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  • /Cytochrome P450 3A5 (CYP3A5) Genotyping

Diseases (24)

Diagnostic Testing (1)

Note:

Therapy selection and management.

Disease Management Testing (23)

Note:

Therapy selection and monitoring.


Note:

Therapy selection and monitoring.


Note:

Long term therapy selection and guidance.


Note:

Therapy selection and monitoring.


Note:

Therapy selection and management.


Note:

Therapy selection and monitoring.


Note:

Therapy selection and management.


Note:

Therapy selection and management.


Note:

Long term therapy selection.


Note:

Therapy selection and monitoring.


Note:

Long term therapy selection and monitoring.


Note:

Therapy selection and guidance.


Note:

Therapy selection and management.


Note:

Therapy selection and monitoring.


Note:

Can aid in drug selection and monitoring.


Note:

Long term therapy selection.


Note:

Therapy selection and monitoring.


Note:

Hyper tension therapy selection and dosing guidance.


Note:

Therapy selection and management.


Note:

Therapy selection and monitoring.


Note:

Therapy selection and monitoring.

Overview

Cytochrome P450 (CYP) represents a large superfamily of enzymes catalyzing oxidation of organic substances. CYP enzymes are integral in metabolizing both endogenous and exogenous substances, which include intermediates of lipids and steroidal hormones, drugs and toxic chemicals.

CYP3A, a subfamily of CYP450, consists of 4 genes CYP3A4, CYP3A5, CYP3A7, and CYP3A43. The substrates of the CYP3A subfamily constitute half of the drugs that are metabolized oxidatively by the CYP superfamily. Together, they help facilitate the elimination of 37% of the 200 most frequently prescribed drugs in the U.S. In adults, CYP3A4 and CYP3A5 are metabolically active and constitute approximately 30% of CYP activity. CYP3A5 expression is highly polymorphic. To date, there are 25 allelic variants of CYP3A5 (alleles numbered *1–*9).

Alleles CYP3A5*1 and CYP3A5*3 are distributed widely across various geographical and ethnic groups. CYP3A5*1 represents a functional CYP3A5 while CYP3A5*3 represents the most common non-functional variant which results in an enzyme with no activity. The CYP3A5*3B and *6 are also null alleles resulting also in no enzyme activity. The CYP3A5 alleles *2, 8 and 9 result in an enzyme that is partially active. Individuals with CYP3A5*1/*1 and *1/*3 genotypes express CYP3A5 and hence metabolize the substrates more rapidly than CYP3A5 3/*3* genotype and other non-expressers. Clinically important substrates include tacrolimus (immunosuppressive drug used in organ transplantation), midazolam, saquinavir (anti-retroviral drug), vincristine (mitotic inhibitor) and the statin group of drugs. The CYP3A5 enzyme activity influences the therapeutic dosing and dose-dependent adverse reactions of these substrates.

CYP3A5 variations have been associated with certain disease states including malignancies such as acute lymphoid leukemia and chronic myeloid leukemia.

Clinical Utility

  • Determining therapeutic strategy for therapeutics that are metabolized by the CYP3A5 gene product (antidepressant and other metabolized drugs)
  • Monitor and manage tacrolimus and statin drug therapy
  • Monitor and manage pain management drug therapy
  • As an aid in therapy of prostate cancer and leukemias

Interpretation

  • If genotype CYP3A5*1/*1 or *1/*3 or *1/*other alleles are detected, this would be reported as normal to intermediate metabolizer
  • If genotype CYP3A5*3/*3 is detected, or if CYP3A5*1 allele is NOT detected, this would be reported as a poor metabolizer

The following is a list of major therapeutic classes with drugs that are substantially metabolized by CYP3A.

Statins: atorvastatin, simvastatin, lovastatin.

Calcium channel blockers: nifedipine, verapamil, nicardipine, felodipine, nisoldipine.

Antiplatelets: clopidogrel, prasugrel, ticagrelor, cilostazol.

Antiarrhythmics: amiodarone, quinidine, disopyramide, lidocaine.

Example of angina treatments: ranolazine.

Angiotensin II Inhibitors: losartan.

Anticoagulants: rivaroxaban, apixaban.

The following is a list of major inhibitors that compete with other drugs for a particular enzyme thus affecting the optimal level of metabolism of the substrate drug which in many cases affect the individual's response to that particular medication, e.g. making it ineffective.

Strong inhibitor is one that causes a > 5-fold increase in the plasma AUC values or more than 80% decrease in clearance. This include: indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole,nefazodone, saquinavir, telithromycin

Moderate inhibitor is one that causes a > 2-fold increase in the plasma AUC values or 50-80% decrease in clearance. This include: aprepitant, erythromycin, fluconazole, grapefruit juice, verapamil, diltiazem

A Weak inhibitor is one that causes a > 1.25-fold but < 2-fold increase in the plasma AUC values or 20-50% decrease in clearance such as cimetidine, amiodarone, chloramphenicol, boceprevir, ciprofloxacin, delaviridine, diethyl, dithiocarbamate, fluvoxamine, gestodene, imatinib, mibefradil, mifepristone, norfloxacin, norfluoxetine, starfruit, telaprevir, voriconazole

Reference Ranges

CYP3A5 *1 (Normal-Intermediate metabolizer)

Methodology

PCR (Polymerase Chain Reaction) and hybridization to allele-specific probe; PCR and ARMS on Chip array technology, Real-Time PCR, Sequencing.

Specimen Collection

Acceptable specimens include buccal swab and peripheral blood (EDTA) or saliva. Buccal swabs can be collected by rubbing the inside of the cheeks with a swab (similar to a Q-tip and generally 4 swabs). The swabs are transported to the laboratory in a liquid medium (see manufacturer guidelines for details) or dry swab. Peripheral blood is collected through venipuncture. A minimum of 5-10 ml of whole blood is required. The specimen is collected in a lavender top (EDTA) tube.

Stability (Blood specimens):

  • Ambient: 5 days
  • Refrigerated: 7 days

Additional Testing

Therapeutic drug monitoring is the standard of care for monitoring patients on tacrolimus. Drug toxicity tests and clinical assessments are recommended for other drugs; other CYP enzymes such as CYP2D6, CYP2C19, and CYP2C9.

Turnaround Time

3-5 days.

CPT

81231

LOINC

ICD10

C91Lymphoid leukemia
C91.0Acute lymphoblastic leukemia [ALL]
C91.9Lymphoid leukemia, unspecified
D72.810Lymphocytopenia
D72.820Lymphocytosis (symptomatic)
E78Disorders of lipoprotein metabolism and other lipidemias
E78.0Pure hypercholesterolemia
E78.1Pure hyperglyceridemia
E78.2Mixed hyperlipidemia
E78.4Other hyperlipidemia
E78.5Hyperlipidemia, unspecified
F06Other mental disorders due to known physiological condition
F06.4Anxiety disorder due to known physiological condition
F10.1Alcohol abuse
F12.25Cannabis dependence with psychotic disorder
F16.20Hallucinogen dependence, uncomplicated
F20Schizophrenia
F20.0Paranoid schizophrenia
F20.1Disorganized schizophrenia
F20.2Catatonic schizophrenia
F20.3Undifferentiated schizophrenia
F20.5Residual schizophrenia
F20.8Other schizophrenia
F20.81Schizophreniform disorder
F20.89Other schizophrenia
F20.9Schizophrenia, unspecified
F22Delusional disorders
F23Brief psychotic disorder
F25.1Schizoaffective disorder, depressive type
F28Other psychotic disorder not due to a substance or known physiological condition
F29Unspecified psychosis not due to a substance or known physiological condition
F30.10Manic episode without psychotic symptoms, unspecified
F32Major depressive disorder, single episode
F32.0Major depressive disorder, single episode, mild
F32.1Major depressive disorder, single episode, moderate
F32.2Major depressive disorder, single episode, severe without psychotic features
F32.3Major depressive disorder, single episode, severe with psychotic features
F32.4Major depressive disorder, single episode, in partial remission
F32.5Major depressive disorder, single episode, in full remission
F32.8Other depressive episodes
F32.9Major depressive disorder, single episode, unspecified
F33Major depressive disorder, recurrent
F33.1Major depressive disorder, recurrent, moderate
F33.2Major depressive disorder, recurrent severe without psychotic features
F33.8Other recurrent depressive disorders
F39Unspecified mood [affective] disorder
F40Phobic anxiety disorders
F40.0Agoraphobia
F40.240Claustrophobia
F41Other anxiety disorders
F41.1Generalized anxiety disorder
F41.3Other mixed anxiety disorders
F41.9Anxiety disorder, unspecified
F42Obsessive-compulsive disorder
F43.0Acute stress reaction
F44.5Conversion disorder with seizures or convulsions
F45.4Pain disorders related to psychological factors
F45.41Pain disorder exclusively related to psychological factors
F60.8Other specific personality disorders
F90Attention-deficit hyperactivity disorders
F90.1Attention-deficit hyperactivity disorder, predominantly hyperactive type
F90.2Attention-deficit hyperactivity disorder, combined type
F90.8Attention-deficit hyperactivity disorder, other type
F90.9Attention-deficit hyperactivity disorder, unspecified type
F98Other behavioral and emotional disorders with onset usually occurring in childhood and adolescence
F99Mental disorder, not otherwise specified
G08Intracranial and intraspinal phlebitis and thrombophlebitis
G40Epilepsy and recurrent seizures
G40.1Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures
G40.89Other seizures
G40.9Epilepsy, unspecified
G45.3Amaurosis fugax
G45.9Transient cerebral ischemic attack, unspecified
G46.4Cerebellar stroke syndrome
G56.0Carpal tunnel syndrome
G73.7Myopathy in diseases classified elsewhere
G89Pain, not elsewhere classified
G89.1Acute pain, not elsewhere classified
G89.11Acute pain due to trauma
G89.12Acute post-thoracotomy pain
G89.18Other acute postprocedural pain
G89.21Chronic pain due to trauma
G89.22Chronic post-thoracotomy pain
G89.28Other chronic postprocedural pain
G89.3Neoplasm related pain (acute) (chronic)
G89.4Chronic pain syndrome
I10Essential (primary) hypertension
I11.0Hypertensive heart disease with heart failure
I15Secondary hypertension
I15.2Hypertension secondary to endocrine disorders
I15.8Other secondary hypertension
I15.9Secondary hypertension, unspecified
I20Angina pectoris
I20.0Unstable angina
I20.1Angina pectoris with documented spasm
I20.8Other forms of angina pectoris
I20.9Angina pectoris, unspecified
I24Other acute ischemic heart diseases
I24.8Other forms of acute ischemic heart disease
I32Pericarditis in diseases classified elsewhere
I39Endocarditis and heart valve disorders in diseases classified elsewhere
I41Myocarditis in diseases classified elsewhere
I61Nontraumatic intracerebral hemorrhage
I61.9Nontraumatic intracerebral hemorrhage, unspecified
I62Other and unspecified nontraumatic intracranial hemorrhage
I62.0Nontraumatic subdural hemorrhage
I63Cerebral infarction
I63.0Cerebral infarction due to thrombosis of precerebral arteries
I63.00Cerebral infarction due to thrombosis of unspecified precerebral artery
I63.8Other cerebral infarction
I63.9Cerebral infarction, unspecified
I67Other cerebrovascular diseases
I67.1Cerebral aneurysm, nonruptured
I67.82Cerebral ischemia
I87.39Chronic venous hypertension (idiopathic) with other complications
J99Respiratory disorders in diseases classified elsewhere
M05Rheumatoid arthritis with rheumatoid factor
M06Other rheumatoid arthritis
M06.9Rheumatoid arthritis, unspecified
M13Other arthritis
M13.0Polyarthritis, unspecified
M13.8Other specified arthritis
M15Polyosteoarthritis
M15.0Primary generalized (osteo)arthritis
M15.9Polyosteoarthritis, unspecified
M16Osteoarthritis of hip
M17Osteoarthritis of knee
M18Osteoarthritis of first carpometacarpal joint
M19Other and unspecified osteoarthritis
M19.0Primary osteoarthritis of other joints
M19.90Unspecified osteoarthritis, unspecified site
M19.93Secondary osteoarthritis, unspecified site
M25Other joint disorder, not elsewhere classified
M25.5Pain in joint
M33Dermatopolymyositis
M33.2Polymyositis
M34Systemic sclerosis [scleroderma]
M34.1CR(E)ST syndrome
M40Kyphosis and lordosis
M43.0Spondylolysis
M43.00Spondylolysis, site unspecified
M43.02Spondylolysis, cervical region
M43.04Spondylolysis, thoracic region
M43.06Spondylolysis, lumbar region
M43.10Spondylolisthesis, site unspecified
M45Ankylosing spondylitis
M47Spondylosis
M47.819Spondylosis without myelopathy or radiculopathy, site unspecified
M47.899Other spondylosis, site unspecified
M47.9Spondylosis, unspecified
M48.00Spinal stenosis, site unspecified
M48.04Spinal stenosis, thoracic region
M48.06Spinal stenosis, lumbar region
M48.3Traumatic spondylopathy
M48.30Traumatic spondylopathy, site unspecified
M48.4Fatigue fracture of vertebra
M48.8Other specified spondylopathies
M48.9Spondylopathy, unspecified
M51.24Other intervertebral disc displacement, thoracic region
M51.26Other intervertebral disc displacement, lumbar region
M51.87Other intervertebral disc disorders, lumbosacral region
M53.2X7Spinal instabilities, lumbosacral region
M53.2X9Spinal instabilities, site unspecified
M53.8Other specified dorsopathies
M53.86Other specified dorsopathies, lumbar region
M53.9Dorsopathy, unspecified
M54Dorsalgia
M54.0Panniculitis affecting regions of neck and back
M54.06Panniculitis affecting regions of neck and back, lumbar region
M54.1Radiculopathy
M54.10Radiculopathy, site unspecified
M54.17Radiculopathy, lumbosacral region
M54.2Cervicalgia
M54.3Sciatica
M54.30Sciatica, unspecified side
M54.5Low back pain
M54.6Pain in thoracic spine
M54.8Other dorsalgia
M65Synovitis and tenosynovitis
M67Other disorders of synovium and tendon
M70Soft tissue disorders related to use, overuse and pressure
M76.0Gluteal tendinitis
M79.0Rheumatism, unspecified
M79.1Myalgia
M79.603Pain in arm, unspecified
M79.65Pain in thigh
M79.7Fibromyalgia
M94.2Chondromalacia
R03Abnormal blood-pressure reading, without diagnosis
R10.10Upper abdominal pain, unspecified
R42Dizziness and giddiness
R52Pain, unspecified
R56Convulsions, not elsewhere classified
R56.1Post traumatic seizures
Z13.220Encounter for screening for lipoid disorders
Z79Long term (current) drug therapy
Z82.0Family history of epilepsy and other diseases of the nervous system
Z82.3Family history of stroke
Z86.59Personal history of other mental and behavioral disorders
Z86.69Personal history of other diseases of the nervous system and sense organs
Z86.73Personal history of transient ischemic attack (TIA), and cerebral infarction without residual deficits
Z91.19Patient's noncompliance with other medical treatment and regimen

References