Elimination of Drugs by Passive Diffusion from Blood to Intestinal Lumen: Factors Influencing Nonbiliary Excretion by the Intestinal Tract

Dayton, Peter G.; Israili, Zafar H.; Henderson, James D.

doi:10.3109/03602538308991427

Cited by 26 publications

(5 citation statements)

References 37 publications

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“…The mechanism of excretion depends on the chemical (33). A few earlier studies suggested that some xenobiotics, including HCB, may excrete into feces through direct transfer to the intestinal content by passive diffusion (46,57,58). However, in the present study, we detected persistent OCs in bile, which indicates that the hepatic excretory system still plays a major role in the elimination of xenobiotics in humans.…”

Section: Age-and Sex-dependent Accumulationcontrasting

confidence: 89%

Specific accumulation and elimination kinetics of tris(4-chlorophenyl)methane, tris(4-chlorophenyl)methanol, and other persistent organochlorines in humans from Japan.

Minh

Watanabe

Tanabe

et al. 2001

Environ Health Perspect

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We examined human adipose tissue, liver, and bile from humans in Japan to understand the contamination status, specific accumulation, and elimination of two newly identified environmental contaminants, tris(4-chlorophenyl)methane (TCPMe), tris(4-chlorophenyl)methanol (TCPMOH), and other persistent organochlorines such as polychlorinated biphenyls (PCBs), DDT and its metabolites (DDTs), hexachlorocyclohexane isomers (HCHs), hexachlorobenzene (HCB), and chlordane compounds (CHLs). TCPMe and TCPMOH concentrations in Japanese human adipose tissue were slightly higher than those reported previously, indicating widespread exposure to these compounds in humans. Elevated residues of PCBs and DDTs are found in adipose tissue and liver. Concentrations in bile strongly correlated with concentrations in adipose fat and liver, which may suggest an equilibration in adipose fat/bile and liver/bile and possible biliary excretion of persistent organochlorines in humans. Composition of the organochlorines accumulated further indicates a metabolic capacity in humans higher than that of marine mammals. We observed age-dependent accumulation for TCPMe, TCPMOH, and other organochlorines, but there were no significant gender differences. p,p'-DDE and TCPMe were estimated to have low biliary excretion rate. Elimination potential of persistent organochlorines may be related to their octanol-water partition coefficient. The relationship between excretion rate and octanol-water partition coefficient may be used to predict the biliary excretion potential of some other lipophilic organochlorines such as dioxins and dibenzofurans in humans. The presence of organochlorines in bile suggests that the hepatic excretory system plays a major role in the elimination of xenobiotics in humans. To our knowledge, this is the first study of accumulation and elimination of TCPMe and TCPMOH in humans.

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Section: Age-and Sex-dependent Accumulationcontrasting

confidence: 89%

Specific accumulation and elimination kinetics of tris(4-chlorophenyl)methane, tris(4-chlorophenyl)methanol, and other persistent organochlorines in humans from Japan.

Minh

Watanabe

Tanabe

et al. 2001

Environ Health Perspect

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“…The subject of IE was reviewed three decades ago when there was little understanding of drug transporters, and again in 1998 when the breast cancer resistance protein (BCRP) was discovered. − Although studies have been reported to assess IE of selected drugs for the substrates of P-glycoprotein (P-gp), BCRP, and multidrug resistance-associated protein (MRP) 2, mostly in the context of drug absorption, IE has not been widely considered as a disposition mechanism. − …”

Section: Introductionmentioning

confidence: 99%

Intestinal Excretion, Intestinal Recirculation, and Renal Tubule Reabsorption Are Underappreciated Mechanisms That Drive the Distribution and Pharmacokinetic Behavior of Small Molecule Drugs

Zhang¹,

Wei

Hop³

et al. 2021

J. Med. Chem.

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Drug reabsorption following biliary excretion is well-known as enterohepatic recirculation (EHR). Renal tubular reabsorption (RTR) following renal excretion is also common but not easily assessed. Intestinal excretion (IE) and enteroenteric recirculation (EER) have not been recognized as common disposition mechanisms for metabolically stable and permeable drugs. IE and intestinal reabsorption (IR:EHR/EER), as well as RTR, are governed by dug concentration gradients, passive diffusion, active transport, and metabolism, and together they markedly impact disposition and pharmacokinetics (PK) of small molecule drugs. Disruption of IE, IR, or RTR through applications of active charcoal (AC), transporter knockout (KO), and transporter inhibitors can lead to changes in PK parameters. The impacts of intestinal and renal reabsorption on PK are under-appreciated. Although IE and EER/RTR can be an intrinsic drug property, there is no apparent strategy to optimize compounds based on this property. This review seeks to improve understanding and applications of IE, IR, and RTR mechanisms.

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“…When a drug is administered parenterally, the route by which it is distributed to the large intestine is thought to be biliary and intestinal excretion. Recently, intestinal excretion has become a well-recognized phenomenon (3,4,7,13,22). However, little is known about the pharmacokinetics of injectable drugs for swine dysentery in relation to efficacy.…”

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confidence: 99%

Role of intestinal excretion in the effect of subcutaneously administered sedecamycin on cecal infection caused by Treponema hyodysenteriae in mice

Hayashi

Okada

Kondo

et al. 1991

Antimicrob Agents Chemother

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The therapeutic effects of subcutaneously administered sedecamycin on experimental Treponema hyodysenteriae infection in mice were evaluated. Sedecamycin was more active than tiamulin and lincomycin. The efficacy of sedecamycin upon subcutaneous administration was similar to that upon oral administration. Sedecamycin given subcutaneously provided similar degrees of protection in bile duct-ligated and intact mice. Pharmacokinetic studies utilizing a liquid chromatographic technique were carried out to determine the concentration of sedecamycin in the cecum, the site of T. hyodysenteriae infection in mice. Little sedecamycin was found; however, lankacidinol, a major metabolite of sedecamycin, was found in the cecal contents of intact mice after subcutaneous or oral administration of sedecamycin. Lankacidinol was also found in the cecal contents of bile duct-ligated mice, although the concentration found after subcutaneous administration of sedecamycin was much lower than that found after subcutaneous or oral administration to intact mice. These results indicate that sedecamycin is excreted directly into the intestinal tract as an active metabolite by a route other than the bile duct. It is suggested that this intestinal excretion plays an important role in the efficacy of subcutaneously administered sedecamycin against cecal infection of mice by T. hyodysenteriae.Treponema hyodysenteriae, the etiologic agent of swine dysentery, is characterized by mucohemorragic diarrhea (9,25). In general, severely infected animals are reluctant to consume the medicated feed. In such cases, parenteral administration of effective drugs, lincomycin (8) and tiamulin (1, 2), is used for treatment. Swine dysentery is infection with T. hyodysenteriae in the large intestine (5, 10); therefore, a sufficient amount of a drug must be distributed to the large intestine. When a drug is administered parenterally, the route by which it is distributed to the large intestine is thought to be biliary and intestinal excretion. Recently, intestinal excretion has become a well-recognized phenomenon (3,4,7,13,22). However, little is known about the pharmacokinetics of injectable drugs for swine dysentery in relation to efficacy.Experimental infection of mice and rabbits with T. hyodysenteriae had failed until Joens and Glock (14) reported that CF1 mice inoculated with T. hyodysenteriae for 2 consecutive days after a 72 h of fasting developed cecal and colonic lesions. Later, Suenaga and Yamazaki (24) reported that they examined mouse strains and found that Ta:CF#1 mice developed gross cecal lesions after a single oral administration of T. hyodysenteriae without fasting. By using this animal model, we have shown that orally administered sedecamycin, a 17-member macrocyclic antibiotic ( Fig. 1), shows good efficacy in mice (11).The objective of this study was to evaluate the efficacy of subcutaneous administration of sedecamycin against experimental infection of mice with T. hyodysenteriae and to explain the mechanisms of the efficacy by the concentra...

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Elimination of Drugs by Passive Diffusion from Blood to Intestinal Lumen: Factors Influencing Nonbiliary Excretion by the Intestinal Tract

Cited by 26 publications

References 37 publications

Specific accumulation and elimination kinetics of tris(4-chlorophenyl)methane, tris(4-chlorophenyl)methanol, and other persistent organochlorines in humans from Japan.

Specific accumulation and elimination kinetics of tris(4-chlorophenyl)methane, tris(4-chlorophenyl)methanol, and other persistent organochlorines in humans from Japan.

Intestinal Excretion, Intestinal Recirculation, and Renal Tubule Reabsorption Are Underappreciated Mechanisms That Drive the Distribution and Pharmacokinetic Behavior of Small Molecule Drugs

Role of intestinal excretion in the effect of subcutaneously administered sedecamycin on cecal infection caused by Treponema hyodysenteriae in mice

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