New Insight Concerning Therapeutic Drug Monitoring-The Importance of the Concept of Psychonephrology.

Recently, the concept of psychonephrology was developed and has been recognized as a field of study that focuses on nephrology and mental health fields, such as psychiatry and psychosomatic medicine. Indeed, patients with chronic kidney disease frequently suffer from mental problems as the disease stage progresses. Most psychotropic drugs are hepatically metabolized, but some are unmetabolized and eliminated renally. However, renal disease may affect the pharmacokinetics of many psychotropic drugs, as the decreased renal function not only delays the urinary excretion of the drug and its metabolites but also alters various pharmacokinetic factors, such as protein-binding, enterohepatic circulation, and activity of drug-metabolizing enzymes. Therefore, when prescribing drug therapy for patients with both renal disease and mental issues, we should consider reducing the dosage of psychotropic drugs that are eliminated mainly via the kidney and also carefully monitor the blood drug concentrations of other drugs with a high extrarenal clearance, such as those that are largely metabolized in the liver. Furthermore, we should carefully consider the dialyzability of each psychotropic drug, as the dialyzability impacts the drug clearance in patients with end-stage renal failure undergoing dialysis. Therapeutic drug monitoring (TDM) may be a useful tool for adjusting the dosage of psychotropic drugs appropriately in patients with renal disease. We herein review the pharmacokinetic considerations for psychotropic drugs in patients with renal disease as well as those undergoing dialysis and offer new insight concerning TDM in the field of psychonephrology.

Melinjo seed extract increases adiponectin multimerization in physiological and pathological conditions.

Melinjo seed extract (MSE) contains large amounts of polyphenols, including dimers of trans-resveratrol (e.g. gnetin C, L, gnemonoside A, B and D), and has been shown to potentially improve obesity. However, there is no clinical evidence regarding the anti-obesity effects of MSE, and its mechanisms are also unclear. We investigated the hypothesis that MSE supplementation increases the adiponectin (APN) multimerization via the up-regulation of disulfide bond A oxidoreductase-like protein (DsbA-L) under either or both physiological and obese conditions. To investigate the effect of MSE on the physiological condition, 42 healthy young volunteers were enrolled in a randomized, double-blind placebo-controlled clinical trial for 14 days. The participants were randomly assigned to the MSE 150 mg/day, MSE 300 mg/day or placebo groups. Furthermore, in order to investigate the effect of MSE on APN levels under obese conditions, we administered MSE powder (500 or 1000 mg/kg/day) to control-diet- or high-fat-diet (HFD)-fed C57BL/6 mice for 4 weeks. All participants completed the clinical trial. The administration of MSE 300 mg/day was associated with an increase in the ratio of HMW/total APN in relation to the genes regulating APN multimerization, including DsbA-L. Furthermore, this effect of MSE was more pronounced in carriers of the DsbA-L rs191776 G/T or T/T genotype than in others. In addition, the administration of MSE to HFD mice suppressed their metabolic abnormalities (i.e. weight gain, increased blood glucose level and fat mass accumulation) and increased the levels of total and HMW APN in serum and the mRNA levels of ADIPOQ and DsbA-L in adipose tissue. The present study suggests that MSE may exert beneficial effects via APN multimerization in relation to the induction of DsbA-L under both physiological and obese conditions.

The Effect of Yokukansan, a Traditional Herbal Preparation Used for the Behavioral and Psychological Symptoms of Dementia, on the Drug-Metabolizing Enzyme Activities in Healthy Male Volunteers.

The concomitant use of herb and prescription medications is increasing globally. Herb-drug interactions are therefore a clinically important problem. Yokukansan (YKS), a Japanese traditional herbal medicine, is one of the most frequently used herbal medicines. It is effective for treating the behavioral and psychological symptoms of dementia. We investigated the potential effects of YKS on drug-metabolizing enzyme activities in humans. An open-label repeat-dose study was conducted in 26 healthy Japanese male volunteers (age: 22.7±2.3 years) with no history of smoking. An 8-h urine sample was collected after a 150-mg dose of caffeine and a 30-mg dose of dextromethorphan before and after the administration of YKS (2.5 g, twice a day for 1 week). The activities of cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A, xanthine oxidase (XO) and N-acetyltransferase 2 (NAT2) were assessed based on the urinary metabolic indices of caffeine and dextromethorphan, and the urinary excretion ratio of 6ß-hydroxycortisol to cortisol. There were no statistically significant differences in the activities of the examined enzymes before or after the 7-d administration of YKS. Although further studies assessing the influence of YKS on the pharmacokinetics and pharmacodynamics of the substrates of the drug-metabolizing enzymes are needed to verify the present results, YKS is unlikely that a pharmacokinetic interaction will occur with concomitantly administered medications that are predominantly metabolized by the CYP1A2, CYP2D6, CYP3A, XO and NAT2.

Effects of Seijo-bofu-to, a traditional Japanese herbal medicine containing furanocoumarin derivatives, on the drug-metabolizing enzyme activities in healthy male volunteers.

Seijo-bofu-to, a traditional medicine used to treat acne in Asian countries, contains twelve herbal components, including Angelica dahurica root, a source of furanocoumarin derivatives. In this study, we investigated potential herb-drug interactions of seijo-bofu-to in healthy male volunteers. Thirty-two young, healthy, non-smoking males were assessed for the baseline activity of cytochrome P450 (CYP) 1A2, CYP3A, CYP2D6, N-acetyltransferase 2 and xanthine oxidase according to the urinary metabolic indices of 8-hr urine samples collected after the administration of a 150-mg dose of caffeine and a 30-mg dose of dextromethorphan, and the ratio of urinary excretion of 6ß-hydroxycortisol to cortisol. Thereafter, the volunteers received 3.75 g of seijo-bofu-to twice daily for 7 days and underwent the same tests on post-dose day 7. The geometric mean ratio of the CYP1A2 activity on day 7 to that observed at baseline was 0.66 (95% CI, 0.55-0.79, p = 0.001). The geometric mean phenotypic indices for CYP3A, CYP2D6, N-acetyltransferase 2 and xanthine oxidase on day 7 did not differ from the baseline values. The findings of the present study suggest that seijo-bofu-to may inhibit the activity of CYP1A2, whereas it is unlikely to participate in herb-drug interactions involving medications predominantly metabolized by CYP3A, CYP2D6, N-acetyltransferase 2 or xanthine oxidase.

A herbal-drug interaction study of keishi-bukuryo-gan, a traditional herbal preparation used for menopausal symptoms, in healthy female volunteers.

OBJECTIVES: Many patients use herbal medicines to relieve menopausal symptoms. Keishi-bukuryo-gan contains five herbal components, and has been used for treating hypermenorrhoea, dysmenorrhoea and menopausal symptoms in Asian countries. In this study, we investigated the potential herb-drug interactions of keishi-bukuryo-gan in healthy female subjects. METHODS: Thirty-one healthy females (20-27 years) were studied to evaluate their baseline activity of cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A, xanthine oxidase (XO) and N-acetyltransferase 2 (NAT2) based on the urinary metabolic indices of an 8-h urine sample collected after a 150-mg dose of caffeine and a 30-mg dose of dextromethorphan, and also the urinary excretion ratio of 6ß-hydroxycortisol to cortisol. Thereafter, the subjects received 3.75g of keishi-bukuryo-gan twice daily for seven days, and underwent the same tests on post-dose day 7. KEY FINDINGS: The geometric mean phenotypic index for CYP1A2 significantly decreased by 16% on day 7 compared with the baseline (P=0.026). Keishi-bukuryo-gan did not alter the indices for CYP2D6, CYP3A, XO and NAT2. CONCLUSIONS: Keishi-bukuryo-gan may inhibit the activity of CYP1A2, which is predominantly involved in oestrogen metabolism. However, TJ-25 is unlikely to participate in herb-drug interactions involving medications predominantly metabolized by CYP2D6, CYP3A, XO and NAT2. K

The effect of Shoseiryuto, a traditional Japanese medicine, on cytochrome P450s, N-acetyltransferase 2 and xanthine oxidase, in extensive or intermediate metabolizers of CYP2D6.

OBJECTIVE: Shoseiryuto (TJ-19) contains eight herbal components, including Ephedra sinica, and has been used for treating asthma and allergic rhinitis in Asian countries for several centuries. In this study, we investigated the potential herb-drug interaction of TJ-19 in healthy volunteers and attempted to ascertain whether or not the interaction might be affected by the cytochrome P450 (CYP) 2D6 genotype. METHODS: We assessed the effect of TJ-19 on the activities of CYP1A2, CYP2D6, CYP3A, xanthine oxidase (XO), and N-acetyltransferase 2 (NAT2) in 37 healthy subjects. The subject pool consisted of 19 extensive metabolizers (EMs) with CYP2D6*Wild/*Wild, and 18 intermediate metabolizers (IMs) with CYP2D6*10/*10. The baseline activities of five enzymes were ascertained by their respective urinary metabolic ratios from an 8-h urine sample, after an oral 150-mg and 30-mg dose of caffeine and dextromethorphan were administrated, respectively. Thereafter, the subjects received 4.5 g of TJ-19 twice daily for 7 days, and underwent the same phenotyping test on postdose day 7. RESULTS: The activities of all enzymes examined did not differ before or after the 7-day administration of TJ-19. Consequently, the influence of the CYP2D6 genotype on the herb-drug interaction remained unsolved. CONCLUSION: Our results indicate that TJ-19 at the generally recommended dosage is unlikely to cause pharmacokinetic interaction with co-administered medications primarily dependent on the CYP1A2, CYP2D6, CYP3A, XO, and NAT2 pathways for elimination.

The in-vivo effect of bakumondo-to (TJ-29), a traditional Japanese medicine used for treatment of chronic airway disease, on cytochrome P450 1A2, xanthine oxidase and N-acetyltransferase 2 activity in man.

In Japan, patients with chronic airway disease are administered bakumondo-to (TJ-29), a mixture of six herbal components. We have assessed the effects of TJ-29 on the activities of cytochrome P450 (CYP) 1A2, xanthine oxidase and N-acetyltransferase 2 in 26 healthy subjects under a double-blind, randomized, placebo-controlled cross-over study design. The baseline activities of the three enzymes were assessed by the respective urinary metabolic ratios of an 8-h urine sample after an oral 150-mg dose of caffeine. Thereafter, the subjects received a thrice-daily 3.0-g dose of TJ-29 or placebo for seven days, and underwent the same caffeine test on the post-dose days 1 and 7. No statistically significant difference was observed in the activity of the three enzymes between those at baseline, and on day 1 after dosing with TJ-29 or placebo. The mean activity of CYP1A2, xanthine oxidase and N-acetyltransferase 2 tended to be lower on day 7 after dosing with TJ-29 compared with those at baseline and on day 7 after dosing with placebo. However, these changes were not statistically significant in CYP1A2 (P = 0.120), xanthine oxidase (P = 0.123) or N-acetyltransferase 2 (P = 0.056). In conclusion, TJ-29 did not appear to substantially affect the activity of CYP1A2, xanthine oxidase or N-acetyltransferase 2 in man.

The in-vivo effects of sho-saiko-to, a traditional Chinese herbal medicine, on two cytochrome P450 enzymes (1A2 and 3A) and xanthine oxidase in man.

The Chinese herbal medicine sho-saiko-to is a mixture of seven herbal components (Bupleurum root, Pinellia tuber, Scutellaria root, Jujube fruit, Ginseng root, Glycyrrhiza root and Ginger rhizome) that is widely administered to patients with chronic hepatitis in Japan. We assessed the effects of sho-saiko-to on the activity of cytochrome P450 (CYP) 1A2, CYP3A and xanthine oxidase (XO) in man. Twenty-six healthy subjects were studied to evaluate their baseline activity of CYP1A2 and XO by the respective urinary metabolic ratios of an 8-h urine sample after an oral 150-mg dose of caffeine and of CYP3A by a urinary excretion ratio of 6beta-hydroxycortisol (6beta-HC) to free cortisol (FC). Thereafter, the subjects received a twice-daily 2.5-g dose of sho-saiko-to for five days, and underwent the caffeine test on day 1 and day 5. The mean activity of CYP1A2 decreased by 16% on both day 1 and day 5 compared with the baseline (P=0.001). The mean activity of XO also significantly decreased by 25% on day 1 and 20% on day 5 (P<0.0001) compared with the baseline value. The activity of CYP3A tended to be lower on day 5 than the baseline (P=0.146). It is concluded that sho-saiko-to reduces CYP1A2 and XO activity in man.