From the Guidelines
Diphenoxylate is metabolized in the liver and its metabolism is not fully understood, but it is known to have a significant effect on the gut.
Metabolism Details
- The study 1 does not provide detailed information on the metabolism of Diphenoxylate, but it mentions that Loperamide, a peripherally acting opiate, is devoid of abuse potential due to extensive hepatic extraction and faecal excretion.
- Although the study does not directly discuss Diphenoxylate metabolism, it can be inferred that liver metabolism plays a crucial role in the metabolism of drugs that affect gut motility.
- Diphenoxylate is often used in combination with atropine, and its effects on the gut are significant, but the exact mechanism of its metabolism is not clearly stated in the provided study.
- It is essential to consider that Diphenoxylate has central effects and is habit-forming, which may be related to its metabolism and interaction with the body.
- The study 1 focuses more on Loperamide, which has a different metabolism profile, with extensive hepatic extraction and faecal excretion, making it less likely to have central effects.
From the FDA Drug Label
CLINICAL PHARMACOLOGY Diphenoxylate is rapidly and extensively metabolized in man by ester hydrolysis to diphenoxylic acid (difenoxine), which is biologically active and the major metabolite in the blood After a 5 mg oral dose of carbon-14 labeled diphenoxylate hydrochloride in ethanolic solution was given to three healthy volunteers, an average of 14% of the drug plus its metabolites was excreted in the urine and 49% in the feces over a 4-day period Urinary excretion of the unmetabolized drug constituted less than 1% of the dose, and diphenoxylic acid plus its glucuronide conjugate constituted about 6% of the dose.
The metabolism of Diphenoxylate is by ester hydrolysis to diphenoxylic acid (difenoxine), which is the major metabolite in the blood. The drug is extensively metabolized and the majority of the dose is excreted in the feces (49%) with a smaller amount excreted in the urine (14%) 2.
From the Research
Metabolism of Diphenoxylate
- The metabolism of diphenoxylate involves the cytochrome P450 (CYP) enzymes, specifically CYP2C19, CYP1A2, and CYP2C9, which are induced by continuous administration of diphenoxylate 3.
- This induction of drug metabolizing enzymes by diphenoxylate may reduce the efficacy of other drugs.
- High dosage of diphenoxylate may also cause hepatotoxicity 3.
Pharmacokinetics and Interactions
- Diphenoxylate has been shown to affect the plasma concentrations of other drugs, such as omeprazole, phenacetin, and tolbutamide, in rats 3.
- There is no correlation between the ingested dose of diphenoxylate and the severity of symptoms in cases of poisoning 4.
- Diphenoxylate does not decrease physiologic bowel FDG activity on PET/CT scans of the abdomen and pelvis 5.
Clinical Uses and Effects
- Diphenoxylate has a constipating effect, which has been demonstrated in a double-blind controlled trial in patients with ulcerative colitis 6.
- Diphenoxylate has been used to treat methadone withdrawal symptoms, providing substantial relief from detoxification symptoms with no drug-associated adverse effects 7.