Compositions for cyp450 phenotyping using saliva samples

Abstract

Disclosed are methods and compositions which may be used in human cytochrome P450 (CYP450) enzyme phenotyping. The methods and compositions typically utilize a mélange of substrates for different CYP450 enzymes which may be administered orally to a patient. Subsequently, the metabolites of the substrates may be detected in the patient's saliva as well as any non-metabolized substrates to calculate a metabolic ratio for any given CYP450 enzyme in order to generate a phenytopic CYP450 enzyme profile for the patient.

1 . A method comprising:
 (a) administering to a subject in need thereof a composition comprising:
 (i) a substrate for CYP1A2 (SUB CYP1A2 ), wherein CYP1A2 catalyzes conversion of SUB CYP1A2  to a metabolite (MET CYP1A2 ); 
 (ii) a substrate for CYP2C19 (SUB CYP2C19 ), wherein CYP2C19 catalyzes conversion of SUB CYP2C19  to a metabolite (MET CYP2C19 ); and 
 (iii) a substrate for CYP2D6 (SUB CYP2D6 ), wherein CYP2D6 catalyzes conversion of SUB CYP2D6  to a metabolite (MET CYP2D6 ); and 
   (b) quantifying in a saliva sample from the subject:
 (i) MET CYP1A2  and unconverted SUB CYP1A2 ; 
 (ii) MET CYP2C19  and unconverted SUB CYP2C19 ; and 
 (iii) MET CYP2D6  and unconverted SUB CYP2D6 . 
   
     
     
         2 .- 24 . (canceled) 
     
     
         25 . A composition comprising:
 (i) a substrate for CYP1A2 (SUB CYP1A2 ), wherein CYP1A2 catalyzes conversion of SUB CYP1A2  to a metabolite (MET CYP1A2 );   (ii) a substrate for CYP2C19 (SUB CYP2C19 ), wherein CYP2C19 catalyzes conversion of SUB CYP2C19  to a metabolite (MET CYP2C19 ); and   (iii) a substrate for CYP2D6 (SUB CYP2D6 ), wherein CYP2D6 catalyzes conversion of SUB CYP2D6  to a metabolite (MET CYP2D6 ).   
     
     
         26 .- 43 . (canceled) 
     
     
         44 . A method comprising:
 (a) administering to a subject in need thereof a composition comprising eplerenone; and   (b) quantifying in a saliva sample from the subject 6β-hydroxyeplerenone and/or 21-hydroxyeplerenone.   
     
     
         45 . The method of  claim 44 , further comprising determining a metabolic ratio for 6β-hydroxyeplerenone and/or 21-hydroxyeplerenone versus unconverted eplerenone. 
     
     
         46 . The method of  claim 44 , wherein the method further includes administering a dose of a drug, optionally by determining a metabolic ratio for 6β-hydroxyeplerenone and/or 21-hydroxyeplerenone versus unconverted eplerenone. 
     
     
         47 . The method of  claim 44 , wherein the subject is experiencing or at risk for developing hepatic failure and optionally the method includes assessing hepatic function in the patient, optionally by determining a metabolic ratio for 6β-hydroxyeplerenone and/or 21-hydroxyeplerenone versus unconverted eplerenone. 
     
     
         48 . The method of  claim 44 , wherein the method is performed in order to assess the subject's suitability for a drug study prior to the subject participating in the drug study, optionally by determining a metabolic ratio for 6β-hydroxyeplerenone and/or 21-hydroxyeplerenone versus unconverted eplerenone. 
     
     
         49 . The method of  claim 44 , wherein the composition comprising eplerenone is administered orally. 
     
     
         50 . The method of  claim 44 , wherein the subject in need thereof is a subject in need of an assessment of CYP3A4 activity. 
     
     
         51 . The method of  claim 44 , further comprising quantifying in the saliva sample from the subject 6β-hydroxyeplerenone and/or 21-hydroxyeplerenone. 
     
     
         52 . The method of  claim 51 , further comprising assessing CYP3A4 activity in the subject based on the quantified 6β-hydroxyeplerenone and 21-hydroxyeplerenone versus unconverted eplerenone. 
     
     
         53 . The method of  claim 44 , wherein the composition further comprises a substrate for an enzyme selected from a group consisting of an N-acetyl transferase (NAT), a methyl transferase, a UDP glucuronosyl transferase (UGT), a sulfo transferases, and an oxidative enzyme, or a combination thereof. 
     
     
         54 . The method of  claim 44 , wherein the composition further comprises a substrate for a UDP glucuronosyl transferase (UGT) selected from the group consisting of UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B 7. 
     
     
         55 . The method of  claim 44 , further comprising administering ketoprofen to the subject, and the method further comprising quantifying in a biological sample from the subject metabolites selected from the group consisting of beta-estradio-3-glucuronide, trifluoperazine-N-glucuronide, 5-hydroxytryptophol-O-glucuronide, propofol-O-glucuronide, zidovudine-5′-glucuronide, and combinations thereof. 
     
     
         56 . The method of  claim 44 , further comprising determining a metabolic ratio for 6β-hydroxyeplerenone and 21-hydroxyeplerenone versus unconverted eplerenone, and after determining the metabolic ratio, the method further comprising administering a dose of a drug that is metabolized by CYP3A4. 
     
     
         57 . The method of  claim 44 , wherein the subject is experiencing hepatic failure.