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

Abstract

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...

Oxybutynin and trospium are substrates of the human organic cation transporters

“…The maximum uptake rate (V max ) showed the following rank order at the hOCTs: hOCT 3 >>hOCT 1 >>hOCT 2 for trospium, and hOCT 2 >hOCT 3 >hOCT 1 for oxybutynin. In agreement with previous observations (Geyer et al 2009(Geyer et al , 2010, oxybutynin exhibited a very high non-specific uptake which was about 30-fold higher than that of trospium, and which is obviously a consequence of the high lipophilicity of this drug and its potential to passively diffuse through plasma membranes (Wiedemann and Schwantes 2007;Kay et al 2009). However, we cannot exclude that a part of this high non-OCT-mediated uptake of oxybutynin may also be due to yet undefined transporters endogenously expressed in HEK293 cells.…”

“…However, OCTs play also a role for the hepatic uptake of drugs. Since up to 15% and 25% of trospium has been shown to be hepatically eliminated in man and mice, respectively (Singh-Franco et al 2005;Geyer et al 2009), hOCT 1 and hOCT 3 which are expressed at the basolateral membrane of human hepatocytes, may be actively involved in the hepatic uptake of trospium. As already mentioned above, trospium is also transported by the efflux carrier P-gp that is expressed in the luminal membrane of proximal tubules in the kidney and in the canalicular membrane of hepatocytes in the liver (Thiebaut et al 1987).…”

“…1), are poorly taken up by the brain and, therefore, are not prone to CNS side effects (Todorova et al 2001;Diefenbach et al 2003, Staskin andHarnett 2004;Staskin et al 2010). Moreover, Geyer et al (2009Geyer et al ( , 2010 recently demonstrated that the blood brain barrier permeability of trospium-in contrast to that of oxybutynin-is highly restricted by the drug efflux carrier P-glycoprotein (P-gp), and that P-gp also contributes to the hepatobiliary excretion and intestinal secretion of this drug.…”

Pharmacodynamics of Overactive Bladder Drugs: Shifting the Curve

“…Studies in mice have shown that systemic distribution of trospium, a weak substrate for P-gp, is controlled, and its passage through the BBB is dependent on P-gp [45]. Fesoterodine, 5-HMT, and darifenacin are also P-gp substrates and can be actively transported out of the CNS, whereas solifenacin is not [37,42].…”

“…The P-gp efflux transporter limits the concentration levels of drugs found in the CNS and other tissues [45]. Studies in mice have shown that systemic distribution of trospium, a weak substrate for P-gp, is controlled, and its passage through the BBB is dependent on P-gp [45].…”