Non-Renal Routes of Drug Excretion

NON-RENAL ROUTES OF DRUG EXCRETION

Drugs and their metabolites may also be excreted by routes other than the renal route, called as the extrarenal or nonrenal routes of drug excretion. The various such excretion processes are:

1. Biliary excretion

2. Pulmonary excretion

3. Salivary excretion

4. Mammary excretion

5. Skin/dermal excretion

6. Gastrointestinal excretion

7. Genital excretion

1. Biliary Excretion of Drugs-Enterohepatic Cycling

The hepatic cells lining the bile canaliculi produce bile. The production and secretion of bile are active processes. The bile secreted from liver, after storage in the gall bladder, is secreted in the duodenum. In humans, the bile flow rate is a steady 0.5 to 1 ml/min. Bile is important in the digestion and absorption of fats. Almost 90% of the secreted bile acids are reabsorbed from the intestine and transported back to the liver for re-secretion. The rest is excreted in faeces.

Being an active process, bile secretion is capacity-limited and subject to saturation. The process is exactly analogous to active renal secretion. Different transport mechanisms exist for the secretion of organic anions, cations and neutral polar compounds. A drug, whose biliary concentration is less than that in plasma, has a small biliary clearance and vice versa. In some instances, the bile to plasma concentration ratio of drug can approach 1000 in which cases, the biliary clearance can be as high as 500 ml/min or more.

Compounds that are excreted in bile have been classified into 3 categories on the basis of their bile/plasma concentration ratios:

Group A compounds whose ratio is approximately 1, e.g. sodium, potassium and chloride ions and glucose.

Group B compounds whose ratio is >1, usually from 10 to 1000, e.g. bile salts, bilirubin glucuronide, creatinine, sulphobromophthalein conjugates, etc.

Group C compounds with ratio < 1, e.g. sucrose, inulin, phosphates, phospholipids and mucoproteins.

Drugs can fall in any of the above three categories.

Several factors influence secretion of drugs in bile –

1. Physicochemical Properties of the Drug

The most important factor governing the excretion of drugs in bile is their molecular weight. Its influence on biliary excretion is summarized in the Table 6.3.

Polarity is the other physicochemical property of drug influencing biliary excretion. Greater the polarity, better the excretion. Thus, metabolites are more excreted in bile than the parent drugs because of their increased polarity. The molecular weight threshold for biliary excretion of drugs is also dependent upon its polarity. A threshold of 300 Daltons and greater than 300 Daltons is necessary for organic cations (e.g. quaternaries) and organic anions respectively. Nonionic compounds should also be highly polar for biliary excretion, e.g. cardiac glycosides.

TABLE 6.3

Influence of Molecular Weight on Excretion Behaviour of Drugs

2. Nature of Biotransformation Process

A metabolic reaction that greatly increases the polarity as well as the molecular weight of drug favours biliary excretion of the metabolite. Thus, phase II reactions, mainly glucuronidation and conjugation with glutathione, result in metabolites with increased tendency for biliary excretion (increase the molecular weight by 176 and 300 Daltons respectively). Examples of drugs excreted in the bile as glucuronides are morphine, chloramphenicol and indomethacin. Stilbestrol glucuronide is almost entirely excreted in bile. Glutathione conjugates are exclusively excreted via bile and are not observable in the urine because of their large molecular size. Conjugation with amino acids and acetylation and methylation reactions do not result in metabolites with greatly increased molecular weight and therefore have little influence on biliary excretion of xenobiotics. For a drug to be excreted unchanged in the bile, it must have a highly polar functional group such as - COOH (cromoglycic acid), -SO₃H (amaranth), -NH₄⁺ (oxyphenonium), etc. Clomiphene citrate, an ovulation inducer, is almost completely removed from the body via biliary excretion.

3. Other Factors

Miscellaneous factors influencing biliary excretion of drugs include sex and species differences, protein-drug binding, disease states, drug interactions, etc.

Substances having high molecular weight show good excretion in bile in case of rats, dogs, and hen and poor excretion in rabbits, guinea pigs and monkeys. The route is more important for the excretion of drugs in laboratory animals than in man. Protein bound drugs can also be excreted in the bile since the secretion is an active process. In cholestasis, the bile flow rate is reduced thereby decreasing biliary excretion of drugs. Agents such as phenobarbital stimulate biliary excretion of drugs, firstly, by enhancing the rate of glucuronidation, and secondly, by promoting bile flow. The route of drug administration also influences biliary drug excretion. Orally administered drugs which during absorption process go to the liver, are excreted more in bile in comparison to parenterally administered drugs. Food also has a direct influence on biliary excretion of drugs. Protein and fat rich food increase bile flow.

The efficacy of drug excretion by the biliary system and hepatic function can be tested by an agent that is exclusively and completely eliminated unchanged in the bile, e.g. sulphobromophthalein. This marker is excreted within half an hour in the intestine when the hepatic function is normal. A delay in its excretion is indicative of hepatic and biliary malfunction. The marker is also useful in determining hepatic blood flow rate.

The ability of liver to excrete the drug in the bile is expressed by biliary clearance (equation 6.24).

Biliary clearance = Biliary clearance rate / Plasma drug concentration (6.24a)

= ( Bile flow x Biliary drug clearance ) / Plasma drug concentration (6.24b)

Just as the major portion of bile salts excreted in intestine is reabsorbed, several drugs which are excreted unchanged in bile are also absorbed back into the circulation. Some drugs which are excreted as glucuronides or as glutathione conjugates are hydrolysed by the intestinal or bacterial enzymes to the parent drugs which are then reabsorbed. The reabsorbed drugs are again carried to the liver for resecretion via bile into the intestine. This phenomenon of drug cycling between the intestine and the liver is called as enterohepatic cycling or enterohepatic circulation of drugs (Fig. 6.5.).

Fig. 6.5. Enterohepatic cycling of drugs

Such a recycling process continues until the drug is biotransformed in the liver or is excreted in the urine or both. The drugs which are secreted via bile in the intestine but not reabsorbed, are finally excreted in the faeces.

Enterohepatic circulation is important in the conservation of important endogenous substances such as vitamin B₁₂, vitamin D₃, folic acid, several steroid hormones and bile salts. The process results in prolongation of half-lives of several drugs (e.g. carbenoxolone) which are extensively excreted in bile. The half-life of agents such as DDT, which are resistant to biotransformation and are highly lipophilic, may increase to several days due to such a recycling phenomenon. The prolonged therapeutic activity of oral contraceptives (upto 12 hours) is also due to such a recirculation. Other examples of drugs undergoing enterohepatic circulation are cardiac glycosides, rifampicin, chlorpromazine and indomethacin. Drug interactions affecting enterohepatic cycling occur when agents such as antibiotics kill the intestinal microflora and thus retard hydrolysis of drug conjugates and their subsequent reabsorption, or the unabsorbable ion exchange resins such as cholestyramine which bind strongly to the acidic and neutral drugs (e.g. digitoxin) and thus prevent their reabsorption. The principle of adsorption onto the resins in the GIT can however be used to treat pesticide poisoning by promoting their faecal excretion.

Biliary excretion of drugs can be assessed by giving the drugs parenterally and detecting their presence in faeces. This also rules out the doubt about the incomplete absorption of such drugs when given orally and observed in faeces.

2. Pulmonary Excretion

Gaseous and volatile substances such as the general anaesthetics (e.g. halothane) are absorbed through the lungs by simple diffusion. Similarly, their excretion by diffusion into the expired air is possible. Factors influencing pulmonary excretion of a drug include pulmonary blood flow, rate of respiration, solubility of the volatile substance, etc. Gaseous anaesthetics such as nitrous oxide which are not very soluble in blood are excreted rapidly. Generally intact gaseous drugs are excreted but metabolites are not. Compounds like alcohol which have high solubility in blood and tissues are excreted slowly by the lungs. The principle involved in the pulmonary excretion of benzene and halobenzenes is analogous to that of steam distillation.

3. Salivary Excretion

Excretion of drugs in saliva is also a passive diffusion process and therefore predictable on the basis of pH-partition hypothesis. The pH of saliva varies from 5.8 to 8.4. The mean salivary pH in man is 6.4. Unionised, lipid soluble drugs at this pH are excreted passively in the saliva. Equations analogous to 6.3, 6.5, 6.6 and 6.7 can be written for drugs with known pK_a at the salivary pH and percent ionisation and saliva/plasma drug concentration ratio (S/P) can be computed.

for weak acids,

for weak bases,

where, f_plasma and f_saliva are free drug fractions in plasma and in saliva respectively.

The S/P ratios have been found to be less than 1 for weak acids and greater than 1 for weak bases i.e. basic drugs are excreted more in saliva as compared to acidic drugs. The salivary concentration of some drugs reaches as high as 0.1%. Since the S/P ratio is fairly constant for several drugs, their blood concentration can be determined by detecting the amount of drug excreted in saliva, e.g. caffeine, theophylline, phenytoin, carbamazepine, etc. Some drugs are actively secreted in saliva, e.g. lithium, the concentration of which is sometimes 2 to 3 times that in plasma. Penicillin and phenytoin are also actively secreted in saliva.

Fig. 6.6. Salivary cycling of drugs

The bitter after taste in the mouth of a patient on medication is an indication of drug excretion in saliva. In few instances, the process is responsible for side effects such as black  hairy tongue in patients receiving antibiotics, gingival hyperplasia due to phenytoin, etc.

Some basic drugs inhibit saliva secretion and are responsible for dryness of mouth.

Drugs excreted in saliva can undergo cycling in a fashion similar to enterohepatic cycling, e.g. sulphonamides, antibiotics, clonidine, etc. (Fig. 6.6.).

4. Mammary Excretion

Excretion of a drug in milk is important since it can gain entry into the breast-feeding infant.

Milk consists of lactic secretions originating from the extracellular fluid and is rich in fats and proteins. About 0.5 to 1 litre/day of milk is secreted in lactating mothers

Excretion of drugs in milk is a passive process and is dependent upon pH-partition behaviour, molecular weight, lipid solubility and degree of ionisation. The pH of milk varies from 6.4 to 7.6 with a mean pH of 7.0. Free, unionised, lipid soluble drugs diffuse into the mammary alveolar cells passively. The extent of drug excretion in milk can be determined from milk/plasma drug concentration ratio (M/P). Since milk is acidic in comparison to plasma, as in the case of saliva, weakly basic drugs concentrate more in milk and have M/P ratio greater than 1. The opposite is true for weakly acidic drugs. It has been shown that for acidic drugs, excretion in milk is inversely related to the molecular weight and partition coefficient and that for basic drugs, is inversely related to the degree of ionisation and partition coefficient. Drugs extensively bound to plasma proteins, e.g. diazepam, are less secreted in milk. Since milk contains proteins, drugs excreted in milk can bind to it. The amount of drug excreted in milk is generally less than 1% and the fraction consumed by the infant is too less to reach therapeutic or toxic levels. But some potent drugs such as barbiturates, morphine and ergotamine may induce toxicity in infants. Some examples of toxicity to breast-fed infants owing to excretion of drug in milk are –

·           Chloramphenicol: Possible bone marrow suppression.

·           Diazepam: Accumulation and sedation.

·           Heroin: Prolonged neonatal dependence.

·           Methadone: Possible withdrawal syndrome if breast-feeding is stopped suddenly.

·           Propylthiouracil: Suppression of thyroid function.

·           Tetracycline: Permanent staining of infant teeth.

Wherever possible, nursing mothers should avoid drugs. If medication is unavoidable, the infant should be bottle-fed.

5. Skin Excretion

Drugs excreted through the skin via sweat also follow pH-partition hypothesis. Passive excretion of drugs and their metabolites through skin is responsible to some extent for the urticaria and dermatitis and other hypersensitivity reactions. Compounds such as benzoic acid, salicylic acid, alcohol and antipyrine and heavy metals like lead, mercury and arsenic are excreted in sweat.

6. Gastrointestinal Excretion

Excretion of drugs into the GIT usually occurs after parenteral administration when the concentration gradient for passive diffusion is favourable. The process is reverse of GI absorption of drugs. Water soluble and ionised form of weakly acidic and basic drugs is excreted in the GIT, e.g. nicotine and quinine are excreted in stomach. Orally administered drugs can also be absorbed and excreted in the GIT. Drugs excreted in the GIT are reabsorbed into the systemic circulation and undergo recycling.

7. Genital Excretion

Reproductive tract and genital secretions may contain the excreted drugs. Some drugs have been detected in semen.

Drugs can also get excreted via the lachrymal fluid.

A summary of drugs excreted by various routes is given in Table 6.4.

TABLE 6.4

Excretion Pathways, Transport Mechanisms and Drugs Excreted