The urinary excretion of five C-monohydroxy metabolites and the N-oxide metabolite of methaqualone in the 24 h period immediately after oral dosing with 250 mg methaqualone (Melsed) has been measured in ninteen healthy adults (13 male, 6 female) to assess interindividual variations and in five adults (3 male, 2 female) on five separate occasions to assess intraindividual variation. The overall importance of the six metabolites was 4'-hydroxy greater than N-oxide greater than 2'-hydroxymethyl greater than 3'-hydroxy greater than 6-hydroxy = 2-hydroxymethyl. Variations in this order both within the 24 h period and within each of the three eight-hour periods constituting the 24 hours were minor and variations in the absolute amount of each metabolie excreted ranged from two to three-fold. Intraindividual variations were generally smaller than interindividual variations and for each individual the pattern of metabolism was similar on the five occasions. There is evidence that the C-oxidation of methaqualone may be more sensitive to cyclical variations in hormone levels than is N-oxidation.
1. Oral administration of therapeutic doses (250 mg) of methaqualone (Melsed) to adult human subjects gives rise to the urinary excretion of methaqualone-N-oxide. This metabolite has been identified by chromatography and mass spectrometry and quantitatively determined by reduction with titanium trichloride to methaqualone which was then determined by g.l.c. 2. The N-oxide accounts for 5-9% of the dose in 24 h. 3. 2-Nitrobenzo-o-toluidide, a possible oxidation product of methaqualone-N-oxide, has not been detected. 4. The urinary excretion of unchanged methaqualone is less than 0-3% of the dose. The ease with which methaqualone-N-oxide is thermally converted to methaqualone casts doubts on the previously published figures for the urinary excretion of methaqualone.
The urinary excretion of five C-monohydroxy metabolites and the N-oxide of methaqualone has been measured in a group of eleven geriatric patients aged 71--90 years. The total excretion of the six metabolites in 24 h after the oral administration of a single dose was approximately one-half of that in a group of young healthy adults. The relative importance of the six metabolites was 4'-hydroxy greater than N-oxide greater than 2'-hydroxymethyl = 3'-hydroxy greater than 6-hydroxy = 2-hydroxymethyl which was the same order as that in young adults. The ratio of C-to N-oxidation was also the same in the two groups. There was no impairment of conjugation of the C-hydroxy metabolites with glucuronic acid in the geriatric group but there was greater interindividual variation in metabolite excretion. There was also evidence for delayed metabolism in the geriatric patients.
1. Six monohydroxy metabolites of methaqualone have been identified by g.l.c.-mass spectrometry in the urine of healthy human subjects who received therapeutic doses (250 mg) of the drug (Melsed) daily for ten day. 2. The three major metabolites were 2-methyl-3-(2'-hydroxymethylphenyl)-4(3H)-quinazolinone, 2-methyl-3-(2'-methyl-3'-hydroxyphenyl)-4(3H)-quinazolinone and 2-methyl-3-(2'-methyl-4'-hydroxyphenyl)-4(3H)-quinazolinone. Three minor metabolites in descending order of importance were 2-hydroxymethyl-3-o-tolyl-4(3H)-quinazolinone, 2-methyl-6-hydroxy-3-o-tolyl-4(3H)-quinazolinone and 2-methyl-8-hydroxy-3-o-tolyl-4(3H)-quinazolinone. 3. The 8-hydroxy metabolite is identified as a urinary metabolite or methaqualone in humans for the first time.
The metabolism of methaqualone has been studied in three patients with secondary carcinoma of the liver and two with biliary cirrhosis. The urinary excretion of five C-monohydroxy metabolites and the N-oxide was studies in the 24 h period immediately after oral dosing with 250 mg methaqualone (Melsed). In both patients with biliary cirrhosis and one with primary carcinoma of the bile duct or pancreas with secondaries in the liver the pattern of metabolites was normal. In a patient with oat cell carcinoma with secondaries in the liver some metabolite patterns were disturbed and increased metabolite excretion occurred. A patient with primary carcinoma of the breast with secondaries in the liver gave a completely abnormal metabolite pattern.
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