On the Mechanism of Absorption of Drugs from the Gastrointestinal Tract

Schanker, Lewis S.

doi:10.1021/jm50011a001

Cited by 128 publications

(34 citation statements)

References 6 publications

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“…Studies of drug absorption have shown that lipid-soluble, unionized molecules readily penetrate the intestinal epithelium (see Schanker 1960), and it has been suggested that there is an optimal partition coefficient (octanol/buffer) for intestinal absorption of xenobiotics (Houston, Upshall and Bridges 1974).…”

Section: Lipid-solubility and Intestinal Absorption During Enterohepamentioning

confidence: 99%

Enterohepatic recycling of phenolphthalein, morphine, lysergic acid diethylamide (LSD) and diphenylacetic acid in the rat Hydrolysis of glucuronic acid conjugates in the gut lumen

1980

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1. Biliary elimination in female Wistar albino rats 3 h after i.p. injection of [3H]phenolphthalein, [3H]morphine, 14C-LSD and [14C]diphenylacetic acid was 90%, 45%, 75% and 57% respectively, predominantly as glucuronides. 2. Infusion of 3 h bile from the previous experiments into the duodena of bile-duct-cannulated animals demonstrated enterohepatic circulation, amounting in 24 h to 85%, 41%, 28% and 66% of the infused doses of the conjugates of phenolphthalein, morphine, LSD and diphenylacetic acid respectively. 3. Pretreatment with antibiotics to suppress intestinal microflora decreased this enterohepatic recirculation to 22%, 8.6% and 21% in 24 h for phenolphthalein, morphine and diphenylacetic acid glucuronides respectively. Antibiotic pretreatment did not influence the absorption and re-excretion of infused doses of the free aglycones, thus demonstrating the importance of bacterial beta-glucuronidase hydrolysis of the biliary conjugates. 4. The extent of intestinal absorption of the aglycones after bacterial beta-glucuronidase hydrolysis of the conjugates is related to their lipid-solubility as estimated by octan-1-ol:0.1 M phosphate buffer partition ratios (P-values). 5. The persistence of compounds in the enterohepatic circulation is determined by the faecal and urinary elimination of the circulating compounds. Faecal elimination is governed by the extent of intestinal absorption of the circulating compounds, which is influenced by the efficacy of intestinal hydrolysis of the conjugates and the relative lipophilicity of the aglycones released.

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Section: Lipid-solubility and Intestinal Absorption During Enterohepamentioning

confidence: 99%

Enterohepatic recycling of phenolphthalein, morphine, lysergic acid diethylamide (LSD) and diphenylacetic acid in the rat Hydrolysis of glucuronic acid conjugates in the gut lumen

1980

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“…Although phosphanilic acid (pK., 1.8 to 2) (3) readily redissolved when the pH was raised from 1.2 to 6.2, it would exist primarily in the ionized form (99.99%) in the intestine at pH 6 to 8. Therefore, the lack of oral absorption was also related to low membrane permeability as a result of extensive in situ ionization at the site of absorption (11). The prolongation in Tmax could be indicative of diffusion-limited absorption of the ionized species from the subcutaneous site and dissolution-limited absorption of precipitated free acid in the gastrointestinal tract at the highest dose level studied.…”

Section: Resultsmentioning

confidence: 95%

Bioavailability and Metabolism of Potassium Phosphanilate in Laboratory Animals and Humans

Lee¹,

Harken²,

Vasiljev³

et al. 1980

Antimicrob Agents Chemother

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Phosphanilic acid is an antibacterial agent with a mode of action and antibacterial spectrum similar to those of sulfamethoxazole, with the exception that it has potent antipseudomonal activity. Bioavailability studies in rats (50, 300, and 600 mg/kg, oral and subcutaneous), dogs (50, 150, and 450 mg/kg, oral and intravenous infusion), and humans (400 and 800 mg, oral) showed that the extent of oral absorption of potassium phosphanilate was low. The bioavailability, calculated by comparing the oral values for area under the plasma concentration curve with those for the respective parenteral doses, was 10% for rats and 45 (50 and 150 mg/kg) and 19% (450 mg/kg) for dogs. The 24-h urinary recovery also confirmed the low oral bioavailability, i.e., rat, 13 (oral) and 75% (subcutaneous); dog, 15 to 29 (oral) and 87% (intravenous) of the dose. Plasma levels and urinary recovery (4%, oral) were low and variable in humans. The poor absorption of oral doses may be due to drug precipitation in the stomach, low permeability of the soluble species due to extensive in situ ionization (pKa, 1.8 to 2) in the intestine, or first-pass metabolism to N-acetylphosphanilic acid. The plasma t1/2 values after parenteral administration were 0.3 h in rats and 1.3 h in dogs. Although the lack of adequate blood levels of phosphanilic acid after oral administration in humans precludes the use of this compound for treatment of systemic infections, the sustained urinary concentration at levels severalfold higher than the minimal inhibitory concentration (1 ,ug/ml) for at least 10 h postdose was indicative of the therapeutic usefulness in urinary tract infections.

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“…The absorption of PEA from the jejunum appears to be a passively mediated process, which is influenced by blood flow. The order of PEA absorption rates from the different gut regions (colon > ileum > jejunum) can be explained in terms of the pH partition hypothesis (Schanker 1960). PEA has a pK, of 9-83 (Hong & Connors 1968) and the proportion of nonionized drug will therefore increase with the increase in pH from jejunum to ileum to colon.…”

Section: Discussionmentioning

confidence: 99%

Intestinal contribution to the presystemic elimination of β-phenethylamine in the rat

Worland

Ilett

1983

Journal of Pharmacy and Pharmacology

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The metabolism of beta-phenethylamine (PEA) has been investigated in intestinal, liver and lung homogenates from the rat. Metabolic activity was ranked liver much greater than lung much greater than duodenum greater than jejunum greater than ileum greater than colon. Absorption and metabolism of PEA was also studied using in-situ intestinal loops from rats. Absorption of PEA appeared to be a passively mediated process with metabolism occurring in jejunum, ileum and colon. When isolated loops of jejunum were used, phenylacetic acid was the only metabolite formed. Presystemic elimination of PEA in anaesthetized rats, was largely attributable to the intestine and lung with a relatively small hepatic contribution.

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On the Mechanism of Absorption of Drugs from the Gastrointestinal Tract

Cited by 128 publications

References 6 publications

Enterohepatic recycling of phenolphthalein, morphine, lysergic acid diethylamide (LSD) and diphenylacetic acid in the rat Hydrolysis of glucuronic acid conjugates in the gut lumen

Enterohepatic recycling of phenolphthalein, morphine, lysergic acid diethylamide (LSD) and diphenylacetic acid in the rat Hydrolysis of glucuronic acid conjugates in the gut lumen

Bioavailability and Metabolism of Potassium Phosphanilate in Laboratory Animals and Humans

Intestinal contribution to the presystemic elimination of β-phenethylamine in the rat

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