TY - JOUR
T1 - Correlation of cytochrome p450 (CYP) ia2 activity using caffeine phenotyping and olanzapine disposition in healthyvolunteers
AU - Shirley, Kara Lee
AU - Hon, Yuen Y.
AU - Penzak, Scott Robert
AU - Francis Lam, Y. W.
AU - Spratlin, Vicky
AU - Jann, Michael W.
PY - 2003/5
Y1 - 2003/5
N2 - Olanzapine has previously been shown to have predominant metabolism by cytochrome (CYP) P450 IA2. Caffeine has been shown to provide an accurate phenotypic probe for measuring CYP1A2 activity. The purpose ofthis study is to determine if a significant correlationexists between olanzapine disposition and caffeine metabolic ratios. Subjects were phenotyped for CYP1A2 activity with caffeine probemethodology. After 200-mg caffeine administration, blood (4 h), saliva (6 and 10 h), and urine (8 h total) were collected for highperformance liquid chromatography (HPLC) analysis of caffeine and its metabolites.CYP1A2 activity was measured as plasma (PMR^h), saliva (SMR6hand SMR10h), and three urinary metabolic (UMR18h, UMR28h, and UMR38h) ratios. Each ofthe 14 healthy nonsmokers(13 male) received a single 10 mg olanzapine dose after which blood was collected for HPLC determination of olanzapine concentrationsat predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, and 120 h postdose. Olanzapine pharmacokinetic parameters in thisstudy were similar to those previously published. Allcaffeine metabolic ratios (PMR4h, SMR6h, SMR10h, UMR18h, and UMR28h)significantly correlated with each other (p<0.001) except for UMR38 h, which did not correlate. A significant correlation (p<0.05) wasalso found between olanzapine clearance and PMR_4h(r =0.701), SMR6h(r = 0.644), SMR10h(r = 0.701), UMR18h(r = 0.745), andUMR28h(r = 0.710). A negative correlation was observed between olanzapine clearance and UMR38h(r =0.029, p=NS). Asignificant correlation was found between olanzapine clearance and various caffeine metabolic ratios. Interpatient variability in CYP1A2activity may explain the wide interpatient variability in olanzapine disposition. Compounds that modulate CYP1A2 activity may beexpected to alter olanzapine pharmacokinetics accordingly.
AB - Olanzapine has previously been shown to have predominant metabolism by cytochrome (CYP) P450 IA2. Caffeine has been shown to provide an accurate phenotypic probe for measuring CYP1A2 activity. The purpose ofthis study is to determine if a significant correlationexists between olanzapine disposition and caffeine metabolic ratios. Subjects were phenotyped for CYP1A2 activity with caffeine probemethodology. After 200-mg caffeine administration, blood (4 h), saliva (6 and 10 h), and urine (8 h total) were collected for highperformance liquid chromatography (HPLC) analysis of caffeine and its metabolites.CYP1A2 activity was measured as plasma (PMR^h), saliva (SMR6hand SMR10h), and three urinary metabolic (UMR18h, UMR28h, and UMR38h) ratios. Each ofthe 14 healthy nonsmokers(13 male) received a single 10 mg olanzapine dose after which blood was collected for HPLC determination of olanzapine concentrationsat predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, and 120 h postdose. Olanzapine pharmacokinetic parameters in thisstudy were similar to those previously published. Allcaffeine metabolic ratios (PMR4h, SMR6h, SMR10h, UMR18h, and UMR28h)significantly correlated with each other (p<0.001) except for UMR38 h, which did not correlate. A significant correlation (p<0.05) wasalso found between olanzapine clearance and PMR_4h(r =0.701), SMR6h(r = 0.644), SMR10h(r = 0.701), UMR18h(r = 0.745), andUMR28h(r = 0.710). A negative correlation was observed between olanzapine clearance and UMR38h(r =0.029, p=NS). Asignificant correlation was found between olanzapine clearance and various caffeine metabolic ratios. Interpatient variability in CYP1A2activity may explain the wide interpatient variability in olanzapine disposition. Compounds that modulate CYP1A2 activity may beexpected to alter olanzapine pharmacokinetics accordingly.
KW - CYPIA2
KW - Caffeine
KW - Olanzapine
KW - Pharmacokinetics
UR - http://www.scopus.com/inward/record.url?scp=0038050712&partnerID=8YFLogxK
U2 - 10.1038/sj.npp.1300123
DO - 10.1038/sj.npp.1300123
M3 - Article
C2 - 12644842
AN - SCOPUS:0038050712
SN - 0893-133X
VL - 28
SP - 961
EP - 966
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 5
ER -