| Summary: | 碩士 === 臺北醫學大學 === 藥學研究所 === 97 === Inter- or intra-individual variability of second-generation antipsychotics in therapeutic outcomes has been reported. Olanzapine (OLZ) exerts its benefits in therapeutic action; however, they can lead to metabolic complications. Drugs, such as metformin and topiramate, activates AMP-activated protein kinase (AMPK) were reported to ameliorate weight gain induced by OLZ. Here, we aimed to establish an analytical system to undergo OLZ therapeutic drug monitoring (TDM). Effects of OLA, N-Desmethyl-olanzapine (DMO) or Rehmannia dride rhizome crude extracts on AMPK were investigated. Methods: First, a high performance liquid chromatography with electrochemical detector (HPLC-ECD), was set up for OLZ and DMO serum concentration determinations, and further applied for patients (June 2007 to October 2008) who were diagnosed with schizophrenia and schizoaffective disorder and have been taking OLZ for 3 months. The determined OLZ and DMO serum concentrations were used to calculate OLZ, DMO concentration-dose ratio (C/D ratio). The correlations between dose or C/D ratios and various parameters will be examined. C2C12 myoblasts cell culture system was used to test effects of OLZ, DMO or Rehmannia dride rhizome crude extracts on AMPK. Results: (I) the HPLC-ECD system condition such as guard cell was set at +400 mV, the analytical cells was set at -200 mV (channel I) and +300 mV (channel II). Analytical C18 column with 15 cm length was used while eluted with mobile phase containing 50 mM phosphate salt buffer: acetonitrile: methanol=67:22:11. The flow rate was set at 1.0 ml/min to complete one sample for OLZ, DMO, and internal standard within 30 minutes. The detection limitation of OLZ or DMO was 1 ng/ml. (II) seventy-nine patients with 99 samples were included in this study. There are correlations between OLZ daily dose and patients’ weight, BMI, waist, BUN, progesterone [r=0.228 (p=0.022), r=0.230 (p=0.021), r=0.260 (p=0.009), r=0.227 (p=0.022), r=-0.153 (p=0.018)]. OLZ serum concentrations correlate with OLZ daily dose [r=0.311 (p=0.002)]. In this study, OLZ C/D ratios, but not DMO or DMO C/D ratio, of patients who were female (50.5%) or non-smokers (67.68%) were higher than male or smokers significantly (p<0.05). There are negative correlations between OLZ serum concentration and progesterone, testosterone [r=-0.220 (p=0.028), r=-0.213 (p=0.033)]. OLZ C/D ratio correlates negatively with waist [r=-0.207 (p=0.038)]. The mean and median of DMO C/D ratio were 0.54 and 0.43 ng/ml/mg (n=99). There are negative correlations between DMO C/D ratio and systolic blood pressure, waist [r=-0.238 (p=0.018), r=-0.247 (p=0.014)]. There are correlations between DMO serum concentration and prolactin, BUN, creatinine [r=0.488 (p<0.001), r=0.299 (p=0.002), r=0.606 (p<0.001)]. The serum concentrations of OLZ and DMO obtained from adults showed inter- and intra-individual variability. Pearson’s correlation was used to analyze the correlation between the intra-individual differences of OLZ and DMO serum concentration or C/D ratio with the factors among 11 patients. There are negative correlations between the difference of OLZ serum concentration and patients’ height, C-peptide, uric acid, triglyceride, testosterone [r=-0.558 (p=0.016), r=-0.539 (p=0.021), r=-0.506 (p=0.032), r=-0.470 (p=0.049), r=-0.629 (p=0.005)]. There are correlations between the differences of DMO serum concentration and age, creatinine [r=0.503 (p=0.033), r=0.671 (p=0.002)]. (III) C2C12 treated with OLZ or DMO（0.2, 2, 10, 20μM）did not change phosphate-AMPK at 120 minutes significantly. Rehmannia dride rhizome crude extracts (3, 10, 30 μg/ml) had dose-dependent activity to increase phosphated-AMPK, significantly (30 μg/ml, 2.02 ± 0.33 fold, p<0.05). Conclusions: Our results suggest that obese patients may need higher OLZ daily doses and higher OLZ serum concentration may also observed in patients who have higher OLZ daily doses. TDM is suggested for patient who is on OLZ including its metabolite DMO since serum concentration may provide possible prediction on metabolic syndrome, even though there are inter- or intra-individual variability in C/D ratio present in this adult patient study group. OLZ (0.2~20μM) did not cause phosphated-AMPK changes and future study on establishing OLZ-induced metabolic dysregulation study model is needed in order to identify potential modulation roles for Rehmannia dride rhizome.
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