Pil Whan Park

Effect of polymorphic CYP3A5 genotype on the single-dose simvastatin pharmacokinetics in healthy subjects

Simvastatin, a cholesterol‐lowering agent, is mainly metabolized by CYP3A4/5. The objective of this study was to investigate the effect of CYP3A5*3 genotype on the pharmacokinetics of simvastatin in humans. Twenty‐two men with CYP3A5*1/*1 (n = 4), CYP3A5*1/*3 (n = 8), or CYP3A5*3/*3 (n = 10) genotypes were enrolled. Each subject ingested a 20‐mg dose of simvastatin, and plasma simvastatin concentrations were measured for 12 hours after dosing. The mean (±SD) area under the plasma concentration‐time curve for simvastatin in the CYP3A5*1/*1 carriers (4.94 ± 2.25 ng • h/mL) was significantly lower than CYP3A5*3/*3 carriers (16.35 ± 6.37 ng • h/mL; P = .013, Bonferroni test). The mean (±SD) oral clearance was also significantly different between CYP3A5*1/*1 carriers (4.80 ± 2.35 L/h) and CYP3A5*3/*3 carriers (1.35 ± 0.61 L/h; P < .05, Dunns test). However, other pharmacokinetic parameters including peak plasma concentrations and half‐life did not show any difference between genotype groups. These findings suggest that the polymorphic CYP3A5 gene affects the disposition of simvastatin and provides a plausible explanation for interindividual variability of simvastatin disposition.

Cytochrome P450 3A inhibitor itraconazole affects plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients

Despite the belief that cytochrome P450 (CYP) 2D6 alone is responsible for the metabolism of risperidone, several studies suggest that CYP3A may be involved. The aim of this study was to evaluate the effect of itraconazole, a CYP3A inhibitor, on the plasma concentrations of risperidone and 9‐hydroxyrisperidone in schizophrenic patients in relation to CYP2D6 genotype.

Randomized, open-label, two-period crossover comparison of the pharmacokinetic and pharmacodynamic properties of two amlodipine formulations in healthy adult male Korean subjects.

BACKGROUND Amlodipine, a third-generation dihydropyridine calcium antagonist, is prescribed in the management of angina and hypertension. A newly developed amlodipine formulation (amlodipine camsylate) is associated with similar physical properties, melting point, and solubility-and improved stability against long-term stability test and accelerated temperature test-compared with the conventional formulation (amlodipine besylate). OBJECTIVE This study was performed to compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties and safety profiles of a newly developed amlodipine formulation with a conventional formulation in healthy male subjects. METHODS This randomized, open-label, 2-period crossover comparative study was conducted at the Clinical Trial Center, Gil Medical Center, Gachon Medical School (Incheon, Korea). Eighteen healthy male Korean subjects aged 20 to 40 years were enrolled. All subjects received a single oral dose (5-mg tablet) of a conventional (reference) or newly developed (test) amlodipine formulation. Blood samples for PK analysis of amlodipine were obtained during the 144-hour period after dosing. Systolic and diastolic blood pressure (BP) (SBP and DBP, respectively) and pulse rate (PR) were measured just before each blood sampling. Assessment of safety profiles, including hematology and biochemistry, electrocardiography, urinalysis, and monitoring of adverse events (AEs), was performed. RESULTS All participants completed both treatment periods. Their mean (SD) age was 22.3 (1.5) years (range, 20-25 years) and their mean (SD) body weight was 67.9 (5.6) kg (range, 57-77 kg). The plasma concentration-time profiles of amlodipine were similar after administration of the 2 formulations. The reference and test formulations were pharmacokinetically equivalent. The 90% CIs for the mean treatment ratios of the log-transformed peak plasma concentration and the area under the plasma concentration-time curve were within the predetermined equivalence range of 80% to 125%. Despite administration of a single dose, significant maximal changes in SBP, DBP, and PR were achieved after drug administration for both formulations compared with baseline values (all, P < 0.001). No significant differences in PD profiles were found between the 2 formulations. No clinically relevant changes were observed in physical, biochemical, hematologic, electrocardiographic, or urinalysis findings during the study. Neither formulation caused any AEs during the study. CONCLUSIONS The 2 amlodipine formulations were pharmacokinetically equivalent and showed similar PD characteristics in these healthy male subjects.

Effect of Rifampin, an Inducer of CYP3A and P-glycoprotein, on the Pharmacokinetics of Risperidone

The authors studied the effect of rifampin, a dual inducer of CYP3A and P‐glycoprotein, on the pharmacokinetics and pharmacodynamics of risperidone in humans. Ten healthy male subjects were treated daily for 7 days with 600 mg rifampin or with placebo. On day 6, a single dose of 1 mg risperidone was administered. Plasma risperidone and 9‐hydroxyrisperidone concentrations were measured. Rifampin significantly decreased the mean area under the plasma concentration–time curve by 51% for risperidone, by 43% for 9‐hydroxyrisperidone, and by 45% for the active moieties (risperidone + 9‐hydroxyrisperidone). Rifampin also decreased the peak plasma concentration of risperidone by 38%, 9‐hydroxyrisperidone by 46%, and the active moieties by 41%. The apparent oral clearance of risperidone approximately doubled after rifampin treatment. Thus, rifampin reduced the exposure to risperidone, probably because of a decrease in its bioavailability through the induction of CYP3A and probably P‐glycoprotein.

The relationship between iron parameters and platelet parameters in women with iron deficiency anemia and thrombocytosis

Changes of platelet count (PLT) and platelet parameters have been reported in iron deficiency anemia (IDA). However, the relationship between iron metabolism and thrombopoiesis is not yet fully known. We studied the relationship between iron and platelet parameters in women with IDA and thrombocytosis. Forty-one adult women with IDA and thrombocytosis were enrolled. The relationship between iron parameters (such as serum iron, serum ferritin, total iron-binding capacity (TIBC)C, and transferrin saturation (Tfsat)), and platelet parameters (PLT, platelet crit (PCT), mean platelet volume (MPV), mean platelet component (MPC), mean platelet mass, platelet distribution width, and large platelet (LPLT)), which measured with CBC on ADVIA, were investigated. In addition, the difference in platelet and iron parameters between severe IDA (Hb < 7 g/dl) and non-severe IDA were compared. PLT inversely correlated with serum iron and Tfsat (p < 0.05). Serum iron and TIBC revealed no significant relationships with any platelet parameters. PLT, PCT, and MPV inversely correlated with mean corpuscular hemoglobin concentration (MCHC) but MPC exhibited linear correlation with Hb, hematocrit, and MCHC (p < 0.05). PCT had linear correlation with PLT and MPV (p < 0.001), whereas PCT, MPV, and LPLT (p < 0.001 for two formers, p < 0.05) inversely correlated with MPC. In this study, the important iron parameters affecting PLT were serum iron and Tfsat. In addition, patients with more severe and hypochromic anemia had higher PLT, PCT, and MPV.

Interaction between Brain-Derived Neurotrophic Factor Val66Met Polymorphism and Recent Negative Stressor in Harm Avoidance

There have been controversial results regarding the association between brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and anxiety-related traits such as harm avoidance (HA). We aimed to investigate the interaction between BDNF Val66Met polymorphism and negative life stressors in HA. BDNF Val66Met polymorphism was genotyped in 391 community-dwelling Koreans (152 males, 239 females; 43.2 ± 14.1 years old). The Temperament and Character Inventory (TCI) and the Center for Epidemiological Studies for Depression Scale (CES-D) were self applied. The Structured Clinical Interview for DSM-IV axis I disorders and face-to-face interviews investigating negative life stressors within the last 6 months were also performed. There was no significant difference in TCI score, major depressive disorder prevalence and CES-D score among the 3 genotypes (94 Met/Met, 188 Val/Met and 109 Val/Val subjects). There was no significant difference in TCI scores between subjects with stressors and those without stressors, while more common major depressive episodes (p = 0.03) and higher CES-D scores (p < 0.001) were found in subjects with stressors. However, there was a significant interaction between the BDNF genotype and negative life stressors in HA (p = 0.02). Only subjects with the Val/Val genotype showed higher HA with recent negative stressors. Our finding suggests that BDNF Val66Met polymorphism might influence HA by interacting with recent negative stress experience.

Genetic polymorphisms and linkage disequilibrium of sulfotransferase SULT1A1 and SULT1A2 in a Korean population: Comparison of other ethnic groups

Aims: To determine the allele frequencies of sulfotransferases (SULTs) 1A1 and 1A2 and their linkage disequilibrium in a Korean population and compare them with those of other ethnic groups. Methods: Genotypes of the SULT1A1*1, *2, and *3 and SULT1A2*1, *2, and *3 allelic variants were determined in 234 Korean subjects using polymerase chain reaction (PCR)–restriction fragment length polymorphism (RFLP) methods. Results: Allele frequencies for SULT1A1*1 and *2 were 0.876 [95% confidence interval (CI), 0.843–0.905] and 0.124 (95% CI, 0.096–0.157), respectively. Similarly, those for SULT1A2*1 and *2 were 0.885 (95% CI, 0.852–0.912) and 0.115 (95% CI, 0.088–0.150), respectively. However, no subject with SULT1A1*3 or SULT1A2*3 was detected. These genotype distributions are similar to those of Asian populations including the Chinese and Japanese, but quite different from other ethnic groups such as African-Americans and Caucasians. The expected allelic frequencies of SULT1A1 and SULT1A2 at Hardy–Weinberg equilibrium are quite similar to the observed distributions in the population. SULT1A1*2 and SULT1A2*2, the most common variant alleles of these two genes, are strongly and positively linked in the Korean population (D′=0.8919, χ2 =343.24, P=0.0034). Conclusions: SULT1A1*2 and SULT1A2*2 are the major allelic variants in the Korean population, whereas the SULT1A1*3 and SULT1A2*3 alleles were not found. SULT1A1*2 and SULT1A2*2 are strongly linked.

A Case of B-cell Lymphoma, Unclassifiable, with Features Intermediate between Diffuse Large B-cell Lymphoma and Burkitt Lymphoma in a Korean Child

B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) (intermediate DLBCL/BL), is a heterogeneous group with some features resembling DLBCL and others resembling BL. Here, we report a case of intermediate DLBCL/BL in a Korean child. A 2-yr-old male was admitted for evaluation and management of left hip pain. Immunohistochemistry of a biopsy of the femur neck revealed tumor cells positive for CD20, CD10, BCL2, BCL6, and Ki67. A bone marrow (BM) aspirate smear revealed that 49.3% of all nucleated cells were abnormal lymphoid cells, composed of large- and medium-sized cells. Immunophenotyping of the neoplastic cells revealed positivity for CD19, CD10, CD20, and sIg lambda and negativity for CD34, Tdt, and myeloperoxidase (MPO). Cytogenetic and FISH analyses showed a complex karyotype, including t(8;14)(q24.1;q32) and IGH-MYC fusion. Intensive chemotherapy was initiated, including prednisone, vincristine, L-asparaginase, daunorubicin, and central nervous system prophylaxis with intrathecal methotrexate (MTX) and cytarabine. One month after the initial diagnosis, BM examination revealed the persistent of abnormal lymphoid cells; cerebrospinal fluid cytology, including cytospin, showed atypical lymphoid cells. The patient was treated again with cyclophosphamide, vincristine, prednisone, adriamycin, MTX, and intrathecal MTX and cytarabine. The patient died of sepsis 5 months after the second round of chemotherapy.

Effect of Cytochrome P450 3A5*3 genotype on the stereoselective pharmacokinetics of amlodipine in healthy subjects

Amlodipine is a racemic mixture composed of S- and R-form and metabolized stereoselectively. Cytochrome P450 3A (CYP3A) including CYP3A5 are involved in the metabolism of amlodipine and it was reported that polymorphic CYP3A5 genotype modulates the plasma levels of amlodipine and thus affect its pharmacokinetics. This study was conducted to find whether stereoselective pharmacokinetics of amlodipine was affected by the polymorphic CYP3A5 genotype. Seventeen healthy subjects were genotyped for CYP3A5*3 variant. After a single dose of 10-mg amlodipine, enantiomers of amlodipine were analyzed using HPLC-MS/MS equipped with an AGP column. Amlodipine showed stereoselective pharmacokinetics. S-amlodipine exhibited higher plasma levels than R-amlodipine in both genotype groups. S-amlodipine showed 15% higher mean peak plasma concentrations (Cmax) in CYP3A5*1/*3 carriers (3.28 ng/ml) than CYP3A5*3/*3 carriers (2.85 ng/ml) (P = 0.194) and R-amlodipine also showed 21% higher Cmax in CYP3A5*1/*3 carriers (3.33 ng/ml) than CYP3A5*3/*3 carriers (2.75 ng/ml) (P = 0.114). CYP3A5*1/*3 carriers also have 23 and 12% higher mean area under the time versus concentration curve of R-amlodipine and S-amlodipine than CYP3A5*3/*3 carriers, respectively (for R-amlodipine, 147.1 ng*h/ml for CYP3A5*1/*3 carriers versus 121.8 ng*h/ml for CYP3A5*3/*3 carriers, P = 0.234; for S-amlodipine, 161.6 ng*h/ml for CYP3A5*1/*3 carriers vs. 144.2 ng*h/ml for CYP3A5*3/*3 carriers, P = 0.353). Other pharmacokinetic parameters also showed no significant difference between them. In conclusion, the present study showed that despite the evidence that amlodipine is stereoselectively metabolized, CYP3A5*3 genotype did not affect stereoselective disposition of amlodipine. It provides the evidence that CYP3A5*3genotype plays a minor role in the interindividual variability of stereoselective disposition of amlodipine in humans.

Comparative pharmacokinetic and pharmacodynamic characteristics of amlodipine besylate and amlodipine nicotinate in healthy subjects.

BACKGROUND AND AIM Amlodipine, a dihydropyridine calcium antagonist, is prescribed for the management of angina and hypertension, and is sold as amlodipine besylate. However, a new salt formulation, amlodipine nicotinate, has recently been developed. Here, we evaluated the comparative pharmacokinetic and pharmacodynamic characteristics of the nicotinate and besylate forms of amlodipine. SUBJECTS AND METHODS A randomized, 2-way crossover study was conducted in 18 healthy male volunteers to compare the pharmacokinetics and pharmacodynamics of these two forms, i.e. amlodipine nicotinate (test) and amlodipine besylate (reference), after administration of a single dose of 5 mg of each drug and a washout period between doses of 4 weeks. Blood samples for the pharmacokinetic analysis of amlodipine were obtained over the 144-hour period after administration. Systolic and diastolic blood pressures and pulse rates were recorded immediately prior to each blood sampling. RESULTS All participants completed both treatment periods, and no serious adverse events occurred during the study period. After administering a single dose of each formulation, mean AUC0-infinity and Cmax values were 190.91+/-60.49 ng x h/ml and 3.87+/-1.04 ng/ml for the test formulation and 203.15+/-52.05 ng x h/ml and 4.01+/-0.60 ng/ml for the reference formulation, respectively. The 90% confidence intervals of test/reference mean ratios for AUC0- infinity and Cmax fell within the predetermined equivalence range of 80 - 125%. Pharmacodynamic profiles including systolic and diastolic blood pressures and pulse rates exhibited no significant differences between the two formulations. CONCLUSION The two amlodipine formulations showed similar pharmacokinetic and pharmacodynamic characteristics and the new amlodipine formulation, amlodipine nicotinate, was found to be equivalent for pharmacokinetics to the currently available amlodipine besylate with respect to the rate and extent of amlodipine absorption.