midterm 1.2 - bioavailability and bioequivalence studies

Phase II (conjugation) reactions are catalyzed by __________

Transferase enzymes

_________ metabolites are generally devoid of pharmacological activity and toxicity

Conjugated

__________ and _________ metabolites have terminated or attenuated biological activity (MA)

Methylated, Acetylated

__________ protects the body against chemically reactive compounds

Glutathione conjugates

Hydration (Phase of drug metabolism)

Phase I (Functionalization)

Oxidation (Phase of drug metabolism)

Phase I (Functionalization)

Reduction (Phase of drug metabolism)

Phase I (Functionalization)

Hydrolysis (Phase of drug metabolism)

Phase I (Functionalization)

Glucuronidation (Phase of drug metabolism)

Phase II (Conjugation)

Sulfonation (Phase of drug metabolism)

Phase II (Conjugation)

Amino acid conjugation (Phase of drug metabolism)

Phase II (Conjugation)

Glutathione conjugation (Phase of drug metabolism)

Phase II (Conjugation)

Methylation (Phase of drug metabolism)

Phase II (Conjugation)

Acetylation (Phase of drug metabolism)

Phase II (Conjugation)

Other name of sulfonation

Sulfate conjugation

Occurs primarily with phenols, alcohols, aromatic amines, and N-hydroxy compounds (Phase II reactions)

Sulfonation/Sulfate conjugation

Coenzyme in sulfonation/sulfate conjugation

3-phosphoadenosine-5-phosphosulfate (PAPS)

The amino acids __________ and __________, are used to conjugate carboxylic acids, particularly aromatic acids and arylalkyl acids (GG)

Glycine, Glutamine

The amino acids glycine and glutamine are used to conjugate __________, particularly aromatic acids and arylalkyl acids

Carboxylic acids

The amino acids glycine and glutamine are used to conjugate carboxylic acids, particularly __________ and __________ (AA)

Aromatic acids, Arylalkyl acids

__________ conjugation is common to most mammals

Glycine

__________ conjugation appears to be confined mainly to humans and other primates

Glutamine

Important in detoxifying potentially dangerous environmental toxins or electrophilic alkylating agents (Phase II reactions)

Glutathione conjugation

Xenobiotics conjugated with GSH usually are not excreted as such, but undergo further biotransformation to give S-substituted N-acetylcysteine products called __________

Mercapturic acids

Its function is to terminate pharmacological activity and detoxification (Phase II reactions)

Acetylation

__________ is a variation that is genetic and is caused mainly by differences in N-acetyltransferase activity

Acetylation polymorphism

__________ and __________ are rapid acetylators (EA)

Eskimos, Asians

__________ and some __________ groups are mainly slow acetylators (EW)

Egyptians, Western European

Important in the biosynthesis of many endogenous compounds and in the inactivation of numerous physiologically active biogenic amines (Phase II reactions)

Methylation

Coenzyme in methylation reaction

S-adenosylmethionine (SAM)

Phenobarbital (barbiturates) (Enzyme inducer or inhibitor)

Inducer

Phenytoin (Enzyme inducer or inhibitor)

Inducer

Primidone (Enzyme inducer or inhibitor)

Inducer

Rifampicin (Enzyme inducer or inhibitor)

Inducer

Carbamazepine (Enzyme inducer or inhibitor)

Inducer

Chronic alcoholism (Enzyme inducer or inhibitor)

Inducer

St. John’s wort (Enzyme inducer or inhibitor)

Inducer

Smoking (Enzyme inducer or inhibitor)

Inducer

Metronidazole (Enzyme inducer or inhibitor)

Inhibitor

Erythromycin (Enzyme inducer or inhibitor)

Inhibitor

Enoxacin (Enzyme inducer or inhibitor)

Inhibitor

Disulfiram (Enzyme inducer or inhibitor)

Inhibitor

Diltiazem (Enzyme inducer or inhibitor)

Inhibitor

Diphenhydramine (Enzyme inducer or inhibitor)

Inhibitor

Verapamil (Enzyme inducer or inhibitor)

Inhibitor

Isoniazid (Enzyme inducer or inhibitor)

Inhibitor

Indinavir (Enzyme inducer or inhibitor)

Inhibitor

Chloramphenicol (Enzyme inducer or inhibitor)

Inhibitor

Cimetidine (Enzyme inducer or inhibitor)

Inhibitor

Ciprofloxacin (Enzyme inducer or inhibitor)

Inhibitor

Clarithromycin (Enzyme inducer or inhibitor)

Inhibitor

Ketoconazole (Enzyme inducer or inhibitor)

Inhibitor

Grapefruit juice (Enzyme inducer or inhibitor)

Inhibitor

Acute alcoholism (Enzyme inducer or inhibitor)

Inhibitor

Toxic metabolite of paracetamol

N-acetyl-para-benzo-quinone imine (NAPQI)

Antidote for paracetamol overdose

N-acetylcysteine

Most common phase II reaction

Glucuronidation

In __________, phase II reaction occurs first before phase I

Paracetamol

Reduction of a nitro group yields an __________

Amine

Reduction of a disulfide group yields a __________

Thiol

Oxidation of an amine group yields a _________

Nitro

Oxidation of a thiol group yields a __________

Disulfide

Phase I is more likely to cross the __________ than phase II

Cell membrane

Glucuronidation involves the attachment of glucuronic acid to functional groups like __________, __________, and __________ (PAC)

Phenol, Alcohol, Carboxylic acid

Most common phase I reaction

Oxidation

Glucuronidation (Cofactor) (Phase II reactions)

Uridine diphosphate glucuronic acid (UDPGA)

Glucuronidation (Enzyme) (Phase II reactions)

UDP glucuronosyltransferase

Sulfation (Cofactor) (Phase II reactions)

Phosphoadenosyl phosphosulfate (PAPS)

Sulfation (Enzyme) (Phase II reactions)

Sulfotransferase

Glycine conjugation (Cofactor) (Phase II reactions)

Glycine

Glycine conjugation (Enzyme) (Phase II reactions)

Acyl-CoA glycinetransferase

Glutathione conjugation (Cofactor) (Phase II reactions)

Glutathione (GSH)

Glutathione conjugation (Enzyme) (Phase II reactions)

GSH-S-transferase

Methylation (Cofactor) (Phase II reactions)

S-Adenosylmethionine (SAM)

Methylation (Enzyme) (Phase II reactions)

Transmethylases/Methyltransferases

Acetylation (Cofactor) (Phase II reactions)

Acetyl-CoA

Acetylation (Enzyme) (Phase II reactions)

N-Acetyltransferase

Formula for monooxygenase reaction

Drug-H + O2 + NADPH + H+ -> Drug-OH + NADP + H2O

2 BCS classes not eligible for biowaiver/requires in vivo bioequivalence study

Class II (except weakly acidic), Class IV

3 BCS classes eligible for biowaiver/does not require in vivo bioequivalence study

Class I, Class II (weakly acidic), Class III