Diphenoxylic acid

Pharmacokinetics Bioavailability of tablet vs liquid is approximately 90%. Diphenoxylate is rapidly, extensively metabolized to diphenoxylic acid (difenoxine), the active major metabolite. Elimination half-life is approximately 12 to 14 hours. An average of 14% of drug and metabolites are excreted over 4 days in urine, 49% in feces. Urinary excretion of unmetabolized drug is less than 1% difenoxine plus its glucuronide conjugate constitutes approximately 6%. 

Lactation Diphenoxylic acid may be excreted in breast milk and atropine is excreted in breast milk. 

Pharmacokinetic properties The compound is readily absorbed from the gastrointestinal tract, but rapidly and extensively metabolized in the liver (Karim et al.,1972), which strongly reduces systemic and CNS availability. The main metabolite is the free diphenoxylic acid, which still has anti-diarrheal properties. Other inactive metabolites and their glucuronides are excreted in faeces. 

High Pressure Liquid Chromatography. System HA—diphenoxylate k 0.2, diphenoxylic acid k 0.6 (tailing peak). 

Gas Chromatography-Mass Spectrometry. In plasma diphenoxylic acid, sensitivity 20 ng/ml—G. C. Ford etal., Biomed. Mass Spectrom., 1976, 3,45-47. 

Disposition in the Body. Rapidly absorbed after oral administration but it is usually administered together with a small quantity of atropine and this may delay absorption, especially with high doses. It is extensively metabolised by hydrolysis, hydroxylation, and conjugation with glucuronic acid. The major metabolites are diphenoxylic acid (difenoxin), which is active, and hydroxy-diphenoxylic acid in both free and conjugated forms. About 14% and 50% of a dose, respectively, is excreted in the urine and faeces in 96 hours less than 0.1% of a dose is excreted in the urine as unchanged drug in 24 hours. 

After an oral dose of 5 mg, peak plasma concentrations of diphenoxylate of about 0.01 pg/ml were attained in 2 hours and peak concentrations of diphenoxylic acid of about 0.04 pg/ml were attained in the same period (A. Karim era/., Clin. Pharmac. Ther., 1972,13, 407-419). 

Half-life. Plasma half-life, diphenoxylate about 2.5 hours, diphenoxylic acid about 4 hours. 

Diphenmethanil methylsulphate, 556 Diphenoxylate, 558 Diphenoxylate hydrochloride, 558 Diphenoxylic acid, 559 Di-phenthane-70, 531 Diphenyl, 559... 

LS Jackson, et al. The evaluation and application of a radioimmunoassay for the measurement of diphenoxylic acid, the major metabolite of diphenoxylate hydrochloride (Lomotil), in human plasma. J Pharmacol Meth 18 189, 1987. 

Yes. Diphenoxylate is metabolized by the liver to diphenoxylic acid, which has therapeutic action. 

Carboxylesterases include cholinesterase (pseudocholinesterase), arylcarboxyesterases, liver microsomal carboxylesterases, and other unclassified liver carboxylesterases. Cholinesterase hydrolyzes oholihe-like esters (succinylcholine) and procaine as well as acetylsalicylic acid. Genetic variant forms of cholinesterase have beeh idehtified in human serum (e.g., succinylcholine toxicity when administered as ganglionic blocker for muscle relaxation). Meperidine is hydrolyzed only by liver microsomal carboxylesterases (Fig. 10.19). Diphenoxylate is hydrolyzed to its active metabolite, diphenoxylic acid, within 1 hour (Fig. 10.19). Presumably, the peripheral pharmacological action of diphenoxylate is attributed to zwitterionic diphenoxylic acid, which is readily eliminated in the urine. 

A Gas-Liquid Chromatographic Method for the Analysis of Diphenoxylic Acid in Urine... 

An Assay for Diphenoxylic Acid in Urine Using an Automated Gas Chromatograph Mass Spectrometer system Quant. Mass Spectrom. Life Sci. 2 287-293 (1978) CA 91 13346w... 

Cl has also been used for the quantitation of diphenoxylic acid (19) in human plasma following the administration of diphenoxylate (18), a drug used in the treatment of diarrhoea (21). The acid was analysed as the methyl ester derivative (20) using the i -analogue as the internal standard (22) (Fig. 8). In this case four ions were selected for monitoring. To compensate for instrument drift the ions at m/e 439.3, 439.4 for methyl diphenyloxalate and m/e 443.3 and 443.4 for the internal standard were chosen. Levels down to 20 ng/ml could be measured. The limit of detection of the gas chromatographic method, previously used... 

MASS FRAGMENTOGRAPHY IN DRUG RESEARCH to quantitate diphenoxylic acid, was 200 ng/ml. 

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