Mbarara News brings you Dr Lutoti Steven,the innovator and brains behind Elocof to highlight on a review of metabolism and Excretion process of drugs.Here is the conversation;
MN: Dr Lutoti aka Dr Elocof , What happens to drugs once they have been adminstered and absorbed into the body? How are they excreted from the body?
Dr Lutoti:In response to your question, allow me address you as follows:
✓Once a medicine/drug has been administered orally, inhaled, applied on the skin or administered by another route, it is absorbed and distributed in the body.
During this process, drug can concentrate in certain tissues as well.The drug will be transformed into another form through a process called metabolism.
Some drugs remain in unchanged form. There are two groups of reactions by which medicines are metabolised – Phase I reactions and Phase II reactions.
Now let me share with you what these reactions, with some examples of drugs that undergo such reactions:
✓ Phase I reactions involve oxidation, reduction or hydrolysis of the medicine and usually either add functional groups through cleavage.
We have microsomal and non microsomal oxidations that occur in endoplasmic reticulum of the liver and mitochondria/plasma respectively.
Sites of oxidation include carbon, nitrogen, sulphur and oxygen atoms of the drug molecule.
At carbon atoms , a number of oxidation reactions occur.Forexample :
✓ Aliphatic oxidation of amylobarbitone to hydroxyamylobarbitone. Other drugs that undergo Aliphatic oxidation include Tolubutamide, glutethimide.
✓Phenobarbitone undergoes aromatic oxidation to p-hydroxy phenobarbitone.
✓Cyproheptadine in your commonly consumed toractin /periactin for appetite undergoes epoxidation to form cyproheptadine epoxide.
At N atom, amphetamine undergoes primary N-oxidation to form N-(1-phenylprop-2-yl) hydroxylamine.
At oxygen atoms, a number of oxidation reactions can occur forexample O-dealkylation of phenacetin to paracetamol, ring fission of catechol to trans-trans-muconic acid, ring formation of proguanil to cycloproguanil.
Also Tertiary N-oxidation of chlorpromazine to Chlorpromazine N-oxide occurs ; N-dealkylation of ephedrine and imipramine. –. the ephedrine is converted to Phenylpropanolamine.
At sulphur atoms, we have forexample S-oxidation of chlorpromazine to Chlorpromazine sulphoxide, s-dealkylation of 6-methylthiopurine to 6-thiopurine , and desulphuration of thiopentone to pentobarbitone.
✓ Reduction reactions are carried out by both microsomal and non microsomal enzymes.
✓ Reduction reactions can occur at carbon, Nitrogen and sulphur atoms.
✓At carbon atoms, aldehyde reduction of chloral to trichloroethanol,ketoreduction of metyrapone to 2-methyl-1,2-di(pyrid-3-yl)propan-1-ol.
Another reduction at carbon atom is dehalogenation of halothane to 1,1,1- trifluorothane.
At Nitrogen atom, there is nitroreduction of nitrofurantoin to 1-(5-aminofurfurylidene-amino) hydantoin, azoreduction of sulphasalazine to sulphapyridine, and hydroxamic acid reduction of salicylhydroxamic acid to salicylamide.
At sulphur atom, sulphoxide reduction of dimethyl sulphoxide to dimethyl sulphide,. Disulphide reduction of disulfiram to diethyldithiocarbamic acid.
✓ Hydrolysis reactions
Hydrolysis is a common metabolic reaction of esters and amides. The responsible enzymes are found in microsomes of the liver, GIT wall + other tissues , blood plasma .
There are different types of hydrolysis reactions that occur during metabolism of drugs , forexample:
✓ Ester Hydrolysis of pethidine, procaine and suxamethonium.
✓ Amide hydrolysis of salicylamide to salicylic acid
✓ Hydrazide hydrolyisis of isoniazid to isonicotinic acid and hydrazine.
✓ Carbamate hydrolysis of mebrobamate to 2-hydroxymethyl-2-methyl-2-methylpentan-1-ol and carbamic acid.
✓ Deacetylation of phenacetin to p-ethoxyaniline
✓ Hydrolytic ring fission of Phenytoin to Alpha-Aminodiphenylacetic acid.
✓ Phase II reactions involve conjunction of the drug molecule, often via the functional group introduced by phase I reactions, with substances such as glucuronic acid, the amino acids glycine and glutamine, and sulphate moeties.
Forexample for ELOCOF syrup, -gingerol undergoes phase 1 and II reactions to form 9-hydroxy -gingerol, gingerdiol, and (S)--gingerol-4′-O-beta-glucuronide.
✓Although there are several routes of drug excretion, the kidneys and the liver are the major organs through which medicines are excreted from the body.
Today, let me share a highlight of key issues in regard to excretion of medicines via the kidneys.
✓Excretion through the kidneys is called Renal excretion. Urine is formed in the kidneys and is a major vehicle for excretion of drugs and their metabolites from the body.
✓Some drugs, like digoxin used for heart failure, are excreted in urine mainly as un changed drug.
✓ some drugs like propranolol ( for migraine headaches and hypertension) are almost completely metabolised before being excreted in the urine.
✓Many drugs are excreted by the kidneys as amixture of changed and unchanged forms.
✓ Changing form of a medicine occurs via metabolism. Elocof contains 6,8,10 and 12-gingerols in addition to their dehydration products the shogoals. Although the metabolites derived from -gingerol have not been detected in the urine, the ethyl acetate extract of the urine after enzymatic hydrolysis has been shown to contain six minor metabolites namely (S)--gingerol-4′-O-beta-glucuronide , vanillic acid , ferulic acid , (S)-(+)-4-hydroxy-6-oxo-8-(4-hydroxy-3-methoxyphenyl) octanoic acid, 4-(4-hydroxy-3-methoxyphenyl)butanoic acid , 9-hydroxy -gingerol and (S)-(+)--gingerol.
✓ Excretion of medicines through the kidneys occurs through three processes: glomerular filtration, passive tubular diffusion and active transport into the renal tubules.
✓During drug distribution, some drugs are bound to proteins in plasma. Only unbound fraction of medicine is available for filtration.
✓Lipid soluble drugs may be excreted into the distal portion of the renal tubule by passive diffusion provided there is concentration gradient and urinary pH which favours un ionised form of the drug.
Lipid soluble compounds already in the glomerular filtrate may be reabsorbed by the same process. Highly lipid soluble drugs are therefore excreted slowly.
✓ Urinary pH varies over range of 5 to 8. Note reabsorption of weak electrolytes from glomerular filtrate is pH dependent.
✓ Weak acids ( pKa 3.0 to 7.5) such as salicylates and phenobarbitone are more readily excreted in alkaline urine.
✓ Weak bases ( pKa 7.5 to 10.5) like amphetamines are more readily excreted in acid urine.
We shall look at excretion via other routes in our next presentation.
MN: Thanks so much Dr Steve,any final remarks?
Dr Lutoti: In case of cough, flu and Sore throat, ask for ELOCOF SYRUP at your nearest Pharmacy, drug shop and clinic across Uganda.
ELOCOF is formulated by an expert and approved as a local medicine in Uganda by the National drug Authority.
For inquiries, call 0758329111.
Dr Lutoti Stephen is the head of pharmacognosy department at Makerere University and the Founder of Eloipharm industries Limited.