ABSTRACT:Placental syncytiotrophoblasts are known to express the efflux transporter proteins P-glycoprotein (ABCB1) and multidrug resistance-associated protein 2 (ABCC2), which are supposed to be a functional part of the human placental barrier. With advancing gestational age, expression of ABCB1 decreases progressively, whereas ABCC2 is more expressed. To evaluate to which extent they contribute to placental barrier function at term, permeability of talinolol, a substrate of both carriers, was measured using a validated human placenta perfusion model. We identified in randomized, crossover experiments a unidirectional transfer of talinolol in the fetomaternal direction because the maternofetal trans- The human placenta brings the maternal and fetal blood circulations closely together, separated only by the single cell layer of the syncytiotrophoblast. It regulates the supply of nutrients and gases, the elimination of fetal waste products, and the exposure to exogenous substances, including drugs. There is growing evidence that energydependent transporter processes are involved in the maternofetal exchange of endogenous and xenobiotic substances. Meanwhile, more than 30 transport proteins were identified that are expressed to the maternal-facing brush-border apical membrane or to the fetal-facing basolateral membrane of the syncytiotrophoblast (Marzolini and Kim, 2005;Evseenko et al., 2006;Myllynen et al., 2007). There is evidence for some of them to be significantly involved in drug disposition, such as the maternal-facing efflux carriers P-glycoprotein (ABCB1) and the multidrug resistance-associated protein 2 (ABCC2), a second member of the ABC transporter family (St. Pierre et al., 2000;Marzolini and Kim, 2005;Ceckova-Novotna et al., 2006;Evseenko et al., 2006). ABCB1 and ABCC2 share a wide overlapping substrate spectrum and may be coregulated, e.g., in the small intestine Jedlitschky et al., 2006). Information on their function in the human placenta, however, is contradictory and limited so far to ABCB1. Because placental ABCB1 expression decreases with advancing gestation age whereas ABCC2 undergoes gestational maturation, we hypothesized that ABCC2 in term placentas may be more important than ABCB1 for the transfer of drugs that are substrates of both carriers (Meyer zu Schwabedissen et al., 2005;Sun et al., 2006). A suitable probe drug to evaluate function of ABCB1 and ABCC2 in humans is the nonmetabolized ␤ 1 -selective blocker talinolol, which is a high affinity substrate of ABCB1 as evidenced by in vitro experiments and pharmacokinetic studies in humans and of ABCC2 as concluded from major changes in disposition in Abcc2-deficient GY/ TR Ϫ rats (Spahn-Langguth et al., 1998;Gramatté and Oertel, 1999;Westphal et al., 2000;Bernsdorf et al., 2003). ␤ 1 -Selective blockers are used in the treatment of hypertension during pregnancy (Magee et al., 2000).We provide evidence from perfusion experiments using the dually perfused human placenta model that the placenta serves as a functional barrier for talinolol a...

The aim of this study was to ascertain the influence of acute and repeated methamphetamine administration on metabolic activity of CYP2D2. The study was performed in the model of isolated perfused rat liver using dextromethorphan as a specific marker of CYP2D2 activity. Acute administration of methamphetamine (10, 20 or 40 mg/kg, i.p., once daily for two days) significantly increased dextrorphan O-formation in the isolated liver mediated by CYP2D2 at all investigated doses in the 120th min of liver perfusion. Repeated administration of methamphetamine (10, 20 or 40 mg/kg, i.p., once daily for six days) significantly stimulated dextromethorphan Odemethylation via CYP2D2 dose-dependently. Thus, an induction of CYP2D2 metabolic activity was proved in these experiments. With regard to a high level of homology between human and rat CYP isoform studied, the results may have clinical impact in pharmacotherapy of methamphetamine abusers. Methamphetamine, Dextromethorphan, CYP2D, liver, isolated perfused, ratThe liver has been recognised for many decades as the major site of drug metabolism. By the 1960s, the drug metabolizing enzymes in the liver were characterized as heme proteins, now known as a cytochrome P450 microsomal enzymes. Adverse drug reactions are possible if compounds that act as inducers or inhibitors of these enzymes alter enzyme function. Enzyme induction results in accelerated enzyme synthesis, faster drug metabolism and sub-therapeutic drug concentration. Enzyme inhibition leads to accumulation of the drug, and if the drug has a narrow therapeutic window, serious toxicity may develop in a short time. Enzyme induction usually represents an absolute increase in enzyme synthesis, but phenobarbital, well-known enzyme inducer, increases blood flow to the liver, and its use results in increased liver size up to 50%. Currently, there are fewer than a dozen P450 inducer drugs of clinical importance. These include an phenobarbital (Levine et al. 1998;Valoti et al. 1998;Tang et al. 1999;Reid et al. 2002), glucocorticoids (Hoen et al. 2000Tamasi et al. 2001;Eeckhoudt et al. 2002), rifampicin (Farombi et al. 1999Branch et al. 2000;Niemi et al. 2003) and St. John's wort (Nebel et al. 1999;Barone et al. 2000; Breidenbach et al. 2000;Karliova et al. 2000;Piscitelli et al. 2000;Dostálek et al. 2005).Methamphetamine has recently been reemerged as a significant drug abuse problem in the Czech Republic. Early study in humans (Caldwell et al. 1972) has shown that the urinary excretion products of this compound include the 4-hydroxy derivative, 4-hydroxymethamphetamine and the N-demethylation product, amphetamine. These two dominant metabolites represent almost 50% of all metabolites excreted (Caldwell et al. 1972). The