Effect of Digestion on Distribution of Blood Flow in the Rat

Reininger, Edward J.; Sapirstein, Leo A.

doi:10.1126/science.126.3284.1176

Cited by 75 publications

(21 citation statements)

References 8 publications

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“…Patients with probable hemodynamic or pathologic alterations of the cardiovascular system were excluded. The fasting state was chosen as the most suitable standard for comparison rather than a nonlipid meal because both mixed and protein feeding have been associated with an elevation in cardiac output (5,6).…”

Section: Methodsmentioning

confidence: 99%

Myocardial Oxygen Consumption During Exercise in Fasting and Lipemic Subjects*

Regan¹,

Timmis²,

Gray³

et al. 1961

J. Clin. Invest.

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Section: Methodsmentioning

confidence: 99%

Myocardial Oxygen Consumption During Exercise in Fasting and Lipemic Subjects*

Regan¹,

Timmis²,

Gray³

et al. 1961

J. Clin. Invest.

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“…For the majority of drugs, transport to the systemic circulation occurs via the portal vein because the flow rate of portal blood is approximately 500-fold higher than that of mesenteric lymph (Bollman et al, 1948;Reininger and Sapirstein, 1957;Porter and Charman, 2001). However, significant lymphatic transport may occur when highly lipophilic drugs (log P Ͼ 5 and triglyceride (TG) solubility Ͼ50 mg/ml) are intercalated into lipid transport and lipoprotein formation processes in the enterocyte Stella, 1986b, 1992).…”

Section: Introductionmentioning

confidence: 99%

The Lymph Lipid Precursor Pool Is a Key Determinant of Intestinal Lymphatic Drug Transport

Trevaskis

Porter

Charman

2006

The Journal of Pharmacology and Experimental Therapeutics

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The influence of the size and turnover kinetics of the enterocyte-based lymph lipid precursor pool (LLPP) on intestinal lymphatic drug transport has been examined. Mesenteric lymph duct-cannulated rats were infused intraduodenally with low (2-5 mg/h) or high (20 mg/h) lipid-dose formulations containing 100 g/h halofantrine (Hf, a model drug) and 1 Ci/h 14 C-oleic acid (OA) (as a marker for lipid transport) until steady-state rates of lipid (dX L /dt) ss and drug (dD L /dt) ss transport in lymph were obtained. After 5 h, the infusion was changed to formulations of the same composition but excluding 14 C-OA and Hf, allowing calculation of the first order rate constants describing turnover of lipid (K X ) and drug (K D ) from the LLPP into the lymph from the washout kinetics. The mass of lipid (X LP ) and drug (D LP ) in the LLPP was also determined. Biliary-lipid output was determined in a separate group of rats that had been infused with the same formulations. The results indicate that after administration of high lipid doses, lymphatic drug transport is dependent on the mass of exogenous lipid available in the LLPP and the rate of lipid pool turnover into the lymph. In contrast, after administration of low lipid doses, biliary-derived endogenous lipids are most likely to be the primary drivers of drug incorporation into the LLPP and lymph. Therefore, the LLPP size and composition seem to be major determinants of lymphatic drug transport, and formulation components, which increase lipid pool size, may therefore enhance lymphatic drug transport.After oral administration, drugs are typically absorbed by the enterocytes lining the small intestine and are subsequently transported to the systemic circulation via the portal blood or mesenteric lymph. For the majority of drugs, transport to the systemic circulation occurs via the portal vein because the flow rate of portal blood is approximately 500-fold higher than that of mesenteric lymph (Bollman et al., 1948;Reininger and Sapirstein, 1957;Porter and Charman, 2001). However, significant lymphatic transport may occur when highly lipophilic drugs (log P Ͼ 5 and triglyceride (TG) solubility Ͼ50 mg/ml) are intercalated into lipid transport and lipoprotein formation processes in the enterocyte Stella, 1986b, 1992).Lymphatic lipid and drug transport are closely related, and historically, lymphatic drug transport was believed to be marginal except when lymph lipid flux was increased by the administration of relatively large quantities of lipid (such as that contained in a high-fat meal). However, a recent study in our laboratory has demonstrated that substantial lymphatic drug transport may occur after administration of small quantities of lipid (i.e., that contained in a single capsule formulation) to fasted greyhound dogs (Khoo et al., 2003). This study reported that administration of a small exogenous lipid dose led to an increase in endogenous fatty acid (FA) uptake into the enterocyte and transfer into lymph, thereby providing the necessary lipid flux to suppo...

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“…intracellularly, and only the fatty acid passed into the portal system. In the present experiments all the absorbed lipid could be accounted for as free fatty acid in the portal blood if the flow was assumed to be about 10 ml/min (31). Thus during bulk absorption of trioctanoin intramucosal lipolysis before portal transport was virtually complete.…”

Section: Examination Of the Distribution Of Lipid-'4cmentioning

confidence: 88%

Rate-limiting steps in steady-state intestinal absorption of trioctanoin-l-14C

Clark¹,

Holt²

1968

J. Clin. Invest.

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A B S T R A C T During continuous intraduodenal infusion of emulsified fat in rats, a steady state of intestinal absorption is achieved.Maximal steady-state absorption of trioctanoin, a medium-chain triglyceride (MCT), by unanesthetized, restrained rats was found to be the same after total bile diversion as in controls (1560 ,/moles of fatty acid per hr).After pancreatic and bile diversion, absorption of MCT was still one-third as rapid as in controls, and mucosal uptake apparently occurred in the form of unhydrolyzed triglyceride. Returning bile to the intestinal lumen during pancreatic diversion did not increase the absorption rate.From intestinal tissue lipid-14C concentrations measured during steady-state maximal absorption it was possible to calculate turnover times for labeled lipid passing through the mucosal cells. Mucosal turnover times of about 4 min for control and bile-diverted rats, and about 20 min for animals with pancreatic diversion were obtained.The rate-limiting step in octanoic acid absorption in control and bile-diverted rats was probably mucosal penetration. During absorption of unhydrolyzed triglyceride by pancreatic flow-diverted rats, both passage from the lumen into the mucosal cell and intracellular lipolysis were rate-controlling factors.This work was published in part as an abstract (1).

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Effect of Digestion on Distribution of Blood Flow in the Rat

Cited by 75 publications

References 8 publications

Myocardial Oxygen Consumption During Exercise in Fasting and Lipemic Subjects*

Myocardial Oxygen Consumption During Exercise in Fasting and Lipemic Subjects*

The Lymph Lipid Precursor Pool Is a Key Determinant of Intestinal Lymphatic Drug Transport

Rate-limiting steps in steady-state intestinal absorption of trioctanoin-l-14C

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