Excretion of Drugs:
It is the process by which drugs and their metabolites are irreversibly transferred from the body to external environment. Excretory organs excrete water soluble and ionized compounds more effectively than lipid soluble and unionized compounds. Drugs are excreted by following routes:
- Renal excretion of drugs:
- It is the most important route of drug excretion.
- Agents soluble in water, non-volatile and small in molecular size are excreted in the urine. Drugs are excreted from kidney in following 3 processes:
a. Glomerular filtration:
- It is non-selective and unidirectional process by which all non-protein bound drugs are filtered through glomerular membranes into the renal tubules.
- Protein bound drugs donot pass through filtrate because of their big size.
- Glomerular filtration of drug depends mainly on PPB and renal blood flow because hydrostatic pressure is the driving force in blood to pass through filtrate.
- If the glomerular filtration and renal blood flow decreased then, the excretion of drugs in urine gets decreased.
b. Tubular secretion:
- It is carrier-mediated process by which drugs and their metabolites are actively secreted from the blood into tubular lumen.
- Transportation is against concentration gradient and energy dependent.
- Two active tubular system have been identified for organic electrolyte drugs, one for acidic drugs and other for basic drugs.
- Both system is bidirectional, i.e. they can transport substrates from blood to tubular fluid and vice-versa.
- Most drugs and metabolites are excreted predominantly while endogenous substance like uric acid are predominantly absorbed.
c. Tubular reabsorption:
- It is a process by which drugs and their metabolites are transported from tubular fluid back into the capillary network.
- Reabsorption results in increase in half-lives of drugs.
- Lipid soluble and unionized drugs are passively reabsorbed after filtration.
- Endogenous substance or nutrients such as glucose, amino acids, etc. are reabsorbed through active tubular reabsorption.
- Biliary excretion:
- It is an important route of drug removal in which drugs and their metabolites are excreted by hepatocytes into bile canaliculi and ultimately into duodenum via bile.
- Greater the polarity, better the biliary excretion.
- Water-soluble conjugates are more excreted in bile than parent compound.
- Relatively large molecules are eliminated in bile.
- Glucuronide conjugation and glutathione conjugates are exclusively excreted via the bile.
- After biliary secretion, some of the conjugated metabolites, especially glucuronide conjugates are deconjugated by intestinal bacteria and the released lipid soluble drugs are reabsorbed into the circulation.
- The reabsorbed drugs are again carried to the liver for resecretion via bile into the intestine.
- The phenomenon of drug cycling between intestine and liver is called enterohepatic cycling or enterohepatic circulation of drugs.
- This process continues till the drug is further biotransformed in liver or excreted in urine, or both.
- The drugs which are excreted via bile in the intestine but donot undergo enterohepatic cycling are finally excreted in feces.
- Pulmonary excretion:
- Gases and volatile substances such as inhalation anaesthetics are absorbed and excreted through lungs by simple diffusion.
- Lipid soluble and unchanged drugs are excreted via lungs.
- Alcohols which have high solubility in blood and tissues are excreted slowly by the lungs.
- Rate of respiration, pulmonary blood flow, solubility of drugs, etc. influence pulmonary excretion of drugs.
- Mammary excretion:
- Most drugs enter milk by passive diffusion and are dependent upon lipid solubility, molecular weight, and degree of ionization.
- As milk is acidic than plasma, weakly basic drug concentrate more in milk.
- Some drugs excreted in milk can bind to milk proteins.
- Lipophilic drugs and toxicants may bind to milk fat and get excreted along with milk.
- Salivary excretion:
- It occurs primarily by passive diffusion process and therefore is predictable on the basis of pH-partition hypothesis.
- Drugs such as penicillin and phenytoin are actively excreted in saliva.
- Drugs excreted in saliva can undergo cycling similar to entero-hepatic cycling.
- Gastro-intestinal excretion:
- It usually occurs after parenteral administration of drugs.
- When the concentration gradient for passive diffusion is favorable, orally administered drugs can also be absorbed and then excreted in GI tract.
- Drugs excreted in GI tract may undergo recycling or excreted in feces.