Robert K. Lynn

Clinical eftects and pharmacokinetics of racemic methadone and its optical isomers

The respiratory and pupillary effects of oral l‐, d‐, and d,l‐methadone were studied in healthy male volunteers 21 to 35 yr of age. The mean half‐life of drug in blood was 22 hr for racemic methadone, 24 hr for 1‐methadone, and 25 hr for d‐methadone. The effects of d‐methadone were not significantly different from the placebo response at a 7.5 mg dose, whereas a 50 and 100 mg dose slightly depressed respiration in one subject each. Both 7.5 mg of l‐methadone and 15 mg of d,l‐methadone induced intense and sustained respiratory depression and miosis. The changes induced by l‐methadone were of longer duration than those of d,l‐methadone, lasting more than 72 hr in some subjects. Whole blood drug concentration correlated weil with respiratory depression and miosis for 1‐ and d,l‐methadone. The potency ratio of l‐methadone to d,l‐methdone, calculated from blood drug concentration data, was found to be 3.0 for respiratory depression and 2.7 for miosis. The antiduretic effect of 15 mg of d,l‐methadone was investigated in three subjects and was found to persist for as long as measurements were taken, namely 11 and 12 hr in two subjects. d,l‐Methadone administeredfrequently for pain may have cumulative effects on respiratory control and ability to excrete a water load.

Metabolism of bisazobiphenyl dyes derived from benzidine, 3,3′-dimethylbenzidine or 3,3′-dimethoxybenzidine to carcinogenic aromatic amines in the dog and rat☆

A series of bisazobiphenyl dyes derived from benzidine, 3-3′-dimethylbenzidine or 3,3′-dimethoxybenzidine were studied in the dog and rat. The dyes, which are commercially useful in the textile and leather industries, possess potential for metabolism to the carcinogenic aromatic amines, benzidine, 3,3′-dimethylbenzidine and 3,3′-dimethoxybenzidine via metabolic reduction of the azo bonds. Dyes were administered orally and the urine analyzed for benzidine, 3,3′-dimethyl- or 3,3′-dimethoxybenzidine using a specific gas chromatographic assay. The identity of the chromatographic peaks was confirmed by gas chromatography-mass spectrometry. Dogs treated acutely (100 mg/kg) with benzidine derived dyes excreted substantial quantities of benzidine (166–1675 μg) in urine (0–48 hr). No benzidine was detected in urine prior to treatment. Benzidine present in dog urine following dye administration exceeded by at least ninefold the benzidine present as impurity in the administered dyes and was comparable to that excreted in urine when pure benzidine was fed (100 mg/kg). Rats chronically dosed (100 mg/kg/day) with benzidine-based dyes excreted N-acetylbenzidine (3–54 μg/day) and traces of benzidine in urine. Bisazobiphenyl dyes derived from 3,3′-dimethylbenzidine and 3,3′-dimethoxybenzidine were metabolized to 3,3′-dimethyl- and 3,3′-dimethoxybenzidine, respectively, in both the dog and rat. The N-acetyl derivatives of 3,3′-dimethyl- and 3,3′-dimethoxybenzidine were identified in urine from rats treated with dyes derived from 3,3′-dimethyl- and 3,3′-dimethoxybenzidine, respectively. Results from this study indicate that the metabolic conversion of bisazobiphenyl dyes, derived from benzidine and 3,3′-dimethyl- and 3,3′-dimethoxybenzidine, to carcinogenic aromatic amines is a general phenomenon and therefore with few exceptions should be anticipated for each member of this class of chemicals.

Excretion of methadone in semen from methadone addicts; Comparison with blood levels☆

Abstract The concentration of methadone was measured in the semen of seven methadone maintenance subjects and compared with the concentration of the drug in blood. The daily dose of methadone in these subjects ranged between 20 and 80 mg and was administered by mouth in the local methadone clinic in the usual manner. Samples of blood and semen were obtained from each subject one to four hours after dosage. The concentration of methadone in the blood ranged between 59 and 126 ng/ml in six of the volunteers. The concentration of methadone in semen ranged between 73 and 420 ng/ml in the seven subjects. The ratio of the concentration of the drug in semen to the concentration in blood ranged from 0.82 to 4.72. Methadone is excreted in small amounts in human semen and is transmitted from male to female during sexual intercourse.

New gas chromatographic assay for the quantification of methadone : Application in human and animal studies

Abstract A new gas chromatographic assay utilizing 2-dimethylamino-4,4-diphenyl-5-nonanone as the internal standard was developed for the quantification of methadone. The method involved extraction of methadone with 1-chlorobutane from tissue at pH 9.8, re-extraction of an aliquot of the organic solvent with 0.5 M sulphuric acid, alkalinization and final extraction into chloroform. The assay was used to determine the concentration of methadone (i) in whole blood samples from a normal volunteer following a single 9.4-mg oral dose of d -methadone hydrochloride, (ii) in whole blood, saliva and gastric juice from a methadone addict maintained on 90 mg of dl -methadone hydrochloride per day, (iii) in mouse liver microsomes incubated with methadone, and (iv) in the perfusate of the isolated perfused rat liver.

Anesthetic effects and elimination of tricaine methanesulphonate (MS-222) in terrestial vertebrates.

Abstract 1. Tricaine methanesulphonate is an effective ip anesthetic in a variety of terrestial poikilotherms. It is not a practical ip anesthetic in mammals or birds because of its extremely rapid metabolism in warm-blooded animals. 2. The anesthetic doses were similar in all poikilothermic species (150–250 mg/kg), however, mammals required at least a 6 fold increase in dose to produce a transient loss of the righting reflex. 3. The whole body concentrations of tricaine associated with return of the righting reflex were of the same order of magnitude in both warm- and cold-blooded vertebrates. 4. In 4 of 6 species tested, 90% or more of the eliminated tricaine was accounted for as MABA or its carboxylic conjugates.

A new N-glucuronide metabolite of carbamazepine.

An N-glucuronide metabolite of carbamazepine was identified in the bile of the isolated perfused rat liver by means of permethylation, gas chromatography and mass spectrometry.

Evidence for the Epoxide‐Diol Pathway in the Biotransformation of Mephenytoin

Summary: A dihydrodiol metabolite of mephenytoin (5‐dihydroxy‐cyclohexadienyl)‐5‐ethyl‐3‐methylhydantoin and other mono‐ and dihydrox‐ylated and N‐demethylated metabolites were identified in urine from a male epileptic patient receiving therapy with mephenytoin (300 mg/day). Metabolites, extracted from urine before and after enzymatic hydrolysis, were de‐rivatized with a trimethylsilyl reagent and analyzed by combined gas chromatography and mass spectrometry. Two previously unreported metabolites were characterized: 5‐ethyl‐5‐(di‐hydroxyphenyl)‐3‐methylhydantoin and 5‐ethyl‐5‐(hydroxy‐methoxy‐phenyO‐S‐methylhydantoin. The structures of several other metabolites were confirmed: N‐demethylmephenytoin, 5‐ethyl‐5‐hydroxyphenylhydantoin, 5‐ethyl‐5‐hydroxyphenyl‐3‐methylhydantoin and mephenytoin dihyrodiol. The dihydrodiol metabolite was of special interest since it was probably produced via an epoxide intermediate, 5‐(epoxy‐cyclohexadienyl)‐5‐ethyl‐3‐methylhydantoin. Previous reports have demonstrated that epoxides of this structural class are extremely reactive compounds, capable of alkylating biologic macromolecules. Covalent binding of the mephenytoin epoxide to macromolecules may be an important factor in the production of adverse and sometimes fatal side effects observed in patients receiving long‐term therapy with mephenytoin.

The metabolism of floctafenin in man and rodents.

Floctafenin (FFn), 2,3-dihydroxypropyl--N--(8--trifluoromethyl--4--quinolyl) anthranilate, a new nonnarcotic analgesic drug, was studied in man, mice, and the isolated perfused rat liver. In all species the drug is rapidly hydrolyzed to floctafenic acid (FFa). In seven volunteer subjects who each received a single oral dose of 400 mg floctafenin on an empty stomach, the blood concentration of FFa usually reached a maximum between 1 and 2 hours (mean 1.57 +/- 1.28 microgram/ml at 1.5 hours) and declined over the next 6 hours. Eight hours after drug administration the mean concentration of FFa in the blood of the volunteers was 0.1 +/- .05 microgram/ml. Approximately 25 per cent of the administered dose of floctafenin was recovered as FFa and hydroxy-FFa in the urine collected from each subject for 48 hours after drug administration. In mice each having received a single intraperitoneal dose of floctafenin (2 mg), the concentration of floctafenin declined by about 50 per cent in 15 minutes, and this decline was accompanied by a rise in the concentration of FFa that remained constant for 3 hours. The analgesic effect observed after administration of floctafenin to humans is likely to be mediated by its major metabolite, FFa. In these volunteers no free floctafenin was detected in the blood.