Tomomi Oki

Effects of Ginkgo Biloba Extract on Pharmacokinetics and Pharmacodynamics of Tolbutamide and Midazolam in Healthy Volunteers

This study was undertaken to clarify the influence of repeated oral administration of Ginkgo biloba extract (GBE) on CYP2C9 and CYP3A4. CYP2C9 probe (tolbutamide, 125 mg) and CYP3A4 probe (midazolam, 8 mg) were orally administered to 10 male healthy volunteers before and after GBE intake (360 mg/d) for 28 days, and they received 75 g glucose after the dosing of tolbutamide. Plasma drug concentrations and blood glucose levels were measured. The area under concentration versus time curve (AUC0–∞) for tolbutamide after GBE intake was slightly but significantly (16%) lower than that before GBE intake. Concomitantly, GBE tended to attenuate AUC0–2 of blood glucose—lowering effect of tolbutamide. AUC0–∞ for midazolam was significantly (25%) increased by GBE intake and oral clearance was significantly (26%) decreased. Thus, it is suggested that the combination of GBE and drugs should be cautious in terms of the potential interactions, especially in elderly patients or patients treated with drugs exerting relatively narrow therapeutic windows.

Muscarinic receptor binding, plasma concentration and inhibition of salivation after oral administration of a novel antimuscarinic agent, solifenacin succinate in mice.

1 A novel muscarinic receptor antagonist, solifenacin succinate, inhibited specific binding of [N‐methyl‐3H]‐scopolamine ([3H]‐NMS) in the mouse bladder, submaxillary gland and heart in a concentration‐dependent manner. This inhibitory effect was greatest in the submaxillary gland, followed by the bladder and heart. 2 After oral administration of oxybutynin (76.1 μmol kg−1) or solifenacin (62.4, 208 μmol kg−1), a significant dose‐ and time‐dependent increase in KD values for specific [3H]‐NMS binding was seen in the bladder, prostate, submaxillary gland, heart, colon and lung, compared with control values. The increase in KD induced by oxybutynin in each tissue reached a maximum 0.5 h after oral administration and then rapidly declined, while that induced by solifenacin was greatest 2 h after administration and was maintained for at least 6 or 12 h, depending on the dose. The muscarinic receptor binding of oral solifenacin was slower in onset and of a longer duration than that of oxybutynin. 3 Plasma concentrations of oxybutynin and its active metabolite (N‐desethyl‐oxybutynin, DEOB) were maximum 0.5 h after its oral administration and then declined rapidly. Oral solifenacin persisted in the blood for longer than oxybutynin. 4 Pilocarpine‐induced salivary secretion in mice was significantly reduced by oral administration of solifenacin and was completely abolished 0.5 h after oral oxybutynin. Although the suppression induced by solifenacin was more persistent than that due to oxybutynin, the antagonistic effect of solifenacin on the dose–response curves to pilocarpine was significantly weaker than that of oxybutynin. It is concluded that oral solifenacin persistently binds to muscarinic receptors in tissues expressing the M3 subtype, such as the bladder.

Human Muscarinic Receptor Binding Characteristics of Antimuscarinic Agents to Treat Overactive Bladder

PURPOSE We characterized the binding affinities of several antimuscarinic agents in human muscarinic receptors. MATERIALS AND METHODS Competitive inhibitory effects of antimuscarinic agents on specific NMS [H] (PerkinElmer Life Sciences, Boston, Massachusetts) binding were examined in human tissue homogenates and in CHO-K1 cell membranes expressing human muscarinic receptor subtypes. RESULTS Oxybutynin, propiverine, tolterodine, the respective metabolites DEOB, DPr-P-4(N-->O) and 5-HM, and darifenacin inhibited in concentration dependent fashion specific [(3)H]NMS binding in homogenates of the human bladder and parotid gland as well as in membranes of CHO-K1 cell lines expressing human muscarinic M(1) to M(5) receptor subtypes. Based on inhibition constant values the inhibitory effects of tolterodine, 5-HM and DPr-P-4(N-->O) were 1.4 to 1.7 times greater in the bladder than in the parotid gland, whereas the inhibitory effects of oxybutynin, DEOB, propiverine and darifenacin were 2 to 10 times greater in the parotid gland. Consequently tolterodine, 5-HM and DPr-P-4(N-->O) compared with oxybutynin, DEOB, propiverine and darifenacin were found to show 3 to 4 times greater affinity to muscarinic receptors in the human bladder than in the parotid gland. Tolterodine and 5-HM were 2-fold more potent for inhibiting specific [(3)H]NMS binding at cell membranes expressing the M(2) vs the M(3) subtype. Conversely oxybutynin, DEOB, propiverine, DPr-P-4(N-->O) and darifenacin showed 2 to 22 times higher affinity to the M(3) than to the M(2) subtype. CONCLUSIONS Compared with oxybutynin, tolterodine, 5-HM and DPr-P-4(N-->O) may bind more selectively to muscarinic receptors in the human bladder than in the parotid gland.

Advantages for Transdermal over Oral Oxybutynin to Treat Overactive Bladder: Muscarinic Receptor Binding, Plasma Drug Concentration, and Salivary Secretion

To clarify pharmacological usefulness of transdermal oxybutynin in the therapy of overactive bladder, we have characterized muscarinic receptor binding in rat tissues with measurement of plasma concentrations of oxybutynin and its metabolite N-desethyl-oxybutynin (DEOB) and salivation after transdermal oxybutynin compared with oral route. At 1 and 3 h after oral administration of oxybutynin, there was a significant increase in apparent dissociation constant (Kd) for specific [N-methyl-3H]scopolamine ([3H]NMS) binding in the rat bladder, submaxillary gland, heart, and colon compared with control values. Concomitantly, submaxillary gland and heart showed a significant decrease in maximal number of binding sites (Bmax) for [3H]NMS binding, which lasted until 24 h. Transdermal application of oxybutynin caused dose-dependent increases in Kd values for specific [3H]NMS binding in rat tissues. The increment of Kd values by transdermal oxybutynin was dependent on the application time. Plasma concentrations of oxybutynin and DEOB peaked at 1 h after oral oxybutynin. In contrast, plasma concentrations of oxybutynin increased slowly, depending on the transdermal application time of this drug until 12 h. Suppression of pilocarpine-induced salivation in rats due to transdermal oxybutynin was significantly weaker and more reversible than that by oral oxybutynin, which abolished salivary secretion. The present study has shown that transdermal oxybutynin binds significantly to rat bladder muscarinic receptors without producing both long-lasting occupation of exocrine receptors and cessation of cholinergic salivation evoked by oral oxybutynin. Thus, the present study provides further pharmacological basis for advantage of transdermal over oral oxybutynin in the therapy of overactive bladder.

Urodynamics and bladder muscarinic receptors in rats with cerebral infarction and bladder outlet obstruction.

We characterized muscarinic receptor binding and urodynamic parameters in rats with cerebral infarction and chronic bladder outlet obstruction as models of detrusor overactivity. Bladder weight showed little significant difference between the cerebral-infarcted and sham rats, but the bladder weight was about three times greater in the bladder outlet-obstructed rats. Bladder capacity and voided volume were significantly lower (36.7 and 55.1%, respectively) in the cerebral-infarcted than in the sham rats. Involuntary contractions before micturition were seen in the bladder outlet-obstructed rats but not in sham rats. The bladder outlet-obstructed rats showed significant increases (2.65 and 2.57 times, respectively) in bladder capacity and voided volume, compared with those in sham rats. Bmax values for specific [N-methyl-3H]scopolamine ([3H]NMS) binding in the bladder were significantly (34%) increased in the cerebral-infarcted rats compared with sham rats, whereas Kd was unaffected by infarction. On the other hand, there was little significant change in Kd and Bmax for specific [3H]NMS binding in the bladder-obstructed rats compared with sham rats. In conclusion, the present study shows that cerebral infarction but not bladder outlet obstruction in rats causes up-regulation of bladder muscarinic receptors, and that such regulation of bladder muscarinic receptors may be at least partly associated with the symptoms of detrusor overactivity subsequent to cerebral infarction.

Natural vanadium-containing Mt. Fuji ground water improves hypo-activity of liver insulin receptor in Goto-Kakisaki rats

After daily treatments with Mt. Fuji ground water containing natural vanadium (approximately 65 μg/l) at doses of 0.53 μg/kg/day for 12 weeks, blood glucose (BG), serum hemoglobin A1C (HbA1C) levels and insulin secretion from the pancreas of Goto-Kakisaki (GK) rats, a genetic model of Type 2 diabetes, were improved. In GK rat liver insulin receptors, the binding properties of [125I] insulin, and the activities of insulin receptor β subunit and primary insulin-like growth factor-1β all recovered to normal levels of those found in Wistar rats. These results suggest that daily treatment with small concentrations of natural vanadium improves hyperglycemia by ameliorating liver insulin receptor activity. (Mol Cell Biochem 267: 203–207, 2004)

Relationship between Prostatic α1-Adrenoceptor Binding and Reduction in Intraurethral Pressure following Continuous Infusion of KMD-3213 in Rats

The relationship between α1-adrenoceptor binding in rat tissues and pharmacodynamic effects of continuous infusion of KMD-3213 was examined. In vivo specific binding of [3H]KMD-3213 after continuous intravenous infusion of the ligand (100 pmol/kg/min for 10 min, followed by 30 pmol/kg/min for 60 or 90 min) differed largely among the tissues examined. Specific binding of [3H]KMD-3213 in aorta, heart, lung, and kidney was not different in terms of infusion time in the case of continuous infusion for 10, 70 and 100 min, whereas the binding in prostate, vas deferens, and submaxillary gland by 70- and/or 100-min infusion was significantly greater than that by the 10-min infusion. A similar extent of specific binding in the prostate was observed by the infusion (100 min) of a three-fold higher dose of [3H]KMD- 3213. Continuous intravenous infusion of KMD-3213 (100 pmol/kg/min for 10 min, followed by 30 pmol/kg/min) for 70 or 100 min significantly reduced the phenylephrine-induced increase in the mean blood pressure and that in the intraurethral pressure of anesthetized rats. Extent and time course of the KMD-3213 effect reduction in the phenylephrine-induced increase in intraurethral pressure were closely associated with those in prostatic [3H]KMD-3213 binding after continuous infusion of the corresponding dosage of the radioligand. The reduction in the phenylephrine-induced increase by the infusion of a three-fold higher dose of KMD-3213 was significantly greater in the case of the intraurethral pressure than in that of the mean blood pressure, thereby suggesting a greater selectivity for the α1-adrenoceptor in the lower urinary tract than for that in the vascular tissue. In conclusion, the present study has shown that specific binding of [3H]KMD-3213 in the rat prostate after the continuous intravenous infusion of the radioligand may be closely associated with the pharmacological effect of this drug on the lower urinary tract.