Intestinal absorption of the quaternary trospium chloride: permeability-lowering factors and bioavailabilities for oral dosage forms

Langguth, Peter; Kubiś, Adam; Krumbiegel, Günter; Lang, W; Merkle, Hans P.; Wächter, W; Spahn‐Langguth, Hildegard; Weyhenmeyer, Roland

doi:10.1016/s0939-6411(97)00050-7

Cited by 27 publications

(15 citation statements)

References 14 publications

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“…A previous in vitro study showed that trospium chloride slightly inhibited the P-gp-mediated digoxin transport across LLC-PK 1 cell monolayers that overexpressed the human P-gp (Sandage et al, 2006). Another in vitro study with P-gp-expressing Caco-2 monolayers showed that trospium chloride was transported from the basolateral to the apical direction in a verapamil-sensitive manner (Langguth et al, 1997). Both findings supported our assumption.…”

supporting

confidence: 84%

The Role of P-Glycoprotein in Limiting Brain Penetration of the Peripherally Acting Anticholinergic Overactive Bladder Drug Trospium Chloride

Geyer¹,

Gavrilova²,

Petzinger³

2009

Drug Metab Dispos

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ABSTRACT:The aim of the present study was to characterize the role of the drug-efflux transporter P-glycoprotein (P-gp) for the disposition of trospium chloride, a widely used anticholinergic drug for the treatment of overactive bladder. P-gp-deficient mdr1a,b(؊/؊) knockout mice were given either 1 mg/kg trospium chloride orally or 1 mg/kg intravenously to analyze brain penetration, intestinal secretion, and hepatobiliary excretion of the drug. The concentrations of trospium chloride in the brain were up to 7 times higher in the mdr1a,b(؊/؊) knockout mice compared with wild-type mice (p < 0.05), making P-gp a limiting factor for the blood-brain barrier penetration of this drug. Moreover, the residence time of the drug in the central nervous system was significantly prolonged in mdr1a,b(؊/؊) knockout mice. Apart from the blood-brain barrier, P-gp also had significant effects on the overall pharmacokinetics of trospium chloride. In the mdr1a,b(؊/؊) knockout mice, hepatobiliary excretion and intestinal secretion were significantly reduced compared with the wild-type mice. Our study indicates that the multidrug resistance transporter P-gp is a major determinant for the distribution of trospium chloride in the body and highly restricts its entry into the brain.Antagonists of the acetylcholine muscarinic receptors, such as trospium chloride, oxybutynin, tolterodine, fesoterodine, darifenacin, and solifenacin are the cornerstone of pharmacotherapy for the symptoms of overactive bladder (OAB) (Andersson, 2005). A potential problem in OAB therapy with such drugs is the undesirable side effects involving the central nervous system (CNS) including dizziness, nervousness, sleep disorders, cognitive impairment, memory impairment, hallucination, and confusion (Scheife and Takeda, 2005;Kay and Ebinger, 2008). The occurrence of these CNS side effects is greatly dependent on the ability of the individual drug to pass the blood-brain barrier (BBB) (Andersson, 2005; Staskin and MacDiarmid, 2006). Although most of the aforementioned antimuscarinic drugs are tertiary amines that are quite lipophilic and can easily penetrate into the brain, trospium chloride is a highly polar quaternary amine that exhibits low lipophilicity (Singh-Franco et al., 2005) (for chemical structure, see Schladitz-Keil et al., 1986). Therefore, trospium chloride can be expected to show much lower penetration through the BBB of patients than other, more lipophilic and uncharged antimuscarinic drugs (Wiedemann and Schwantes, 2007).Apart from their physicochemical properties, brain penetration of many drugs is also affected by drug transporters expressed at the BBB (Löscher and Potschka, 2005). Here, in particular, the drug transporting P-glycoprotein (P-gp) limits the entry of many drugs and xenobiotics into the brain by an efflux-based transport mechanism. Outside of the brain, P-gp is also expressed in tissues with secretory/excretory functions such as the liver (canalicular membrane of hepatocytes), kidney (luminal membrane of proximal tubules), and intest...

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supporting

confidence: 84%

The Role of P-Glycoprotein in Limiting Brain Penetration of the Peripherally Acting Anticholinergic Overactive Bladder Drug Trospium Chloride

Geyer¹,

Gavrilova²,

Petzinger³

2009

Drug Metab Dispos

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“…Its chemical name is spiro[8-azoniabicyclo[3,2,1]octane-8,1′-pyrrolidinium]-3-[(hydroxydiphenylacetyl)-oxy]chloride(1α,3β,5α)-(9CI). Solubility in water exceeds 50 mg per mL at room temperature while in light mineral oil it is 9.2 × 10 –3 mg/mL (Langguth et al 1997). Its log partition coefficient between n-octanol and buffer at pH 7.4 is –1.22 (Langguth et al 1997).…”

Section: Chemistrymentioning

confidence: 99%

“…Solubility in water exceeds 50 mg per mL at room temperature while in light mineral oil it is 9.2 × 10 –3 mg/mL (Langguth et al 1997). Its log partition coefficient between n-octanol and buffer at pH 7.4 is –1.22 (Langguth et al 1997). Synthesis and pharmacological activity of this compound were first described in 1966 (German language literature).…”

Section: Chemistrymentioning

confidence: 99%

“…Absorption of the drug across the intestinal epithelium is complex, involving P-glycoprotein-mediated secretion and saturable binding to intestinal mucus (Langguth et al 1997). Limited permeability across the epithelial cell layer accounts for the low bioavailability.…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Limited permeability across the epithelial cell layer accounts for the low bioavailability. Use of water/oil microemulsions or cyclodextrin did not enhance, and actually reduced, oral bioavailability (Langguth et al 1997). However, oral bioavailability was enhanced by ion pairing using N-alkylsulfates (6- or 7-carbon chain is optimal) or N-alkylsulfonates (7- or 9-carbon chain is optimal) (Langguth et al 1997).…”

Section: Pharmacokineticsmentioning

confidence: 99%

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Trospium chloride: an update on a quaternary anticholinergic for treatment of urge urinary incontinence

Guay¹

2005

tcrm

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Trospium chloride is a quaternary ammonium compound, which is a competitive antagonist at muscarinic cholinergic receptors. Preclinical studies using porcine and human detrusor muscle strips demonstrated that trospium chloride was many-fold more potent than oxybutynin and tolterodine in inhibiting contractile responses to carbachol and electrical stimulation. The drug is poorly bioavailable orally (< 10%) and food reduces absorption by 70%-80%. It is predominantly eliminated renally as unchanged compound. Trospium chloride, dosed 20 mg twice daily, is significantly superior to placebo in improving cystometric parameters, reducing urinary frequency, reducing incontinence episodes, and increasing urine volume per micturition. In active-controlled trials, trospium chloride was at least equivalent to immediate-release formulations of oxybutynin and tolterodine in efficacy and tolerability. The most problematic adverse effects of trospium chloride are the anticholinergic effects of dry mouth and constipation. Comparative efficacy/tolerability data with long-acting formulations of oxybutynin and tolterodine as well as other anticholinergics such as solifenacin and darifenacin are not available. On the basis of available data, trospium chloride does not appear to be a substantial advance upon existing anticholinergics in the management of urge urinary incontinence.

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Permeability—PAMPA

Avdeef

2012

Absorption and Drug Development

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Intestinal absorption of the quaternary trospium chloride: permeability-lowering factors and bioavailabilities for oral dosage forms

Cited by 27 publications

References 14 publications

The Role of P-Glycoprotein in Limiting Brain Penetration of the Peripherally Acting Anticholinergic Overactive Bladder Drug Trospium Chloride

The Role of P-Glycoprotein in Limiting Brain Penetration of the Peripherally Acting Anticholinergic Overactive Bladder Drug Trospium Chloride

Trospium chloride: an update on a quaternary anticholinergic for treatment of urge urinary incontinence

Permeability—PAMPA

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