Therefore, the international Clinical Pharmacogenetics Implementation Consortium CPIC was formed in to provide actionable guidance based on available pharmacogenetic knowledge. CPIC publishes evidence-based, peer-reviewed clinical-practice guidelines for implementing individualized therapy for patient care based on pharmacogenetic tests.
Clinical pharmacogenetic tests targeted to identify these specific genetic variations are increasingly available. The Genetic Testing Registry www. While CPIC provides guidance on implementing an actionable pharmacogenetic result, it does not address who should be tested.
The FDA has also begun to include pharmacogenetic information in package inserts. These now offer pharmacogenetic information on over medications, including boxed warnings that recommend pharmacogenetics testing before initiating certain medications, like abacavir.
Thus, recent federal and international efforts have been playing a more prominent role in optimizing individualized drug therapy to improve both safety and efficacy by applying pharmacogenetics knowledge.
Genetic polymorphism plays an essential role in the process of natural selection and evolution. Everyone has two copies of each allele, one from the biological mother and one from the biological father.
The two identical alleles are classified as homozygous , while two different alleles are classified as heterozygous. Similar to polymorphism, mutations can also be in the germline cells and are heritable e. However, they can also be in the somatic cells localized to a specific tissue originating during the lifetime and nonheritable.
Such mutations form the basis of tumor genomics and make them amenable to the selection of personalized therapies based on pharmacogenetic testing of the tumor genome. Four major types of DNA variability that cause polymorphism or mutations include 1 single nucleotide polymorphism SNP , which is a substitution, insertion, or deletion of a single nucleotide; 2 insertion or deletion indel of more than one nucleotide ranging from a few to several hundred nucleotides; 3 variation in the number of tandem repeats; and 4 gene duplication.
Among these, SNPs are most common allelic variations accounting for genetic polymorphism. CYP enzymes play a major role in drug metabolism. A decrease in any given CYP enzyme activity impacts the hepatic clearance of drugs that are metabolized by that CYP enzyme, thus affecting the plasma concentration and elimination half-life of those drugs.
Patients carrying homozygous two identical copies wild-type CYP alleles with normal enzyme activity have the normal-metabolizers also known as extensive phenotype. However, patients who have heterozygous genotypes with one copy of the wild-type allele and one copy of a reduced-function or loss-of-function allele or who have homozygous with two copies of reduced-function allele would be classified as the intermediate-metabolizers phenotype.
Those who are homozygous with two copies of loss-of-function alleles or heterozygous with one copy of loss-of-function alleles and one copy of reduced-function allele would be classified as poor-metabolizers phenotype. In patients who are CYP intermediate or poor metabolizers, a drug metabolized by that CYP enzyme will not be metabolized as quickly as normal metabolizers.
Any prodrug that is converted to its active metabolite by a CYP enzyme may not be converted to effective therapeutic concentrations by intermediate or poor metabolizers, and there will be a risk of therapeutic failure. One such example is clopidogrel that is converted to its active metabolite by CYP2C Patients carrying loss-of-function CYP2C19 alleles are at increased risk of thrombotic events despite taking the label-recommended dose.
Rarely, allelic variation in CYP can cause an increase in function e. Patients with heterozygous or homozygous genotypes for increased-function CYP alleles have rapid- and ultrarapid-metabolizer phenotypes and will metabolize the drug faster. In these cases, the effective plasma therapeutic concentration may not be achieved, resulting in a risk of treatment failure for the rapid and ultrarapid metabolizers.
Nonsteroidal anti-inflammatory drugs NSAIDs act by inhibiting cyclooxygenase COX , the enzyme responsible for the formation of proinflammatory autacoids called prostaglandins by catalyzing arachidonic acid. NSAIDs are the first-line agents for mild-to-moderate musculoskeletal pain and inflammation for short-term use, as well as chronic noncancer nociceptor pain in conditions such as rheumatoid arthritis for long-term use.
There are currently more than 20 oral NSAIDs available in the United States; ibuprofen, meloxicam, and celecoxib are among the top most commonly prescribed.
At equipotent doses, the responses to NSAIDs and their associated risk of adverse effects show interpatient variability owing to pharmacodynamic and pharmacokinetic factors, including pharmacogenetics. Although NSAIDs offer many advantages over opioids and steroids, such as the absence of addictive potential and lower incidence of adverse effects, serious side effects can still be attributed to them, especially when significant drug-drug interactions or relevant comorbidities are present.
Gastrointestinal complications are the most common side effect of nonselective NSAIDs because of the inhibition of COX-1 in the gastric mucosa due to the reduced formation of gastric prostacyclins. Given the large consumption of NSAIDs, these side effects have considerable health and economic impacts. These adverse effects can be seen to a greater extent in older patients and patients with pre-existing gastrointestinal disease, cardiovascular disease, chronic kidney disease, chronic liver disease, or aspirin-exacerbated respiratory disease.
Based on the allelic function, an activity score representing the function is assigned. The activity scores of both alleles present in the patient are added together to determine the activity score of the diplotype, and a phenotype is determined from the resulting diplotype activity score TABLE 2. Patients with one copy of wild-type and one copy of reduced-function allele will have an activity score of 1. Both activity scores, 1.
Lastly, a patient carrying one copy of the reduced-function allele and one copy of loss-of-function allele will have an activity score of 0. Both 0. Because the therapeutic index for PBZ is relatively narrow PBZ exhibits zero order metabolism , the dosage should be adjusted to the minimum possible to maintain comfort and avoid toxicity. GI effects eg, anorexia and depression are the most frequent adverse effects associated with PBZ.
Ulcers may develop in the mouth, stomach, cecum, and right dorsal colon. The ulcerogenic potential of PBZ in horses is greater than that of flunixin and ketoprofen.
In dogs, PBZ has been associated with bleeding dyscrasias, hepatopathies, nephropathies, and rare cases of irreversible bone marrow suppression.
Meclofenamic acid is a fenemate anthranilic acid NSAID available for horses as a granular preparation and for dogs as an oral tablet. The recommended dosage is 2. In horses, meclofenamic acid is rapidly absorbed, but feeding before dosing may delay absorption. The onset of action is slow, requiring 2—4 days of dosing for a clinical effect.
Although it is effective in the treatment of chronic laminitis, meclofenamic acid has a therapeutic index that may be lower than that of other NSAIDs. It is used for fever, postoperative pain, and acute and chronic inflammatory conditions in cats, dogs, cattle, and pigs. In the USA, the nicotinic acid derivative flunixin as the meglumine salt is approved for use in horses as PO and parenteral formulations. The recommended dosage is 1. Elimination is primarily by renal excretion.
Flunixin is effective for the treatment of visceral pain associated with colic in horses. It is also used to reduce the inflammatory-mediated hemodynamic response to endotoxin, although it is unlikely to reduce mortality associated with endotoxemic shock. The dosage recommended in horses is 1. Toxicity in horses is relatively uncommon, but GI ulceration and erosion may develop. Flunixin has been used to treat mastitis and acute pulmonary emphysema in cattle, although it is not approved for these indications.
Chronic administration of flunixin to dogs may result in severe GI ulceration and renal damage. Flunixin is not marketed in the USA for dogs, but it is approved in Europe and other countries.
An injectable formulation is also available in the USA and Europe. Carprofen is approved by the FDA to manage pain and inflammation associated with osteoarthritis and acute pain associated with soft-tissue and orthopedic surgery in dogs. The recommended dosage is 4. In Europe and other countries, carprofen is also registered for use in horses and cattle and for short-term therapy in cats.
Elimination is via hepatic biotransformation, with excretion of the resulting metabolites in feces and urine. Some enterohepatic recycling occurs. The exact mechanism of action of carprofen is unclear. In vitro assays with canine cell lines indicate that it is fold more selective for COX-2, whereas in vitro assays with canine whole blood indicate that it is 7- to fold more selective for COX Equine whole blood assays indicate that it is 1.
Other mechanisms of action, including inhibition of PA 2 , may be responsible for its anti-inflammatory effects. Approximately one-fourth of the adverse reactions reported were GI signs, including vomiting, diarrhea, and GI ulceration. Potentially serious idiosyncratic hepatopathies, characterized by acute hepatic necrosis, have been reported in some dogs. Approximately one-third of the dogs developing hepatopathies while receiving carprofen were Labrador Retrievers, although a true breed predisposition has not been established.
As with any NSAID therapy, clinical laboratory monitoring for hepatic damage is advised, especially in geriatric animals that may be predisposed to more serious complications. Ketoprofen is recommended for acute pain up to 5 days in both dogs and cats. In horses, it is used for pain and inflammation associated with osteoarthritis and for visceral pain associated with colic. Ketoprofen is a potent inhibitor of COX and bradykinin and may also inhibit some lipoxygenases.
Its efficacy is comparable to that of opioids in the management of pain after orthopedic and soft-tissue surgery in dogs. After administration PO, ketoprofen is rapidly absorbed and has a terminal half-life in cats and dogs of 2—3 hr. As with other NSAIDs, ketoprofen is metabolized in the liver to inactive metabolites that are eliminated by renal excretion. Other adverse effects, including hepatopathies and renal disease, have been reported in animals.
Because of potential antiplatelet effects, care should be exercised when using ketoprofen perioperatively. The pyranocarboxylic acid etodolac is approved for use in dogs in the USA. Extensive enterohepatic recirculation has been reported in dogs, followed by elimination of etodolac and its metabolites in the liver and feces.
In in vitro studies, etodolac was more selective in inhibiting COX-2 than COX-1, although in vitro canine whole blood assays have also shown it to be nonselective. Etodolac has been shown to inhibit macrophage chemotaxis and has demonstrated efficacy for the treatment of lameness associated with hip dysplasia.
Although the risk of GI ulceration is low at therapeutic doses, administration of three times the label dosage resulted in GI ulceration, vomiting, and weight loss in toxicity studies.
GI, hepatic, and renal adverse reactions have been reported after administration of etodolac, similar to those of other NSAIDs. The arylpropionic acid derivative vedaprofen is available in Europe in a gel formulation for horses and dogs and in an injectable formulation for horses.
Vedaprofen is indicated for the treatment of pain and inflammation associated with musculoskeletal disorders in dogs 0. After administration PO, vedaprofen is rapidly absorbed. Bioavailability is generally high but may be reduced if the drug is administered with food.
The terminal half-life is 10—13 hr in dogs and 6—8 hr in horses. Vedaprofen undergoes extensive biotransformation to hydroxylated metabolites, which are excreted in urine and feces. In Europe and other countries, it is approved for use in dogs, cats, cattle, and horses. A potent inhibitor of prostaglandin synthesis, meloxicam is used for the treatment of acute and chronic inflammation associated with musculoskeletal disease and for the management of postoperative pain.
In dogs, a one-time loading dose of 0. Once a therapeutic effect is seen, the dosage can be titrated to the lowest possible dose. GI safety appears to be greater for meloxicam than for nonselective NSAIDs, and meloxicam has been shown to be chondroneutral in rodent studies. COXCOX-2 ratios reported for deracoxib in in vitro cloned canine cell assays indicate it is 1,fold more selective for COX-2, whereas in vitro canine whole blood assays indicate it is to fold selective for COX Firocoxib is a coxib-class NSAID approved in the USA and Europe for the control of pain and inflammation associated with osteoarthritis and for the control of postoperative pain and inflammation associated with soft-tissue and orthopedic surgery in dogs.
In Canada, Australia, and New Zealand it is approved for use in osteoarthritis and soft-tissue and orthopedic surgery. It is available in a chewable tablet formulation. After administration PO, firocoxib is rapidly absorbed and then eliminated by hepatic metabolism and fecal excretion. Robenacoxib is used for the control of pain and inflammation associated with osteoarthritis, orthopedic and soft-tissue surgery in dogs approved in Europe , and for musculoskeletal disorders and soft-tissue surgeries in cats approved in the USA and Europe.
The elimination half-life is 1 hr after oral administration. Administration with food decreases bioavailability of robenacoxib. Inclusion of GSH led to a decrease in the formation of M3 with the concomitant formation of an unusual two-electron reduction product metabolite M7. The formation of M7 is proposed to arise via reduction of the imine bond in 2-oxopropylidene thiourea, an intermediate in the thiazole ring scission pathway in meloxicam.
In conclusion, the results of our analysis suggest that if the covalent binding of the two NSAIDs is important to the overall hepatotoxicity risk, the differences in metabolism differential preponderance of formation of the acylthiourea relative to total metabolism , differential effects of GSH on covalent binding, and finally differences in daily doses of the two NSAIDs may serve as a plausible explanation for the marked differences in toxicity. View Author Information. Tel: E-mail: [email protected].
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