Kimiko Tsutsumi

The effect of pregnancy on cytochrome P4501A2, xanthine oxidase, and N‐acetyltransferase activities in humans

Our objective was to evaluate the activity of cytochrome P4501A2 (CYP1A2), xanthine oxidase (XO), and N ‐acetyltransferase 2 (NAT2) from early to late pregnancy and after delivery.

Effect of St. John's wort on the pharmacokinetics of theophylline in healthy volunteers

The objective of this study was to investigate the effect of St. Johns wort (SJW, Hypericum perforatum) on the pharmacokinetics of theophylline in healthy volunteers. Twelve healthy Japanese male volunteers participated in this randomized, open‐labeled, crossover study. The subjects took an SJW caplet (300 mg) three times a day for 15 days. On day 14, they received a single oral dose of 400 mg of theophylline. They took the same dose of theophylline without SJW treatment on another occasion. Plasma and urine samples were obtained during a 48‐hour period after theophylline administration. Theophylline concentrations in plasma and urine, as well as the major metabolites (13U, 1U, 3X) in urine, were measured. SJW caused no significant changes in the pharmacokinetics of theophylline in plasma. SJW administration tended to increase the ratio of 1U/the total amount excreted in urine. However, no changes in the ratio of unchanged theophylline, 13U, and 3X were observed. It is unlikely that the effect of 15 days of treatment with SJW on CYPs is sufficient to cause a change in plasma theophylline concentrations.

Effect of the Treatment Period With Erythromycin on Cytochrome P450 3A Activity in Humans

The aim of the present study was to estimate the time course change in cytochrome P450 3A (CYP3A) activity during repeated doses of erythromycin. Twelve healthy male volunteers participated in this randomized, 4 × 4 Latin square design study. The pharmacokinetics of a single oral dose of midazolam, a probe for CYP3A activity, were assessed in 4 conditions: (1) midazolam (5 mg) without erythromycin (EM0), (2) erythromycin 2 days + midazolam (2.5 mg) (EM2), (3) erythromycin 4 days + midazolam (2.5 mg) (EM4), and (4) erythromycin 7 days + midazolam (2.5 mg) (EM7). The dose of erythromycin was 800 mg/d. Erythromycin produced a 2.3‐, 3.4‐, and 3.4‐fold increase in dose‐corrected area under the curve of midazolam for EM2, EM4, and EM7, respectively, as compared with EM0 (P <.05/6). A significant prolongation of terminal half‐life was observed in EM4 and EM7. The relationship between the duration of erythromycin treatment and total clearance of midazolam indicated that a plateau level of CYP3A inhibition can be achieved by 4 days or more of erythromycin treatment. The repeated treatment with erythromycin yields CYP3A inhibition in a duration‐dependent manner. A 4‐day course of erythromycin treatment produces 90% or more of the maximal inhibition of CYP3A in humans.

The recovery time‐course of CYP3A after induction by St John's wort administration

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT St Johns wort causes the induction of CYP3A. Little is known about how long the effect remains after cessation of St Johns wort. WHAT THIS STUDY ADDS The in vivo CYP3A activity returns progressively to the basal level approximately 1 week after cessation of St Johns wort administration AIMS To examine the recovery time course of CYP3A after enzyme induction by St Johns wort administration. METHODS The subjects were 12 healthy men, aged 20-33 years. On the first day, they received an oral dose of midazolam 5 mg without St Johns wort (day -14). From the next day, they took St Johns wort for 14 days. On the last day of St Johns wort treatment (day 0) and 3 and 7 days after completion of St Johns wort treatment (days 3 and 7), they received the same dose of midazolam. On each day, blood samples were obtained until 8 h after midazolam administration. Plasma concentrations of midazolam were measured by HPLC. Pharmacokinetic parameters of midazolam were determined using noncompartmental analysis. RESULTS Apparent oral clearance of midazolam was significantly increased after St Johns wort administration from 65.3 +/- 8.4 l h(-1) (day -14) to 86.8 +/- 17.3 l h(-1) (day 0). It returned to the control level 7 days after the completion of St Johns wort (day 7, 59.7 +/- 3.8 l h(-1)). No significant difference in the elimination half-life between the four periods of the study was observed. The changes in apparent oral clearance after St Johns wort discontinuation indicated that CYP3A activity recovers from enzyme induction with an estimated half-life of 46.2 h. CONCLUSIONS CYP3A activity induced by St Johns wort administration progressively returns to the basal level after approximately 1 week. This finding may provide useful information to avoid clinically significant interactions of St Johns wort with CYP3A substrates.

Drug Interaction between Cimetidine and Timolol Ophthalmic Solution: Effect on Heart Rate and Intraocular Pressure in Healthy Japanese Volunteers

Systemic adverse effects of timolol ophthalmic solution given at usual therapeutic doses have been well characterized. Timolol is partially metabolized by cytochrome P450 (CYP) 2D6. Cimetidine inhibits the activity of cytochrome P450, including CYP2D6, leading to reduced systemic clearance of concomitant drugs. Coadministration of cimetidine has been speculated to affect the pharmacological effects of timolol ophthalmic solution, resulting in increased blood concentration. To evaluate whether administration of cimetidine with timolol ophthalmic solution increased the degree of beta‐blockade, 12 healthy Japanese male volunteers ages 19 to 26 received cimetidine (400 mg), an oral placebo, timolol maleate 0.5% (0.05 mL to each eye), or placebo eye drops in a randomized, double‐blind, Latin‐square design. The oral drug alone was given for 3 days, and on the 4th day, eye drops were applied after oral drug administration. At baseline and 1, 3, and 6 hours after eye drop administration, blood pressure and heart rate (HR) were measured before and after exercise. Intraocular pressure (IOP) was measured at rest. A visual analog scale (VAS) was used to assess subjective bodily feelings in exercise tolerance after every physical exercise. The exercise HR, exercise systolic blood pressure (SBP), and resting SBP were reduced following timolol with and without cimetidine compared with the placebo (p < 0.01, respectively). Administration of cimetidine with timolol ophthalmic solution resulted in additional reductions of the resting HR and IOP VAS detected a significant reduction in exercise tolerance from timolol ophthalmic solution (p < .05). In conclusion, administration of cimetidine with timolol ophthalmic solution increased the degree of beta‐blockade.

The Effect of Erythromycin and Clarithromycin on the Pharmacokinetics of Intravenous Digoxin in Healthy Volunteers

Several case reports have suggested an interaction between digoxin and macrolide antibiotics. The authors investigated the effect of erythromycin and clarithromycin on the pharmacokinetics of intravenously administered digoxin (0.5 mg) in healthy subjects. Nine male subjects participated in three studies (digoxin alone, digoxin with erythromycin, and digoxin with clarithromycin). Subjects took erythromycin (800 mg per day) or clarithromycin (400 mg per day) on the day before digoxin dosing and during the kinetic study. Neither of the macrolides affected serum digoxin concentration‐time curves. However, more than 1.3‐fold increases in urinary digoxin excretions were observed during erythromycin and clarithromycin coadministration compared with digoxin alone. There were significant differences in renal clearance between macrolide coadministration and the control condition (digoxin alone: 98.4 ml/min; digoxin with erythromycin: 137.3 ml/min; digoxin with clarithromycin: 133.6ml/min). In conclusion, neither erythromycin nor clarithromycin has a significant effect on serum digoxin disposition after an intravenous administration. Renal digoxin excretion is not inhibited but rather enhanced by both macrolides.

Effect of Fluconazole on the Pharmacokinetics and Pharmacodynamics of Oral and Rectal Bromazepam: An Application of Electroencephalography as the Pharmacodynamic Method

Quantitative analysis of electroencephalography (EEG) is used increasingly to evaluate the pharmacodynamics of benzodiazepines. The present study aimed to apply the EEG method as well as more traditional approaches to an interaction study of bromazepam and fluconazole. Twelve healthy male volunteers participated in a randomized, double‐blind, four‐way crossover study. The subjects received single oral or rectal doses of bromazepam (3 mg) after 4‐day pretreatment of oral fluconazole (100 mg daily) or its placebo. Plasma bromazepam concentrations were measured before and 0.5, 1,2,3,4, 6,12,22,46, and 70 hours after bromazepam administration. Pharmacodynamic effects of bromazepam were assessed using self‐rated drowsiness, continuous number addition test, and EEG. Fluconazole caused no significant changes in pharmacokinetics and pharmacodynamics of oral or rectal bromazepam. Rectal administration significantly increased AUC (1.7‐fold, p < 0.0001) and Cmax (1.6‐fold, p < 0.0001) of bromazepam. These changes following rectal dose may be due to avoidance of degradation occurringin the gastrointestinal tract. Rectal bromazepam also increased the area under the effect curves assessed by EEG (p < 0.05) and subjective drowsiness (p < 0.05). EEG effects were closely correlated with mean plasma bromazepam concentrations (r = 0.92, p < 0.001 for placebo; r = 0.89, p < 0.0001 for fluconazole). Thus, the EEG method provided pharmacodynamic data that clearly reflected the pharmacokinetics of bromazepam.

Gender- or age-related binding characteristics of valproic acid to serum proteins in adult patients with epilepsy.

The aim of the present study was to determine the gender- or age-related binding characteristics of valproic acid (VPA) to serum proteins in the adult population. Serum samples examined in the study were obtained from 70 adult patients (36 males, 34 females) with epilepsy on VPA monotherapy. Their age ranged from 16 to 68 years (mean age with (SD), 37.7 (15.7) years; <45 years, n=44; >/=45 years, n=26). The in vivo population binding parameters of VPA to serum proteins and theoretical minimal unbound serum VPA fraction (Fu) were determined using an equation derived from the Scatchard equation in: (1), all; (2), male and female subgroups; and (3), younger (<45 years) and older (>/=45 years) subgroups. There was a significant difference in serum concentration of unbound VPA between male and female patients. The mean association constant (K) was 0.010 microM(-1) in all, male, and female patients. The mean total concentration of binding sites (n(Pt)) was 1453 microM for all patients, and 1561 and 1394 microM for male and female patients, respectively. The Fu was 0.064 for all patients, and 0.060 and 0.067 for male and female patients, respectively. There were no significant differences in the binding characteristics of VPA to serum proteins between the male and female groups. On the other hand, there were significant differences in the serum albumin concentration and molar concentration ratio of free fatty acids to albumin in serum between the younger and older patients. The mean value of K was 0.016 microM(-1) for the younger patients and 0.007 microM (-1) for the older patients. The mean n(Pt) was 1157 microM for the younger patients and 1703 microM for the older patients. The Fu was 0.051 for the younger patients and 0.077 for the older patients. Thus, significant differences were observed in the binding characteristics of VPA to serum proteins between the younger and older groups. Our results show that age, but not gender, has significant influences on the binding characteristics of VPA to serum proteins in our patient population.

No effect of gender or age on binding characteristics of valproic acid to serum proteins in pediatric patients with epilepsy

The gender‐ and age‐related binding characteristics of valproic acid to serum proteins were determined in the pediatric population. Serum samples examined in the study were obtained from 61 pediatric patients (28 males, 33 females) with epilepsy on valproic acid monotherapy. Their ages ranged from 1to 15 years (mean age with [SD]: 7.8 [3.9] years; < 10 years, n = 41; /10 years, n = 20). The in vivo population binding parameters of valproic acid to serum proteins and theoretical minimal unbound serum fraction (fu) of valproic acid were determined in (1) all, (2) male and female subgroups, and (3) prepubescent (< 10 years) and pubescent (/10 years) subgroups. The association constant (K) was approximately 1.4 times higher in male (0.018 L/μmol) than in female (0.013 L/μmol) patients, while the total concentration of binding sites (n(Pt)) was 1.2 times greater in female (1235 μmol/L) than in male (997 mmol/L) patients. The fu was 0.053 and 0.059 for male and female patients, respectively. The value of K was approximately 1.6 times higher in the pubescent (0.019 L/μmol) than in the prepubescent (0.012 L/μmol) patients, while the n(Pt) was 1.2 times higher in the prepubescent (1244 μmol/L) than in the pubescent (1057 μmol/L) patients. The fu was 0.063 for the prepubescent and 0.047 for the pubescent patients. No significant differences were observed in binding characteristics of valproic acid to serum proteins between male and female or younger and older patients. However, the differences in valproic acid binding to serum proteins appear to be relatively larger in binding affinity than in binding capacity between the two groups. Because no significant differences were observed in serum concentrations of total and unbound valproic acid, albumin, or free fatty acids between any subgroups (male and female, younger and older), the results suggest that gender or age may not be factors for the determination of the binding characteristics of valproic acid to serum proteins in pediatric patients.

Effect of Unbound Clearance on Binding Parameters of Valproic Acid to Serum Proteins

Nine healthy subjects received 400 mg sodium valproate orally in the fasting state. Binding parameters of valproic acid to serum proteins were determined by Scatchard analysis for individual series of valproic acid data. Total and unbound (intrinsic) clearances (Cht and CLu) were calculated by dividing the dose by the appropriate area under the serum drug concentration‐time curve. Unbound clearance correlated positively with the product of association constant (Ka) and concentration of free protein ((UP)) (P < .05). Conversely, no significant correlation was found between CLt and binding parameters. The average unbound concentration correlated negatively with both CLu and ka(P) values. The result indicates an effect of CLu on Ka(P) value of valproic acid.