PGx drug transporter and metabolism Flashcards
Sources of variability in drug response
-genetic (targets, transporters, metabolizers)
-environemental (inducers, inhibitors)
-physiological (age, disease)
Performance
-ability of drug to elicit response and stay safe
-PK and PD
-function of the drug, formulation, and body: can be a moving target (pharmacogenetics/genomics)
-clinical testing not always accounting for SNPs
Bioavailability
-rate and extent of drug absorption
-needs may change due to PK/target changes from PGx
Absolute bioavailability
-AUC of given dosage form compared w AUC of IV dose
Bioequivalent
-does NOT mean effect is equivalent
-important for generics esp when PGx issues present
ADME
-inc as absorbed to Cmax, Tmax
-begins declining as disposition begins to in
-disposition phase as it lowers to elimination phase
-kabs
Absorption rate (Kd)
-defined by drug properties: excipient/drug comp and physiological barriers between body systems
-declines as disposition starts to inc
-compensate changes by changes in form or dose
DOSE changes due to PGx
-physiological factors
-formulation factors
-safety/efficacy response
-dosing regimen
-changes dictated by therapeutic window
SLC01B1 SNP and methotrexate (MTX)
-GWAS
-MTX clearance differences associated w SLC01B1 (solute carrier transporter) SNPs
-low cl rate = higher toxicity
-lower dose and inc hydration in children w SLC01B1 phenotypes
Other SNPs and OATPs
-clinical relevance of OATs w therapy have not been as widely reported
-SCL01B1 SNPs influence lopinavir levels and strongly tied to statin induced myopathy
-statins affected by SLC01B1 and ABCG2 (ATP-binding cassette transporter) SNPs
P-glycoprotein
-encoded by human MDR1 gene
-expressed in most organs involved in drug absorption and elmination such as intestine, liver, kidney, brain
-wide variety of LIPOPHILLIC substrates
-over expression associated w MDR phenotype (poor prognosis for cancers)
-4-5 efflux binding sites
-protective role in removing xenobiotics
P-gp SNPs
-normal genotype (CC) pt have lower Cmax, AUC, etc than homozygous (TT) for rifampin and digoxin due to changes in oral absorption
-disposition changes cannot be rules out
ABCG2 and SLC01B1 SNPs affect ethnicity statin PK
-higher exposure to statins within an ethnicity
-only ABCG2 C421>A polymorphism contributed towards between-pop exopsure differences
-individuals carrying WT alleles for both: AUC was higher in chinese and japanese over white
Example of CYP2D6 poor metabolizer effects on PK
-CYP2D6 poor metabolizers have higher levels of tricyclic antidepressants
-more so in whites
-caution w 2D6 inhibitors in normal metabolizers
Uridine Diphosphoclucuronosyl Transferases (UGTs) polymorphisms
-UGT1A128
-UGT1A193
-UgT2B15*2
UGT1A1*28 SNPs
-lower glucuronidation rates that influence toxicity of irinotecan
-severe hematological (esp neutropenia)
-nonhematological: diarrhea
UGT1A1*93
-high dose irinotecan effects
-grade 4 neutropenia
-very low neutrophil counts
UGT2B15*2
-no association w survival observed in breast cancer pt taking tamoxifen
-combo w SULT1A1*2 = shorter progression-free survival and overall survival times are observed
Phase II (conjugation)
-atypical pseudocholinesterase: beginning of pharmacogenetics, exaggerated response to succinylcholine
-glutathione-S-transferase: PM has hemolytic rxn. on primaquine
-Thiopurine-S-methyltransferase (TPMT): PM1 in 300 pt, leukopenia/death on azathioprine or 6-mp
-N-acetyltransferase: slow acetylators: hydralazine induced lupus or isoniazid peripheral neuropathy
-UDP-glucronosyl transferase (UGT) A1: irinotecan neutropenia and diarrhea, due to dec inactivation in PMs
atypical pseudocholinesterase conjugation
-beginning of PGx
-exaggerated response to succinylcholine
Glutathione-S-transferase conjugation
-PM has hemolytic reactions on primaquine
Thiopurine-S-methyltransferase (TPMT) conjugation
-PM in 1/300 pt
-leukopenia/death on azathioprine or 6-mp
N-acetyltransferase conjugation
-slow acetylators:
: hydralazine induced lupus or isoniazid peripheral
neuropathy
UDP-glucuronosyl transferase (UGT) A1 conjugation
Irinotecan neutropenia and diarrhea, due to decreased
inactivation in PMs
