Midterm 1: Drug Metabolism and Toxicity Flashcards
Many drugs are known to undergo metabolism to reactive metabolites that bind to cellular macromolecules and produce a toxicity.
- metabolites are causing the toxicity as opposed to the parent drug and that there are multiple cellular targets.
- While drug metabolite induced toxicities can and do occur in tissues and organs the liver is often the target due to it’s high concentration of metabolizing enzymes and it’s anotomical location
- Many anticancer drugs are either alkylating agents, are designed to be converted to alkylating agents or promote destructive processes such a redox cycling to reactive oxygen species. They also cause toxicities and often widespread cell death including healthy cells. We won’t talk about those.
Examples of Post-marketing Drug Induced Liver Toxicities (DILI)
Black Box Warnings: Dacarbazine, Dantrolene, Felbamate, Flutamide, Halothane, Ketoconazole, Leflunomide Tolcapone Valproic Acid Zalcitabine Zidovudine
Withdrawn from Market: Benoxaprofen Bromfenac Iproniazid Nefazadone Pemoline Temafloxacin Ticrynafen Troglitazone Trovafloxacin
Definition: Black Box Warning
mandated by the FDA and warns to the potential for a serious adverse drug reaction (ADR). It must be placed on the label or package insert. It almost always reduces drug utilization and may be a prelude to a drug being removed from the market.
Drug Induced Liver Toxicities (DILI) Properties
- Quite often the molecular basis for the ADR is not known. Particularly troublesome are rare and unpredictable (idiosyncratic) ADRs.
- Toxicity may be either acute or cumulative. In some immune-based ADRs the toxicity is observed upon repeat exposure.
- Certain types of functional groups (moieties) are most suspect. Drugs that contain or can be metabolized to the following structures may cause toxic effects via the formation of reactive metabolites:
- – Hydrazines and hydrazides
- – Arylacetic or aryl propionic acids
- – Thiophene, furan, pyrrole, polycyclic aromatics.
- – Anilines or anilides
- – Quinone and quinone imines
- – Medium chain fatty acids
- – Halogenated hydrocarbons and some halogenated aromatics
- – Nitroaromatics
- – Moieties that can form reactive α,β-unsaturated enal-like structures
- – Thiols, thiono compounds, thiazolidinediones
- We are discovering that in some cases there is a genetic component to risk of ADR. This area of study is called toxicogenomics
Picture of Normal, necrotic and apoptosis hepatocytes
Necrosis
More serious
Apoptosis
Natural, cascades to protect nearby cells
Liver Injury is usually accompanied by a rise of enzymes and other markers in the blood as the cells undergo cell destruction (lyse)
- AST (Aspartate Amino Transferase)
- Ref. Levels = (0-35 Units/L)
- ALT (Aspartate Amino Transferase)
- Ref. Levels = (0-65 Units/L)
- BIL (Total Bilirubin)
- Ref. Levels = (0.1-1 mg/dL)
- Another indication for liver damage. Damage, clotting times go up because liver makes clotting factor. Prothrombin times increases
- AST and ALT levels also rise after a heart attack but BIL does not.
Liver Biopsy
In some cases a liver biopsy is obtained. One type of liver injury occurs with acetaminophen. This is called centrolobular necrosis which is defined as necrosis restricted to the hepatocytes immediately surrounding the central venule.
(A below after acetaminophen; B is normal). The clear area in the middle is the central vein.
Flutamide and liver failure.
- Flutamide is an anti-androgen (advanced prostate cancer, acne and hirsutism)
- Flutamide administration has been associated with acute hepatitis and it’s more serious stage acute liver failure (fulminant). As in many cases of DLIL the incidence is fairly low but can be fatal. Flutamide is a nitroaromatic compound.
- The reduction steps has been shown to be catalyzed by cytochrome P450 reductase (CPR). In general nitroaromatic structures are avoided in new drugs as they are readily reduced and lead to hepatic toxicity.
- The oxidation is a P450 catalyzed oxidative dehydrogenation. The same type of reaction that produces NAPQI from acetaminophen.
- Multiple isomers of the GSH adducts are formed. The protein adducts have never been characterized.
- The blood panels of some affected patients in Chile is shown below. BIL, AST and ALT are massively higher than normal. PT% less than 100 means prolonged bleeding times due to underproduction of prothrombin by the damaged liver. The liver is also unable to convert bilirubin to bilirubin diglucuronide for excretion in bile so bilirubin levels in the blood rise (jaundice). Note that all but one patient recovered after removal of the drug.
- Cytology indicates that hepatocytes undergo apoptosis rather than necrosis.
Flutamide Black Box Warning
Note First Signs and Symptoms
- Evidence of hepatic injury included increased serum transaminase levels, jaundice, hepatic encephalopathy (loss of mental capacity as toxins like ammonia to brain) and death related to acute hepatic failure
- Serum transaminase levels should be measured prior to starting treatment with flutamide.
- First signs and symptoms suggestive of liver dysfunction (e.g. nausea, vomitting, abdominal pain, fatiue, anorexia, “flu” like symptoms, hyperbilirubinia, jaundice, right upper quadrant tenderness)
Halothane is an inhalation anesthetic used in surgery and is hepatoxic.
- 1950s, non-flammable inhalation anesthetics. Discontinued in the USA where it has been supplanted by less toxic alternatives such as sevoflurane and desflurane which are halogenated ethers and do not cause hepatoxicity. However, it is on the WHO list of essential medicines as it is inexpensive and widely used in the third world.
- In 1 in 10,000 cases severe liver toxicity is observed. This is often referred to as halothane hepatitis.
- During halothane anesthesia as much as 30% of the dose is metabolized by P450 enzymes (CYP2E1 mainly) to the acid choride which undergoes rapid reaction with water to generate trifluoroacetic acetic acid which is found in the urine. Lysine residues of proteins become trifluoro-acetylated.
- Halothane hepatitis is usually seen after repeated use and is believed an immune mediated toxicity where the immune system responds to trifluoracetylated proteins that are haptens. There may be a genetic component and glutathione depletion is observed in animals.
- This is an example of an idiosyncratic heptotoxic drug that has been removed from the market. Here the antigen may well be the drug metabolite covalently adducted to the P450 that made it (Ticrynafen (tienilic acid) and CYP2C9)
Isoniazid (anti-tuberculosis; widely used; liver toxicity)
- Higher incidence of hepatoxicity Usually given with rifampicin. Inhibits synthesis of components of bacterial cell membrane called the mycolate acids.
- Major clearance route via a conjugation reaction with N-acetyl transferase, a liver enzyme. Slow acetylator phenotype (50% of the population) have higher concentrations of the drug however dose does not undergo adjustment for PM’s.
- Phase II reactions. A number of drugs are acetylated by NAT. NAT uses acetyl-CoA as the cosubstrate
- There is fairly good evidence that the fast acetylators are at lower risk because the formation of diacetylhydrazine is more rapid and the toxification route is disfavored. However there is some controversy about the mechanism of the human toxicity since the toxicology has been carried out in animals.
- Increased risk with alcohol. Alcohol induces CYP2E1 which is believed to be involved in the bioactivation of the acetylhydrazine metabolite
