Pharm 5: Pharmacokinetics 2

Describe how metabolism affects drug structure and function (4 different ways)

1 - terminates biological activity 2 - makes it less lipophilic (more polar) so it will not be reabsorbed in kidney tubules 3 - the breakdown product is an active or toxic metabolite, 4 - an inactive prodrug may be converted into an active drug

Explain the first-pass effect

a fraction of the drug is metabolized in the gut wall and liver before reaching systemic circulation -> happens in enteral drug administration

List phase I reactions of drug metabolism

oxidations, reductions, decarboxylations, deaminations, hydrolytic reactions -> convert parent drug to a more polar metabolite by introducing or unmasking a functional group (OH, NH2, SH) -> mostly happens in ER, catalyzed by cytochrome P450


example of a prodrug that is bioactivated by metabolism to an active anticancer metabolite

List phase II reactions of drug metabolism

the functional group exposed in phase I is then conjugated -> usually with gluconurate, acetate, glutathione, amino acids or sulfate -> becomes generally inactive and rapidly excreted (except for morphine-6-gluconuride which becomes more potent) -> mostly

Isoniazid (phase II before phase I)

acetylated by N-acetyltransferase in phase II reaction then the acetylated conjugate is then substrate for phase I reaction -> hydrolysis to isonicotinic acid

List the main features and properties of the cytochrome P450 enzyme family

serves as terminal electron acceptors -> contains a single heme prosthetic group that binds oxygen and contains binding sites for substrates -> heme iron must be reduced from ferric to ferrous state so that oxygen may bind to the heme iron -> two electron

Explain the clinical relevance of enzyme induction

a drug can increase its own metabolism, a drug can increase the metabolism of a coadministered drug, this may reduce drug plasma concentrations below therapeutic levels -> can also produce toxic levels of a reactive metabolite resulting in tissue damage

Explain the clinical relevance of enzyme inhibition

metabolism of drugs will decrease, drug levels may reach toxic concentrations

List the main drugs that can act as inducers of cytochrome P450 isoenzymes

phenobarbital, phenytoin, rifampin and carbamazepine increase the synthesis of one or more P450 isoforms

List the main drugs that can act as inhibitors of cytochrome P450 isoenzymes

amiodarone, Cimetidine, azole antifungals (ketoconazole), macrolide antibiotics (erythromycin), chloramphenicol, ritonavir, grapefruit juice

Outline the main molecular mechanism of cytochrome P450 induction

drugs can enter hepatocytes and bind to xenobiotic receptors and activate them -> they then translocate to the nucleus and bind to promoters and increase gene expression

Explain the clinical relevance of the induction of drug transporters

some drugs need to be actively transported across membranes -> affects oral bioavailability, hepatic metabolism and renal clearance

MDR1 multidrug resistance protein 1

actively transports compounds back into the intestinal lumen -> can be induced or inhibited affecting the bioavailability of several drugs including digoxin and HIV-1 protease inhibitors

Macrolide antibiotics

can inhibit MDR1 which can lead to increased serum levels of drugs, such as digoxin, that are excreted by MDR1


transcriptionally regulates MDR1 -> drugs that induce P450 enzymes via this pathway also induce MDR1


95% of the drug is glucuronylated or sulfated and excreted by kidney (phase II reactions), about 5% is metabolized by CYP2E1 to give NAPQI (highly toxic and conjugated with glutathione to be excreted by the kidney) -> at high doses of the drug more is con

N-acetyl cysteine

precursor for glutathione production that is an antidote for acetaminophen poisoning because it reacts directly with NAPQI

List the main factors that can affect drug metabolism

genetic, diet (grapefruit juice inhibits CYP3A4 and MDR1) and environmental (pollutants, charcoal-broiled foods and cruciferous vegetables induce CYP1A, pesticides), age (slower in children and elderly), diseases (especially those affecting the liver), dr