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July 2007 Biol. Pharm. Bull. 30(7) 1297—1300 (2007) 1297 Analysis of Pharmacological Effects of Drugs Used for Treatment of Urinary Disturbance Based on Anticholinergic and Smooth Muscle- Relaxing Effects a a a a b Risa TAKAYANAGI, Haruhi MIZUSHIMA, Takeshi OZEKI, Haruko YOKOYAMA, Tatsuji IGA, and ,a Yasuhiko YAMADA* a Department of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences; 1432–1 Horinouchi, Hachioji, Tokyo 192–0392, Japan: and b International University of Health and Welfare; Kitakanemaru, Ohtawara, Tochigi 324–8501, Japan. Received November 21, 2006; accepted April 2, 2007 Propiverine hydrochloride, oxybutynin hydrochloride and terodiline hydrochloride have both anticholiner- gic and antispasmodic effects, and are used for the management of urinary frequency and incontinence. The av- erage standard therapeutic doses of these drugs differ greatly. We retrospectively analyzed their pharmacological effects with consideration given to muscarinic acetylcholine receptor binding affinities, anticholinergic activities, and inhibitory effects on KCl-induced contraction. Muscarinic acetylcholine receptor occupancies and the in- hibitory ratios of the drugs for both acetylcholine-induced and KCl-induced contraction in a steady state after oral administration of standard doses were calculated based on pharmacokinetics and the receptor occupancy theory. The average muscarinic acetylcholine receptor occupancy and inhibitory ratio of acetylcholine-induced contraction were estimated to be 12.6؎1.06% and 3.27؎0.74%, respectively, with no significant differences found between the drugs for those parameters. A significant linear relationship was found between muscarinic acetylcholine receptor occupancy and the maximum ratio of increase in bladder urinary capacity. On the other hand, the inhibitory ratios of KCl-induced contraction varied from 0.01 to 0.48%. The present results suggest that muscarinic acetylcholine receptor occupancy is a principal determinant of the therapeutic effect of a drug used for treatment of urinary disturbance. Key words muscarinic acetylcholine receptor; receptor occupancy; bladder urinary capacity; propiverine; oxybutynin; terodiline Drugs for the treatment of urinary disturbance with anti- Values for the primary pharmacokinetic parameters, i.e., total cholinergic and smooth muscle-relaxing effects are used for body clearance (CLtot), bioavailability (F), area under the the management of urinary frequency and incontinence. plasma concentration time curve (AUC0—ϱ), and plasma un- 3—8) Oxybutynin hydrochloride, propiverine hydrochloride, bound fraction (fu), were obtained from previous reports. terodiline hydrochloride, and flavoxate hydrochloride have The receptor dissociation constant (KI) and anticholinergic been marketed in Japan as drugs for treatment of urinary dis- activity (KB) values were also obtained as data for the mus- turbance, and tolterodine tartrate and solifenacin succinate carinic acetylcholine receptor binding affinity of the drugs 1,9—15) were put on the market in 2006. Sales of terodiline hy- from literature. KI values were determined by in vitro drochloride, however, have been stopped because of its ad- radiolabeled ligand binding inhibition experiments using verse arrhythmic effect. The average standard therapeutic guinea pig bladders, while KB values were determined by in doses of the remaining available drugs differ greatly. In re- vitro pharmacological experiments with guinea pig bladders. gard to anticholinergic and smooth muscle-relaxing effects of The inhibitory effects of KCl-induced contraction (IC50) val- oxybutynin, propiverine, and terodiline, it has been reported ues were also obtained as data regarding the direct effects of 16) in studies using extracted rabbit bladders that in order to the drugs on smooth muscle from a previous study. IC50 nearly completely inhibit contraction of the musculus detru- values were determined by in vitro pharmacological experi- sor urinae, each of those effects independently was insuffi- ments using rat bladders. cient and both were required.1,2) Those results were from in Analysis of Muscarinic Acetylcholine Receptor Occu- vitro pharmacological experiments, while there is no known pancy and Inhibitory Ratio of Acetylcholine-Induced report that considered the inhibitory actions toward musculus Contraction The muscarinic acetylcholine receptor occu- detrusor urinae contraction using oral administration of the pancy and inhibitory ratio of acetylcholine-induced contrac- drugs with standard doses. tion of each drug for urinary disturbance following oral ad- We investigated the anticholinergic and antispasmodic ef- ministration with a standard dose were calculated using data fects of oxybutynin hydrochloride, propiverine hydrochlo- obtained as noted above. We assumed that the drugs used for ride, and terodiline hydrochloride to inhibit bladder smooth urinary disturbance bound competitively to muscarinic muscle contraction, by calculating the muscarinic acetyl- acetylcholine receptors and expressed the concentration (nM) choline receptor occupancies and inhibitory ratios of both of bound receptors (R) using the following equation: acetylcholine-induced and KCl-induced contractions in a RC⋅⋅RC Rϭ max U ϩ max M (1) steady state after oral administrations of standard doses. ϩϩ ϩϩ CKdCKdUU(/)11 MMCKdCKdMM (/) UU MATERIALS AND METHODS where Rmax is the maximum concentration (nM) at the recep- tors; CU and CM are the concentrations (nM) of the unchanged Pharmacokinetic and Pharmacodynamic Parameters drug and its metabolite, respectively, at the juxtareceptors; ∗ To whom correspondence should be addressed. e-mail: [email protected] © 2007 Pharmaceutical Society of Japan 1298 Vol. 30, No. 7 Table1. Pharmacokinetic and Pharmacodynamic Parameters of Drugs Used for Urinary Disturbance Smooth Anticholinergic effect muscle Standard dose AUC Cf Drug 0—ϱ f ss relaxing (mg/d) (ng/ml·h)u (nM) KI KB effect (nM)(nM)IC50 (nM) Propiverine 20 Unchanged propiverine 9753) 0.096) 9.9 3729) 43714) 390016) Metabolite 2163) 0.666) 15.9 1059) 135014) — Oxybutynin 7.5 26a),4) 0.177) 0.5 410) 2015) 450016) Terodiline 24 4960a),5) 0.048) 31.6 203b),11—13) 7591) 660016) —, no activity. a) Calculated based on the relationship between dosage and AUC. b)Average data. and KdU and KdM are the receptor dissociation constants, cor- ratio and pharmacodynamic parameters were then examined. responding to KB or KI, of the drug. We assumed that the Analysis of Relationships of Receptor Occupancy and substances acted as full antagonists toward muscarinic Inhibitory Ratio of Contraction with Clinical Effect The acetylcholine receptors and expressed the receptor occu- muscarinic acetylcholine receptor occupancy and inhibitory pancy, F (%), according to the receptor occupation theory ratio of contraction of each of the drugs following oral ad- using the following equation: ministration of a dose found acceptable in clinical trials were calculated using Eqs. 1—3. We then examined the relation- R Φ ϭ ⋅100 ships of receptor occupancy and inhibitory ratio with clinical Rmax (2) effect, which was defined as the maximum ratio of increase C C ϭ U ϩ M ⋅100 in bladder urinary capacity, data for which were obtained ϩϩ ϩϩ 17—27) CKdCKdUU(/)11 MMCKdCKdMM (/) UU from clinical trial reports. After the drug has been absorbed into the bloodstream RESULTS from the gastrointestinal tract, it passes across blood capil- lary cell walls into extracellular space and binds to mus- Pharmacokinetic and Pharmacodynamic Parameters f carinic acetylcholine receptors on the plasma membranes of Table 1 shows the values of AUC0—ϱ, fu, and Css following bladder cells. If the process of transport of the drug to en- oral administration with standard doses, as well as the values dothelial cells is not active, but rather passive diffusion, or it of KI and KB for the anticholinergic effects, and IC50 for the 1,3—16) is not a rate-limiting step because of fenestration on the muscle-relaxing effects. The values of IC50 did not vary blood capillary cell walls, we assumed that the concentration greatly, whereas the differences between the minimum and of the drug in the extracellular space in the bladder would not maximum values of both KI and KB were nearly 100-fold. be significantly different from the unbound drug concentra- Receptor Occupancy and Inhibitory Ratio of Contrac- tions in plasma. Therefore, we used the unbound drug con- tion in a Steady-State Condition Receptor occupancies of f f centrations (CU and C M) as the concentrations for the recep- propiverine, oxybutynin, and terodiline were 12.9%, 11.4%, tor-binding drugs (CU and CM), respectively. The steady-state and 13.5%. Inhibitory ratios of acetylcholine-induced con- drug concentration in plasma was calculated from CLtot/F or traction were 3.29%, 2.52%, and 3.99%, and inhibitory ratios AUC0—ϱ, as follows: of KCl-induced contraction were 0.25%, 0.01%, and 0.48%. Figure 1 shows the relationships of the pharmacodynamic Dose⋅ F AUC ∞ Cff ϭϭ⋅ f ⋅ 0— (3) parameters with muscarinic acetylcholine receptor occupan- ss u ⋅ττu CLtot cies, and inhibitory ratios for both acetylcholine-induced and KCl-induced contractions in a steady state after oral adminis- where t represents the dosing interval. In order to estimate tration of standard doses of the three drugs. The average the receptor occupancy of the drug in a steady state, we cal- muscarinic acetylcholine receptor occupancy and average in- f culated Css from CLtot/F

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