Transcript
0:00Bile and biliary excretion
Lesson 5.3 of our excretion module: bile and enterohepatic recycling. Metabolites are the products that enzymes make from a drug. Excretion is the removal of a drug and its metabolites from the body, mainly in urine and in bile. Bile is a fluid that liver cells make, and biliary excretion is the transport of a drug or its metabolites into bile. Bile flows from small ducts in the liver through the common bile duct into the duodenum, the first part of the small intestine. Transporters, proteins that carry drugs across cell membranes, affect how much of a drug enters bile. Polarity, the uneven spread of electric charge in a molecule, and molecular weight, the mass of the molecule, also affect this amount. Anions are molecules with a negative charge. In humans, anions are more likely to enter bile when their molecular weight is above about 475 daltons, the unit of molecular mass. Many drugs reach bile as conjugates.
1:21Conjugates
A conjugate forms when an enzyme joins a drug or metabolite to a polar group. For example, glucuronic acid, a sugar acid, gives a glucuronide, an anion about 176 daltons heavier than the drug. Conjugates cross cell membranes poorly, so transporters carry them. A drug goes through three steps from the blood into bile and back to the blood.
1:54Uptake into the hepatocyte
The first step is uptake into the hepatocyte, the liver cell that makes bile. A drug must cross two membranes of the hepatocyte, one on the blood side and one on the bile side. On the blood side, uptake transporters, for example the organic anion transporting polypeptides, OATPs, carry the drug into the cell. Inside the cell, enzymes can conjugate the drug.
2:28Transport into bile
The second step is transport into bile. The membrane on the bile side faces the bile canaliculus, a small channel between adjacent hepatocytes that drains into the bile ducts. Efflux transporters in this canalicular membrane carry the drug or its conjugate out of the cell into bile. Three efflux transporters carry most drugs and conjugates into bile: P-glycoprotein, multidrug resistance-associated protein 2, MRP2, and breast cancer resistance protein, BCRP. All three use energy from the cell for this transport. MRP2 carries anions such as glucuronides.
3:20Return to the blood
The third step is the return of the drug to the blood. Bile carries the drug or its conjugate into the intestine. There, gut bacteria can hydrolyze a conjugate back into the parent drug, the drug before conjugation. Hydrolysis is a reaction in which water splits a chemical bond. The intestine absorbs the parent drug again, and the portal vein carries it from the intestine to the liver.
3:54Enterohepatic recycling
This cycle of biliary excretion and intestinal reabsorption is enterohepatic recycling. Recycling returns the drug to the plasma, the liquid part of the blood. The half-life is the time for the plasma concentration to fall by half. Recycling can produce more than one peak and make the apparent half-life longer. Adsorbents, which bind the drug in the intestine, and other drugs, for example drugs that inhibit the efflux transporters, can interrupt the cycle. Disease and genes can also affect the cycle, because they can increase or decrease the activity of transporters and enzymes.
4:45Mycophenolate mofetil
Mycophenolate mofetil shows how recycling and a second drug change the plasma concentration over time. It is an immunosuppressant, a drug that reduces the immune response, for example against a transplanted organ. It is a prodrug, which the body converts to the active drug, mycophenolic acid, MPA. Esterases, enzymes in the intestinal wall, blood and liver, make this conversion. Enzymes called UDP-glucuronosyltransferases, UGTs, then conjugate MPA to its main glucuronide, MPAG, which is inactive. Both MPA and MPAG are anions. MPA has a molecular weight of about 320 daltons, and MPAG about 496, above the 475 dalton threshold. MRP2 then carries MPAG into bile. MPAG is the only form of the drug found in bile, so the cycle depends on bacteria in the colon, the large intestine. These bacteria convert MPAG back to MPA, and the colon absorbs MPA again. Plasma MPA peaks within 1 to 2 hours after a dose, and the reabsorbed MPA often gives a second peak at 6 to 12 hours. The AUC, the area under the plasma concentration-time curve, measures the total exposure to the drug. In a study with cholestyramine, an adsorbent, recycling gave about 40 percent of the MPA AUC, with a range of 10 to 60 percent. For MPA, bile is mainly a route of recycling. Over 90 percent of the dose leaves the body in urine, mostly as MPAG.
7:07Ciclosporin
Ciclosporin, another immunosuppressant used with mycophenolate mofetil, inhibits the transport of MPAG into bile by MRP2, so less MPA recycles. Changes in the excretion of MPAG in urine and in the binding of MPA to albumin, a plasma protein, can also contribute. With ciclosporin, the MPA AUC is about 30 to 40 percent lower than with mycophenolate mofetil alone or with tacrolimus, an immunosuppressant without this effect. In kidney transplant patients who stopped ciclosporin, the MPA AUC was 20 to 30 percent higher than in patients who continued low-dose ciclosporin. Patients who change from ciclosporin to tacrolimus can therefore have a higher MPA AUC.
8:13Summary
In summary, the hepatocyte takes up a drug and can conjugate it. Efflux transporters carry the drug or its conjugate into bile. Gut bacteria can convert a conjugate back to the parent drug, which the intestine absorbs again. Drugs, disease and genes that affect any of these steps can change the plasma concentration. For mycophenolate mofetil, recycling of MPA often gives a second peak and gave about 40 percent of the MPA AUC in one study. Ciclosporin inhibits MRP2 and lowers the MPA AUC. This concludes lesson 5.3 on bile and enterohepatic recycling.
Sources
- Esteller A. Physiology of bile secretion. World J Gastroenterol. 2008. PMID 18837079
- Tomaszewska O, Kaleczyc J. The distribution and chemical coding of neurons supplying the sphincter of Oddi in mammals. Pol J Vet Sci. 2013. PMID 24597319
- Chandra P, Brouwer KL. The complexities of hepatic drug transport: current knowledge and emerging concepts. Pharm Res. 2004. PMID 15180326
- Roberts MS, Magnusson BM, Burczynski FJ, et al. Enterohepatic circulation: physiological, pharmacokinetic and clinical implications. Clin Pharmacokinet. 2002. PMID 12162761
- Yang X, Gandhi YA, Duignan DB, et al. Prediction of biliary excretion in rats and humans using molecular weight and quantitative structure-pharmacokinetic relationships. AAPS J. 2009. PMID 19593675
- Järvinen E, Deng F, Kiander W, et al. The role of uptake and efflux transporters in the disposition of glucuronide and sulfate conjugates. Front Pharmacol. 2022. PMID 35095509
- Gissen P, Arias IM. Structural and functional hepatocyte polarity and liver disease. J Hepatol. 2015. PMID 26116792
- Gao Y, Shao J, Jiang Z, et al. Drug enterohepatic circulation and disposition: constituents of systems pharmacokinetics. Drug Discov Today. 2014. PMID 24295642
- Toutain PL, Bousquet-Mélou A. Plasma terminal half-life. J Vet Pharmacol Ther. 2004. PMID 15601438
- Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet. 2007. PMID 17201457
- Bullingham RE, Nicholls AJ, Kamm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet. 1998. PMID 9646007
- Kuypers DR, Ekberg H, Grinyó J, et al. Mycophenolic acid exposure after administration of mycophenolate mofetil in the presence and absence of cyclosporin in renal transplant recipients. Clin Pharmacokinet. 2009. PMID 19566116
- van Gelder T, Klupp J, Barten MJ, et al. Comparison of the effects of tacrolimus and cyclosporine on the pharmacokinetics of mycophenolic acid. Ther Drug Monit. 2001. PMID 11294511
Illustrations adapted from Servier Medical Art (smart.servier.com), CC BY 4.0. Structures drawn with RDKit.
