Intro to Pharm and Tox Topics
Pharmacogenetics is concerned with idiosincratic drug responses that have an hereditary basis. An individual's response to a drug is modulated by his/her genetic predisposition as well as age, disease, diet, hormones, environment, efficiency of DNA repair and immunology. Pharmacogenetics helps understand the contribution of genetic factors to the variability of response to drugs. Genes encoding enzymes or receptors play a role in drug response and differ in some respect from one individual to another.
A gene has two allels at a particular chromosomal site. Phenotype is the observed genetic trait (eye color, hypercholesterolemia, etc.). Genotype is the description of the trait at the gene level. An autosomal recesive trait occurs if the normal allele predominates over the mutant allele (??). An autosomal dominant trait ocurs if a mutant allele predominates over the normal allele (??).
A pharmacogenetic polymorphysm is a monogenatic trait caused by the presence in at least 1% of the population of more than one allele at the same locus representing more than one phenotype in regards to drug interactions with the organism. Pharmacogenetic polymorphysms are detected bu several methods such as clinical observations, twins studies, and family studies. Animal models are useful because some animals have polyorphysms similar to humans. DNA is studied by Restrtiction Fragment Length Polimorphysm (RFLP) studies.
CYP2D6 exhibits a polymorphism that divides the population into poor metabolizers (PM) and extensive metabolizers (EM) regarding CYP2DE substrates. EMs and PMs differ in their ability to perform oxidatidations of numerous drugs. 5-10% of individuals in most populations are PMs: 10% of Europeans, <1% of Chinese/Japanese and 3% of African Americans (?). The defective drug metabolism in PMs is due to the absence in the liver of CYP2D6 which results from a genetically inhereted mutant of the CYP2D6 gene. This is an autosomal recesive trait.
The CYP2D6 polymorphysm was discovered in the 1970's. In the UK 1975 clinical study of debisoquin (an antihypertensive) disposition, one volunteer out of 10 showed a sustained effect from the drug. The same volunteer showed a slow metabolism of the parent compound. The enzyme was called debisoquin hydroxylase. About the same time in Germany, another sudy had similar findings regarding the drug sparteine and the enzyme was called sparteine oxidase.
A xenobiotic probe is used to identify if a person is an EM or PM. The person is given a drug like debisoquin, bufaralol, spartein or dextromethorphan. Then amounts of parent drug and metabolites excreted in the urine are measured to calculate a metabolic ratio:
MR = parent drug excreted / metabolite excreted
EMs have higher metabolite ratios than PMs.
Consequences for poor metabolizers include accumulation of drug and active metabolite (ex. tricyclic antidepresants), reduced formation of active metabolites (ex. codeine, encaine), or increased formation of toxic metabolite (??). Consequences for ultra-rapid metabolizers include elimination of drug before it can have an effect, formation of toxic metabolites and accumulation of metabolites.
CYP2C19 shows a monogenetic PM polymorphism in 3-5% of caucasians and 15-20% of asians. S-mephenytoin is commonly used to measure CYP2C19 activity, converting it into 4-hydroxymephenytoin.
CYP3A is very abundant and responsible for metabolism of many drugs. CYP3A5 may be polymorphic in about 50% of the population. Erythromycin and midazolams can be used as markers of CYP3A activity.
Succinylcholine causes muscle relaxation of short duration because of very rapid metabolic degradation by cholinesterases of plasma and liver. Some patients experience proonged muscular relaxation and apnea because they have atypical plasma cholinesterase. Dibucaine is used as a maker for pseudocholinesterases (?) becase it inhibits normal cholinesterase but has little effect on atypical cholinesterase.
Acetylation occurs by N-acetyltransferases and involve the transfer of the acetyl group from CoA to the cceptor amines resulting in the formation of amides. There are slow and rapid acetylators, a cobdition initially called isoniazid acetylation polymoirphism (because it acts on the drug isoniazid). In humans, NAT1 may be associated with a distinct polymorphysm involving p-aminosalicylate and PABA (a bimodal distrtibution), and NAT2 shows classical acetylation polymorphism.
A common "drug coctail" given to asses phenotype includes caffeine, tolbutamide, S-mephenytoin, dextromethorphan, chlorzoxazone, midazolan and isoniazid.
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