Detrol
Biotransformation of tolterodine, a new muscarinic receptor antagonist, in mice, rats, and dogs.

Andersson SH, Lindgren A, Postlind H.

Department of Drug Metabolism, Pharmacia & Upjohn AB, S-751 82 Uppsala, Sweden.

Tolterodine is a new muscarinic receptor antagonist intended for the treatment of urinary urge incontinence and other symptoms associated with an overactive bladder. The in vivo metabolism of 14C-labeled tolterodine was investigated in rats, mice, and dogs by analysis of blood and urine samples, whereas in vitro metabolism studies were performed by incubation of [14C]tolterodine with mouse, rat, dog, and human liver microsomes in the presence of NADPH. Tolterodine was extensively metabolized in vivo. Mice and dogs showed similar metabolite patterns, which correlated well with that observed in humans. In these species, tolterodine was metabolized along two different pathways, with the more important being the stepwise oxidation of the 5-methyl group to yield the 5-hydroxymethyl metabolite of tolterodine and then, via the aldehyde, the 5-carboxylic acid metabolite. The other pathway involved dealkylation of the nitrogen. In the subsequent phase II metabolism, tolterodine and the metabolites were conjugated with glucuronic acid to various degrees. Rats exhibited more extensive metabolism and a markedly different metabolite pattern, with metabolites also being formed by hydroxylation of the unsubstituted benzene ring. In addition, a gender difference was observed, with male rats showing more extensive metabolism than females. Incubation of [14C]tolterodine with liver microsomes yielded a total of five metabolites with rat liver microsomes and three with mouse, dog, and human liver microsomes. The 5-hydroxymethyl metabolite of tolterodine and N-dealkylated tolterodine were major metabolites in all incubations, representing 83-99% of total metabolism. Although the extent of metabolism varied among species, the metabolic profiles were similar. However, rat liver microsomes also formed metabolites hydroxylated in the unsubstituted benzene ring. These results show that the metabolism of tolterodine in mice and dogs corresponds to that observed in humans, whereas rats exhibit a different metabolite pattern.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9616187&dopt=Abstract tolterodine Detrol



Detrol
Comparison of the in vitro and in vivo profiles of tolterodine with those of subtype-selective muscarinic receptor antagonists.

Gillberg PG, Sundquist S, Nilvebrant L.

Department of Pharmacology, Pharmacia and Upjohn, Uppsala, Sweden.

Tolterodine [(R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine ] is a new potent and competitive muscarinic receptor antagonist developed for the treatment of urinary urge incontinence and other symptoms of overactive bladder. In vivo, tolterodine exhibits functional selectivity for the urinary bladder over salivary glands, a profile that cannot be explained in terms of selectivity for a single muscarinic receptor subtype. The aim of this study was to compare the in vitro and in vivo antimuscarinic profiles of tolterodine with those of muscarinic receptor antagonists with distinct receptor subtype-selectivity profiles: darifenacin [(S)-2-[1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl]-2,2-d iphenylacetamide; selective for muscarinic M3 receptors]; UH-AH 37 (6-chloro-5,10-dihydro-5-[(1-methyl-4-piperidinyl)acetyl]-11H-dibenzo-[b ,e][1,4]diazepine-11-one; low affinity for muscarinic M2 receptors); and AQ-RA 741 (11-([4-[4-(diethylamino)butyl]-1-piperidinyl]acetyl)-5,11-dihydro-6H-py rido[2,3-b][1,4]benzodiazepine-6-one; high affinity for muscarinic M2 receptors). The in vitro profiles of these compounds were in agreement with previous reports; darifenacin and UH-AH 37 demonstrated selectivity for muscarinic M3/m3 over M2/m2 receptors, while the converse was observed for AQ-RA 741. In vivo, AQ-RA 741 was more potent (1.4-2.7-fold) in inhibiting urinary bladder contraction than salivation in the anaesthetised cat (i.e., a profile similar to that of tolterodine [2.5-3.3-fold]), while darifenacin and UH-AH 37 showed the reverse selectivity profile (0.6-0.8 and 0.4-0.5-fold, respectively). The results confirm that it is possible to separate the antimuscarinic effects on urinary bladder and salivary glands in vivo. The data on UH-AH 37 and darifenacin support the view that a selectivity for muscarinic M3/m3 over M2/m2 receptors may result in a more pronounced effect on salivation than on bladder contraction. The data on AQ-RA 741 may indicate that muscarinic M2/m2 receptors may have a role in bladder contraction.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9671109&dopt=Abstract tolterodine Detrol



Detrol
Cost-effectiveness of new treatments for overactive bladder: the example of tolterodine, a new muscarinic agent: a Markov model.

Kobelt G, Jonsson L, Mattiasson A.

Health Dynamics, London, United Kingdom. gisela.kobelt easynet.fr

Economic analyses of interventions for chronic diseases require evaluations over a long timeframe to illustrate the benefits and costs of treatments. Clinical trials are generally short and carried out in strictly controlled conditions. They are therefore of limited value for economic evaluation aimed at facilitating decisions about resource allocation. The objective of this study was to develop a simulation model that allows integration of data from different sources to calculate the incremental cost-effectiveness and cost-utility of new treatments for overactive bladder. The model compares tolterodine, a new treatment that aims at alleviating symptoms and improving patients' quality of life, to no treatment. Simulations for Sweden are presented as an example. The Markov model combines clinical, observational, and economic data. Markov states are defined based on severity of symptoms of overactive bladder (frequency of voids and leaks). Specific costs for drug treatment and use of sanitary protections as well as utilities are assigned for each state. The effectiveness of tolterodine is based on controlled clinical trials and open long-term extensions of these trials. Outcome is measured as quality-adjusted life years (QALYs) and as the number of months spent in a state with no or very limited symptoms. During the course of 1 year, patients treated with tolterodine spend more time in states with no or limited symptoms compared to those receiving no treatment. Tolterodine-treated patients having a better quality of life during the year. The mean utility of the treated cohort is 0.70, compared to 0.67 in the no-treatment cohort, which is equivalent to the entire cohort moving by one level to a state with less severe symptoms. Mean total costs per patient in the tolterodine arm are SEK8,595 (US $1,131; 1 US$ = 7.6 SEK) compared to SEK3,286 (US$432) in the no-treatment arm. The extra cost due to tolterodine is SEK380 (US$50) per month, which falls within the range of monthly amounts that patients were willing to pay out of pocket for a 25 or 50% improvement of their symptoms in a previous study. The cost for pads is reduced by 23%. The marginal cost per QALY gained with tolterodine is estimated at SEK213,000 (US$28,000). Based on this simulation model, it appears that treatment of overactive bladder with a well-tolerated pharmacological treatment such as tolterodine is cost-effective.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9829424&dopt=Abstract tolterodine Detrol



Detrol
Column switching in capillary liquid chromatography-tandem mass spectrometry for the quantitation of pg/ml concentrations of the free basic drug tolterodine and its active 5-hydroxymethyl metabolite in microliter volumes of plasma.

Swart R, Koivisto P, Markides KE.

Uppsala University, Department of Analytical Chemistry, Sweden.

A capillary column switching system was developed for the determination of low, unbound concentrations of the basic drug tolterodine and its active 5-hydroxymethyl (5-HM) metabolite in human plasma. Free concentrations of tolterodine and 5-HM at pM and nM (pg/ml and ng/ml) levels were obtained by ultrafiltration of 40-400 microliters plasma at 37 degrees C. The free fraction (%) was independent of the plasma concentrations of the analytes. Detection of the analytes was performed by sheathless electrospray tandem mass spectrometry in the multiple-reaction monitoring mode. The selectivity of the mass spectrometric detection and the additional clean-up on the pre-column allowed direct injection of the ultrafiltrated plasma samples. Tolterodine and 5-HM were pre-concentrated on a reversed-phase capillary pre-column (1 cm x 200 microns) and subsequently backflushed onto the separation column (25 cm x 200 microns). The stability of the chromatographic system was good; a large number of ultrafiltrated plasma samples could be injected and the relative standard deviation of the retention times was typically < or = 1% (within-day). The accuracy was between 86 and 105% and the precision was between 1 and 7% without the use of an internal standard. Linear calibration curves were obtained between 100 pM and 100 nM.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9916307&dopt=Abstract tolterodine Detrol