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Phase I Reactions

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Gary Theilman, Pharm.D.

Let’s look into more factors that can affect how quickly the liver can clear drug from the body using the well-stirred model this time we’re going to look at intrinsic clearance in the well-stirred equation intrinsic clearance is represented by cl sub i intrinsic clearance reflects how well the liver removes drug by metabolism and by biliary excretion the liver

Puts a lot of effort into changing drug molecules to make them more water-soluble why because the kidneys and the liver via the biliary tract excrete water-soluble drugs much more efficiently than they excrete lipid soluble drugs drugs that are already water-soluble like jenna meissen are eliminated quickly in the urine with the drug largely being undetectable

8 to 12 hours after a dose but think of a drug like marijuana tetrahydrocannabinol is hard to dissolve in water only 2.8 milligrams of thc will dissolve in a liter of water a person might have a positive urine drug test up to a week after a single use of marijuana to get rid of thc the liver has to process it into a more water soluble molecule how does the liver

Make a molecule more water-soluble physically separate the positive charge on the molecule from the negative charge that is make the molecule more polar the liver has two major strategies for doing this phase one which is also called bio transformation this is where the liver physically rearranges the drug molecule to separate the positive and the negative charges

And then phase two which is known as conjugation attach another molecule to the drug to make it longer thus separating the charges phase 1 biotransformation involves oxidation reduction or hydrolysis and is mediated primarily by the cytochrome p450 enzyme system the p450 enzymes are organized based on similarity in their genetic structures for example cyclosporine

Is metabolized by enzymes that are grouped into the cytochrome p450 3 a family cyclosporine is a drug that’s given to people who have undergone an organ transplantation it suppresses the patient’s immune system to prevent it from attacking the newly transplanted organ it’s also very toxic and doses need to be adjusted carefully too much cyclosporine and damage to

The kidneys and high blood pressure might result too little and the patient may reject the new organ like other p450 enzymes the 3a family can be induced or inhibited by other drugs erythromycin is a sip 3a inhibitor giving a patient erythromycin can reduce the activity of 3a enzymes less enzyme activity may cause the metabolism of cyclosporine to decrease this

Can lead to potentially dangerous increases in cyclosporine blood concentrations carbamazepine on the other hand is a sip 3a inducer more enzyme is produced and the metabolism of cyclosporine increases this leads to decreased blood cyclosporine concentrations and an increased risk that the patients in system will attack the transplanted organ and it’s not just

Traditional drugs that can change the activity of p450 enzymes some herbal teas grapefruit juice and even licorice can either induce or inhibit enzymes smoking induces some p450 enzymes and can lead to decreased concentrations of some drugs if the patient is on a stable drug regimen we can compensate for example if the patient is always taking the same dose of

Carbamazepine we can adjust cyclosporine doses to take into account the interaction due to carbamazepine inducing p450 enzymes as long as the patient stays on both cyclosporine and carbamazepine at the same dose things should be pretty stable it’s when interacting drugs are added or taken away from the patient’s regimen that we need to be especially careful for

Example if a patient on cyclosporine gets an infection and started on antibiotics like clarithromycin or refampin we need to anticipate the potential changes to cyclosporine concentrations both when the patient is started on the antibiotic and when the antibiotics are stopped in the world’s third model intrinsic clearance is partially determined by the effect of

Biotransformation of drug molecules into more water soluble forms during phase 1 metabolism interacting drugs can either induce or inhibit the enzymes of the cytochrome p450 system leading to significant changes in a patient’s hepatic clearance

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Phase I Reactions By University of Mississippi School of Pharmacy Educational Videos