Nicholas Gerber

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.

Acute Intoxication with 5,5-Diphenylhydantoin (Dilantin®) Associated with Impairment of Biotransformation: Plasma Levels and Urinary Metabolites; and Studies in Healthy Volunteers

Abstract The plasma levels of diphenylhydantoin in an intoxicated patient were measured and correlated with the clinical features. The patient became intoxicated on a usual therapeutic regimen of 3...

Excretion of valproic acid into semen of rabbits and man.

Dipropylacetic acid (VPA, valproic acid) has been quantified in plasma and semen from rabbits and man using a new gas‐liquid chromatographic assay. The drug assay is rapid, sensitive and free from interference by VPA metabolites. The β phase half‐life of VPA in rabbits after an i.v. dose (50 mg/kg) was 56 ± 6 min. The concentration of VPA in rabbit plasma was 17 to 30 times the concentration in rabbit semen. In man, 500 mg doses of the free acid, p.o., resulted in VPA concentrations in plasma that were 11 to 17 times the concurrent levels in semen. VPA, in concentrations up to 10‐3 M, did not influence the motility of rabbit spermatozoa in vitro.

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.

Separation of permethylated isomeric glucuronides by gas chromatography and analysis of the mass spectra.

Glucuronic acid conjugates of several foreign compounds (1- and 2-naphthols, 2-, 3-, and 4-hydroxybiphenyls, m- and p-hydroxyphenylphenylhydantoins) were produced in the isolated perfused rat liver and identified in the bile as the permethyl derivatives. Permethylated glucuronide isomers were easily separated by gas chromatography on SE-30 and OV-17 columns. The mass spectra of permethylated glucuronide isomers were very similar. Gas chromatography proved to be most useful for the separation and identification of isomeric glucuronides.

Metabolism of Methocarbamol (Robaxin) in the Isolated Perfused Rat Liver and Identification of Glueuronides

1. Permethylation and g.l.c.-mass spectrometric analysis of bile from an isolated rat liver perfusion to which methocarmol was added showed seven components not present in control bile: methocarbamol, glucuronides of methocarbamol and desmethyl-methocarbamol, and four glucuronides of hydroxylated methocarbamol metabolites. 2. An interesting rearrangement of a methyl group has been found in the mass spectrum of 3-(2-methoxyphenyloxy)-1,2-dimethoxypropane, the permethylation product from methocarbamol.