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EXCRETION OF DRUGS A. RENAL EXCRETION MECHANISMS I. GLOMERULAR FILTRATION Examples of drugs eliminated by glomerular filtration: aminoglycosides, vancomycin, fluconazole General features: prerequisites, rate determinants of GF, maximal rate achievable by GF II. RENAL TUBULAR SECRETION Transporters for organic anions (acids): OAT1 MRP4/OA4; examples for competitive inhibition Transporters for organic cations (bases): OCT1 MATE1; examples for competitive inhibition Transporters for neutral compounds (e.g. digoxin): OATP MDR1; ex. for competitive inhibition III. RENAL TUBULAR REABSORPTION OF DRUGS Consequence: delayed elimination Mechanism: carrier-mediated transport (e.g. by PEPT) for some drugs; diffusion for most drugs Influencing factors of reabsorption by diffusion: 1. Chemical factors: a. Concentration in tubular fluid b. The degree of ionization - Alkalinization of tubular fluid decreases the tubular reabsorption of weak organic acids (e.g. salicylate, phenobarbital – alkalinization is used in intoxications) - Acidification of tubular fluid decreases the tubular reabsorption weak organic bases 2. Biological factors: urine flow rate B. BILIARY EXCRETION OF DRUGS I. CHOLEPHILIC COMPOUNDS: relatively large (mw >500Da) amphipatic molecules Cholephilic organic anions: endogenous comp., drugs containing a COOH group, drug conjugates Cholephilic organic cations: quaternary N-compounds, tertiary N-compounds II. MECHANISM OF BILIARY EXCRETION – mediated by transporters Sinusoidal uptake transporters for drugs: OATP, OCT Bile canalicular efflux transporters for drugs: MRP2, BCRP, MDR (Pgp) III. INTESTINAL REABSORPTION OF DRUGS – Enterohepatic circulation (EHC) Drugs undergoing EHC: glucuronides excreted in bile Consequence of EHC: delayed elimination Interruption of EHC: by adsorbents (cholestyramine, charcoal), inadvertently by antibiotics C. OTHER EXCRETORY ROUTES I. PULMONARY EXCRETION (EXHALATION) II. GASTROINTESTINAL EXCRETION Excretion into the stomach (amphetamine, PCP) – pH entrapment in gastric acid Excretion into the intestinal lumen - by transporters (MDR, MRP2) - by diffusion (extremely lipophilic chemicals) III. GLANDULAR EXCRETION Excretion into the milk: weak organic bases and extremely lipophilic chemicals A. RENAL EXCRETION MECHANISMS I. GLOMERULAR FILTRATION – is the mechanism for the elimination of: aminoglycosides, vancomycin, fluconazole, flucytosine, vigabatrin, gabapentin, topiramate, Li GENERAL FEATURES: Prerequisites for efficient filtration: 1. Water solubility 2. Low affinity to plasma proteins Rate determining factors: 1. Free drug concentration in plasma 2. Glomerular Filtration Rate Maximal renal clearance achievable: GFR (= ClKREATININE; only if PP-binding = 0, Reabs. = 0) II. TUBULAR SECRETION – mediated by transporters in the BLM and BBM Certainly involved if the renal clearance of a drug is > GFR (= ClKREATININE) Maximal renal clearance of a drug achievable is: RBF (= ClPAH) For organic anions (acids): BLOOD R-COOH-containing compounds: PAH, penicillins, cephalosporins, flurokinolones, NSAIDs, methotrexate ADP ATP + R-P(O)(OH)2-containing drugs: Cidofovir (against CMV) Acidic conjugates of drugs: Glucuronides: paracetamol-glucuronide Sulfate-conj: paracetamol-sulfate Glycine-conj: salicyl-glycine Urate + Na R-SO2NH2-containing drugs: Thiazides, furosemide URINE + K Na -KG2- OAT4 -KG2- OAOAT1 ATP MRP4 ADP -70 mV Competition at OAT1: Probenecid Penicillin or cidofovir; NSAID Methotrexate Consequence: Probenecid delays the excretion of penicillin and prevents the nephrotoxicity of cidofovir. For organic cations (bases): Quaternary N-containing drugs: tubocurarine, neostigmine BLOOD + + Na K URINE ADP ATP + Tertiary N-containing drugs: metformin, quinidine, quinine, procainamide, H2-rec. bl. (cimetidine, etc), amantadine, amiloride, triamteren, trimethoprim, ethambutol, pindolol Na + H + H OC+ OCT2 Competition: Trimethoprim or cimetidine Procainamide Pyrimethamine Metformin MATE1 -70 mV For organic neutral compounds: e.g. digoxin Competition at MDR1: Quinidine or verapamil Digoxin Consequence: The plasma concentration of digoxin increases with coadministration of quinidine or verapamil. BLOOD ADP ATP + Na + Na Cys GSH Digoxin OATP8 ATP ADP Another reason for increased digoxin plasma conc.: increased digoxin absorption from the gut by inhibition of the MDR1-mediated export of digoxin from the enterocytes back into the gut lumen by quinidine or verapamil. URINE + K -70 mV MDR1 (Pgp) III. RENAL TUBULAR REABSORPTION OF DRUGS Consequence: delayed elimination; examples: Plasma protein binding Glomerular filtration Tubular reabsorption Elimination T1/2 Gentamicin Fluconazole Little: 11% Freely MINIMAL: <2% 3 hrs Little: <10% Freely EXTENSIVE: 80% 30 hrs* *A second reason for slower elimination of fluconazol is its larger volume of distribution (0.6 L/kg) compared to that of gentamicin (0.3 L/kg) Another example: tubular reabsorption also slows the elimination of Li+ Li+ is freely filtered in the glomeruli, yet its renal clearance is only 10-40 ml/min, as Li+ is largely reabsorbed in the tubules. In Li+ intoxication we can speed up the elimination of Li+ by hemodialysis, as the hemodialysis clearance of Li+ is 70-170 ml/min. Mechanism: - For most drugs: diffusion - For some β-lactam antibiotics and ACE-inhibitors: PEPT-mediated Influencing factors of reabsorption by diffusion: 1. Chemical factors: a. Concentration in tubular fluid (increased by water reabsorption along the tubules) b. The degree of ionization Strong acids and strong bases are completely ionized → not reabsorbed - Acids: penicillins, drugs conjugated with glucuronic acid, sulfuric acid, or glycine - Bases: quaternary N-containing drugs, aminoglycoside antibiotics Weak acids and weak bases are partially ionized → reabsorbed - Acids: salicylates, phenobarbital: ionization can be increased by alkalinization (NaHCO3 infusion) → decreased reabsorption → increased urinary excretion (used in intox!) - Bases: amfetamine, ephedrine, phencyclidine (PCP), amantadine, tocainide: ionization can be increased by acidification (NH4Cl infusion) → decreased reabsorption → increased urinary excretion Note: Acidification would increase the urinary excretion of amphetamine and PCP, yet it is NOT used in amphetamine and PCP intoxication – see the next page for expl. 2. Biological factors: Tubular fluid flow rate, if high: it dilutes the drug in the tubular fluid + shortens the residence time in tubules → decreased reabsorption → increased urinary excretion Forced diuresis may be used in intoxications to increase urinary excretion of toxicants. However, it is rarely used because of the risks of volume depletion and electrolyte imbalance. Lower line: FORCED DIURESIS ALONE INCREASES THE CLEARANCE OF PHENOBARBITAL SLIGHTLY. Upper line: FORCED DIURESIS with Na-BICARBONATE INFUSION Phenobarbital clearance (ml/min) INCREASES THE CLEARANCE OF PHENOBARBITAL DRAMATICALLY. alkalinization of urine with NaHCO3 infusion 40 30 20 without NaHCO3 infusion 10 0 0 2 4 6 URINE FLOW (ml/min) Alkalinization of the tubular fluid decreases the renal tubular reabsorption (and in turn increases the urinary excretion) of weak organic acids that are at least partially excreted unchanged in urine. Such are phenobarbital and salicylic acid. Therefore, NaHCO3 infusion is a common therapeutic intervention in phenobarbital- or salicylateintoxicated patients. (Note: Aspirin is rapidly hydrolyzed to salicylic acid in the body.) Acidification of the tubular fluid, in contrast, is a procedure to decrease the renal tubular reabsorption and in turn to increase the urinary excretion of weak organic bases, such as amantadine, in intoxicated patients. This procedure, however, is not used if the organic base is convulsive, such as amphetamine and phencyclidine (PCP). In convulsion, muscle injury (rhabdomyolysis) may occur with myoglobinuria, and myoglobin is prone to precipitate in the acidic tubular fluid, causing renal failure. Note: Neither of these procedures is applicable to enhance the urinary excretion of drugs that are excreted only as metabolites (e.g. tricyclic antidepressants). These are not eliminated by excretion, but by biotransformation! B. BILIARY EXCRETION OF DRUGS I. Cholephilic compounds 1. General properties: - are relatively large molecules (m.w. >500 Da) - are amphipatic molecules Small m.w. organic acids (<500 D) are excreted by the kidneys into urine, Large m.w. amphipatic organic acids (>500 D) are transported into bile. Excreted by renal tubular secretion Excreted by hepatobiliary transport COOH O H2 C C CH2 CH3 N O CH 3 S CH3 N H Benzylpenicillin (Penicillin G) m.w. 334 O N O N N Cefoperazone m.w. 646 COOH O C O H HO C H C N H CH3 N CH 2 S N S HN O O C N COOH S N H N CH2 COOH Cl OH Salicyl-glycine (Salicyluric acid) m.w. 165 N Montelukast m.w. 586 H3C H3C CH3 2. Examples for Cholephilic organic anions Cholephilic organic cations Endogenous compounds: Bile acids (as taurine or glycine conjugates) Bilirubin (as mono- and diglucuronide) Steroid hormones (as glucuronides) Thyroxine (as glucuronide) Drugs containing COOH group: Some cephalosporins: cephoperazone, cephtriaxone Some ACE inhibitors: fosinopril, spirapril Others: statins, fexofenadine, montelukast, chromoglycate, cholecystographic contrast agents Drugs conjugated with - Glucuronic acid: digitoxin, ezetimibe, phenolphthalein, indomethacin, telmisartan carbamazepine, dapsone - Glutathione: sulfobromophthaleine (BSP) Quaternary N-containing drugs: Vecuronium Tertiary N-containing drugs: Rifampin, erythromycin, doxycycline, vincristine, vinblastine, cyclosporine II. Mechanism of biliary excretion – mediated by transporters MRP2 substrates may also be transported into bile by BCRP, another primary active transporter in the bile canalicular membrane of hepatocytes. The chemical property of the glucuronide formed in the liver determines which transporter exports it from the liver cell: MRP1 into blood, or MRP2 into bile. After formed in the liver, chloramphenicol glucuronide (mw 498) is transported into blood via MRP1 and MRP3 and then it is excreted into urine, whereas the larger ezetimibe glucuronide (mw 583; see elsewhere) and bilirubin diglucuronide (mw 934) are transported into the bile via MRP2. Chloramphenicol Chloramphenicol glucuronide (m.w. 498) OH O2N OH UDP-GT UDP-GA CH CH CH2 OH O 2N CH CH CH2 O NH O H 3C CH H N H3C CH2 CH HO H N CH2 CH2 CH2 CH2 CH2 C C O O C CHCl2 OH CH BLOOD URINE Bilirubin diglucuronide (m.w. 934) Bilirubin (not excreted) H N HO OH O Mrp1,3 O _ O C CHCl2 NH COO H N CH CH 3 CH H N H N CH2 H N CH UDP-GT UDP-GA CH3 H N O O CH2 H 3C _ H 3C CH2 CH OOC OH O O OH CH2 CH 2 CH2 CH2 C C O O CH 3 CH CH3 O COO O HO HO OH HO OH Mrp2 O BILE _ CH2 III. INTESTINAL REABSORPTION OF DRUGS Enterohepatic circulation (EHC) Drugs undergoing EHC: Typically, drugs that are excreted in bile as glucuronides (see above) undergo EHC. The intestinal microflora produces β-glucuronidase enzyme hydrolysis of the highly water-soluble glucoronide in the colon release of the relatively lipophilic aglycone reabsorption of the aglycone (i.e., the parent drug) into the portal blood Consequence of EHC: delayed elimination and prolonged action Examples: Dapsone BILE, as dapsone-N-glucuronide, T1/2 = 1 day Carbamazepine BILE, as carbamazepine-N-glucuronide, T1/2 = 1-3 days Digitoxin BILE, as digitoxigenin-monodigitoxoside-glucuronide, T1/2 = 7 days Note, that digitoxin is excreted into bile as the glucuronide via the canalicular MRP2 transporter, whereas digoxin is excreted unchanged into urine by tubular secretion via the luminal MDR1 transporter or Pgp (see above). Interruption of EHC (by preventing reabsorption): facilitates elimination of the drug by fecal excretion Intentional interruption of EHC: Aim: to promote elimination of a drug in drug overdose Method: by oral administration of non-absorbable adsorbents, such as - Cholestyramine: in digitoxin intoxication - Charcoal: in intoxications with - carbamazepine - dapsone Inadvertent interruption of EHC: May be caused by antibiotics that eradicate the colonic microflora. Consequence: decreased hydrolysis of the glucuronide by β-glucuronidase into the relatively lipophilic parent drug (aglycone) decreased reabsorption of the drug into the portal blood Example: Doxycyclin (DC) may cause contraceptive failure in women who take contraceptives containing estrogens (which are excreted into bile as glucuronides) Therapy with DC (a broad spectrum antibiotic) the number of colonic bacteria β-glucuronidase activity in the gut lumen hydrolysis of estrogen-glucuronides reabsorption of estrogens, increased fecal excretion Contraceptive failure and unwanted pregnancy C. OTHER EXCRETORY ROUTES I. PULMONARY EXCRETION (EXHALATION) Volatile compounds: - gases (N2O, toxic gases) - volatile liquids (inhalation anesthetics, solvents) Mechanism: diffusion, driven by the blood-alveolar partial pressure gradient delayed by high solubility in blood or tissues (e.g. N2O vs. halothane) II. GASTROINTESTINAL EXCRETION Excretion into the stomach: lipid-soluble weak organic bases Examples: amphetamine, phencyclidine (PCP), methadone Mechanism: diffusion from the blood into the stomach (HCl) protonation into positively charged cation, which cannot diffuse back to blood = “pH-entrapment” of the drug in the gastric acid Note: Drugs entrapped in the gastric acid can be reabsorbed from the intestinal tract, unless that is prevented by aspiration of the gastric juice. Aspiration of the gastric juice is a procedure used in amphetamine and PCP intoxication to increase elimination these drugs. Excretion into the intestinal lumen: 1. By carrier–mediated transport by transporters (exporters) in the BBM of enterocytes: - Substrates of P-gp = MDR1 (digoxin, vinca alkaloids, ivermectin, etc.) Export into the intestinal lumen by P-gp cause low bioavailability of the P-gp-substrate drugs when given orally, and may contribute to their elimination when given parenterally. - Substrates of MRP-2 (organic acids; significance still requires definition) 2. By diffusion: extremely lipophilic compounds (these are not drugs!) e.g. TCDD (dioxin): The intestinal excretion of TCDD is facilitated by an apolar non-absorbable substance in the gut lumen in which TCDD is dissolved and retained, such as olestra, a nonabsorbable fat-substitute used in chips. Olestra has been used to facilitate intestinal and fecal excretion of TCDD in humans intoxicated with dioxin. (The T1/2 of TCDD is 7 years; after prolonged oral treatment with olestra it decreased to 1.5 years.) + 3. By the K+ secretion mechanism in the colon: Tl (Thallium sulfate is a rodenticide.) Tl+ thus secreted can be trapped by Berliner blue – given orally in Tl-intoxication. Berliner blue = KFe[Fe(CN)6] = potassium-ferri-hexa-cyanoferrate (complexes K+ or Tl+ ions) Tl+ + KFe[Fe(CN)6] TlFe[Fe(CN)6] + K+ III. GLANDULAR EXCRETION Excretion by the mammary gland (via the milk): 1. Weak organic bases: by diffusion and pH-entrapment (milk pH=7.0, more acidic than plasma) e.g.: amphetamine, morphine, heroin These drugs may be transferred via the milk from the lactating mother into the suckling baby. 2. Extremely lipophilic compounds (not drugs): by diffusion and entrapment in milk fat e.g.: TCDD (dioxin) and polychlorinated biphenyls (PCBs) Contamination of the cow milk in grazing areas polluted with such extremely lipid-soluble environmental chemicals (e.g., PCBs) has occurred and it is still of concern.