This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The purose of the porposed project is 1. To study pharmacokinetic (PK) and pharmacodynamic (PD) variability of morphine during the steady state (no pain) in patients with sickle cell disease and 2. To study associated of variability of PK and PD with polymorphisms (SNPs) of UGT1A1, UGT2B7 family of enzyme and mu (u) opioid receptors. Painful episodes are themost common reason for hospitalization in patients with Sickle Cell Disease (SCD). Morphine and other opioid analgesics are frequently needed to control moderate and severe pain in these patients. In practice many patients do not achieve adequate pain control with standard doses of opioids. Studies in patients with SCD during painful crises have demonstrated large inter-patient variability in clearance and other pharmacokinetic (PK) parameters of Morphine in SCD. Variability has been demonstrated in non SCD populations also. The reasons for this variability are poorly understood. Most of the studies in patients with SCD were performed during painful crises. We are not aware of any large PK and PD studies during steady state (no pain) in patients with SCD. Pharmacodynamic (PD) differences have also been demonstrated for morphine and other opioids. Only a few studies have explored genetic differences for opioids. Little work has been done to study the polymorphisms of uridine diphosphate glucuronosyl transferase (UGT) enzymes, which are the main enzymes responsible for metabolim (glucuronidation) of Morphine. Little investigation has been done in exploring the role of mu receptor polymorphism in variability of morphine pharmacodynmaics in SCD. Singel Nucleotide Polymorphine (SNPs) for the two main subfamilies of UGTs, UGT1 and UGT2 focusing on UGT 1A1 and UGT 2B7 as well as for the genes for mu receptors will studied in 100 normal Afro-American adults (without SCD). We will perform a PK, PD studies in 60 adults (ages over 18 years). These patients will be admitted to the General Clinical Research Center for single dose PK of morphine for 36 hours during steady state of health (no pain). Pain tolerane threshold (PTT) will be used as a surrogate PD measure for analgesia. PK will be modeled using NONMEM. Study of SNPs in the genes of interest will be performed in these patients. The primary objective of this study is to: 1) determine pharmacokinetic (PK) and pharmacodynamic (PD) parameters and their inter-patient variability of morphine in a population of adult subjects with SCD in steady state of health and; 2) to explore if variations in PKs and PDs are related to SNPs in UGT and mu receptors. Another objective is to characterize the spectrum of genetic polymorphism that may be associated with variation in morphine pharmacokinetics and pharmacodynamics (UGT1A1, UGT2B7 and opioid mu receptors) in Afrincan Americans. An additional objective is to standardize the use of PTT as a marker for PD of Morphine. We hope this study will serve as a mode for future studies in PK, PK and pharmacogentics of opioids in SCD and African American population. Hypothesis and Specific Aims We hypothesize that there is significant inter subject variability in morphine PK and PD in subjects with SCD in steady state of health. We also hypothesize that varying levels of active morphine metabolites (such as 6-0 glucoronide) and different rates of clearance will be associated with SNPs for UGT1A1 and UGT2B7. Similarly, we hypothesize that variability in pharmacodynamic response to morphine as demonstrated by variability in PTT (Pain Tolerance Threshold) will be associated with polymorphism in mu receptors. Our first step in conducting this research will be to define the frequency of SNPs in the genes of interest in general Afro-American populaton. Second step will be to investigate inter-patient variability in PK and PD parameters and to determine if some or all the variatins in PKs and PDs can be related to single nucleotide polymorphisms (SNPs) in UGT and mu receptors. Our specfici aims for these studies are: 1. To characterize the spectrum of genetic polymorphism that may be associated with variation in morphine pharmacokinetics and pharmacodynamics (UGT1A1, UGT2B7 and opioid mu receptors) in a group of African Americans (non-SCD) by screening the entire genes of interest including exons, exon-intro juctions and promoter regions. 2. To determine pharmacokinetic (PK) and pharmacodynamic (PD) parameters of morphine in a population of adolescent and young adult subjects with sickle cell disease (SCD) in steady state of health. 3. To determine if variations in PKs and PDs are related to single nucleotide polymorphisms (SNPs) in UGT and mu receptors. 4. We hope to use this study as a mode for future studies on pharmacogenetics of analgesia, dependence and addiction to morphine and other opioids in African America
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