography have not been matched by the ability to positively identify or characterize the compounds isolated. Infrared spectroscopy, however, affords the most generally useful and exact, identification that any single measurement can provide. Recently the separation of compounds by paper chromatography, followed by infrared characterization of the isolated material has been studied and found to be a useful procedure.2-4 To date, m&hods involving elution of a chromatographed spot and infrared examination of the eluate have been limited to situations where the compound was reasonably soluble in an acceptable solvent,. It has been found t]hat a great many types of compounds cannot bc