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Martin F Fromm

Publications and source records attributed to Martin F Fromm.

At least 19 recordsLinked to original sources
PubMed2006

Effects of ursodeoxycholic acid on P-glycoprotein and cytochrome P450 3A4-dependent pharmacokinetics in humans.

BACKGROUND AND OBJECTIVE: On the basis of in vitro studies indicating that ursodeoxycholic acid (UDCA) is a cytochrome P450 (CYP) 3A4 inducer and a pregnane X receptor activator and because the pregnane X receptor is a transcriptional regulator of multidrug resistance 1 (MDR1)/P-glycoprotein (P-gp), we postulated that UDCA might decrease the bioavailability of CYP3A4 and P-gp probe drugs in humans. The main objective of this study was to determine whether UDCA alters the pharmacokinetics of digoxin and midazolam. The secondary objective was to determine whether the intestinal expression of P-gp and CYP3A4 is increased by UDCA. METHODS: The effect of UDCA on MDR1 and CYP3A4 messenger ribonucleic acid (mRNA) expression was investigated in human colon carcinoma cell lines LS174T and Caco-2. Eight healthy volunteers participated in this open, nonrandomized 2-period study, in which the effects of UDCA (13 mg.kg(-1).d(-1) during 2 weeks) versus control on the pharmacokinetics of digoxin (0.5-mg single intravenous infusion), d3-digoxin (3-fold deuterated digoxin, 0.5-mg single oral dose), and midazolam (7.5-mg single oral dose) were compared. Duodenal biopsy specimens were obtained during both periods to quantify MDR1/P-gp and CYP3A4 expression. RESULTS: In vitro UDCA induced MDR1 and CYP3A4 mRNA in Caco-2 cells but not in LS174T cells. In humans UDCA significantly decreased the extent of digoxin absorption from 0.77 to 0.70 and the oral d3-digoxin area under the plasma concentration-time curve from 0 to 4 hours from 6.4 +/- 1.7 ng.h.mL(-1) to 5.3 +/- 1.5 ng.h.mL(-1) (P = .01 and P = .05, respectively). UDCA had no detectable effects on the pharmacokinetics of midazolam or the intestinal mRNA and protein expression levels of MDR1/P-gp and CYP3A4. CONCLUSION: Under the conditions in our study, UDCA only modestly decreased digoxin disposition without detectable changes in midazolam pharmacokinetics. The clinical relevance of these findings remains to be determined.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Pharmacogenomics of human OATP transporters.

Organic anion transporting polypeptides (OATPs) mediate the uptake of a broad range of compounds into cells. Substrates for members of the OATP family include bile salts, hormones, and steroid conjugates as well as drugs like the HMG-CoA-reductase inhibitors (statins), cardiac glycosides, anticancer agents like methotrexate, and antibiotics like rifampicin. OATPs are expressed in a variety of different tissues, including intestine, liver, kidney, and brain, suggesting that they play a critical role in drug absorption, distribution, and excretion. The identification and functional characterisation of naturally occurring variations in genes encoding human OATP (SLCO) family members is in the focus of transporter research. As a result of their broad substrate spectrum and their wide tissue distribution, altered transport characteristics or protein localisation can contribute significantly to interindividual variations of drug effects. The analysis of the consequences of genetic variations in genes encoding transport proteins may, therefore, contribute to a better understanding of interindividual differences in drug effects and to individualise treatment regimens with drugs that are substrates for human OATP proteins. In this review, we summarise the current knowledge on genetic variations in transporter genes encoding human OATP family members and their functional consequences analysed by in vitro and in vivo studies.

Haplotypes↗
PubMed2006

ATP-binding cassette transporters in the heart.

Members of the ATP-binding cassette (ABC) protein superfamily are integral membrane proteins involved in energy-dependent transport of a wide variety of substrates across biologic membranes. ATP-binding cassette transporters serve as functional barriers against the entry of xenobiotics, for example, in the intestine or at the blood-brain barrier, or contribute to drug excretion, for example, in the kidney or the liver. Many human ABC transporters, such as ABCB1 (P-glycoprotein), ABCC5 (MRP5), or ABCC9 (SUR2), are expressed in the heart, suggesting an important role of these transporters in cardiac drug effects or physiology. Interestingly, mutations in ABCC9, a constituent of cardiac K(ATP) channels, can cause dilated cardiomyopathy in humans, providing evidence that dysfunction of cardiac ABC transporters might have clinical implications. This review aims to give insights into the possible functions of ABC transporters in the heart, their role in drug disposition, as well as control of intracellular cyclic nucleotide levels or regulation of K(ATP) channel conductivity.

ATP-Binding Cassette Transporters↗
PubMed2006

Effect of SLCO1B1 polymorphism on induction of CYP3A4 by rifampicin.

Rifampicin (rifampin) is a potent inducer of cytochrome P450 (CYP) 3A4. It was recently identified as a substrate of the polymorphic organic anion transporting polypeptide 1B1 (OATP1B1) expressed on the sinusoidal membrane of human hepatocytes. The present study aimed to investigate the possible association of single nucleotide polymorphisms (SNP) in the SLCO1B1 gene encoding for OATP1B1 with the inducing effect of rifampicin on hepatic CYP3A4. A total of 38 healthy volunteers who had participated in drug interaction studies with rifampicin were genotyped for the g. - 11187G > A and c.521T > C SNPs in SLCO1B1, c.3435C > T SNP in ABCB1 and g.6986A > G SNP in CYP3A5. The plasma concentration of 4beta-hydroxycholesterol, an endogenous marker of CYP3A4 activity, was measured before and after administration of 600 mg rifampicin once daily for 9-11 days. Treatment with rifampicin significantly increased the mean +/- SD plasma concentration of 4beta-hydroxycholesterol from 55.2 +/- 17.9 ng/ml to 120.9 +/- 32.0 ng/ml (P < 0.001). A large intersubject variability existed in the induction of CYP3A4 by rifampicin, but no associations were observed between the variability in induction and any of the polymorphisms studied. These data suggest that SLCO1B1 polymorphism does not affect the extent of induction of hepatic CYP3A4 by rifampicin, probably because other uptake transporters, such as OATP1B3, can compensate for reduced uptake of rifampicin by OATP1B1. However, the present study had sufficient power to detect only a considerably smaller rifampicin-induced increase in 4beta-hydroxycholesterol in carriers of the SLCO1B1 c.521C allele compared to subjects with the reference genotype.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2006

Characterization of beta-adrenoceptor antagonists as substrates and inhibitors of the drug transporter P-glycoprotein.

Transporter proteins such as P-glycoprotein are major determinants of intracellular drug concentrations. Moreover, inhibition or induction of transporters is an important mechanism underlying drug interactions in humans. However, very little is known whether beta-adrenoceptor antagonists are substrates and/or inhibitors of P-glycoprotein. Therefore, we investigated the P-glycoprotein-mediated transport of propranolol, metoprolol, bisoprolol, carvedilol and sotalol in P-glycoprotein-expressing Caco-2 monolayers and inhibition of P-glycoprotein-mediated digoxin transport by the beta-adrenoceptor antagonists. A significant inhibition of polarized, basal to apical drug transport by the P-glycoprotein inhibitor PSC-833 was observed for bisoprolol (0.5 and 5 microm) and carvedilol (0.5 microm). Moreover, propranolol and carvedilol inhibited P-glycoprotein-mediated digoxin transport with IC(50) values of 24.8 and 0.16 microm, respectively, whereas metoprolol and sotalol had no effect. Bisoprolol significantly inhibited directional digoxin transport at 50 and 250 microm by 31% and 44%, respectively. Taken together, P-glycoprotein is likely to be one determinant of bisoprolol and carvedilol disposition in humans. In addition, the beta-adrenoceptor antagonists propranolol and carvedilol significantly inhibit P-glycoprotein function thereby possibly contributing to drug interactions in humans (e.g. digoxin-carvedilol and cyclosporine-carvedilol).

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Characterisation of (R/S)-propafenone and its metabolites as substrates and inhibitors of P-glycoprotein.

Digoxin is a drug with a narrow therapeutic index, which is a substrate of the ATP-dependent efflux pump P-glycoprotein. Increased or decreased digoxin plasma concentrations occur in humans due to the inhibition or induction of this drug transporter in organs with excretory function such as small intestine, liver and kidney. It is well known that serum concentrations of digoxin increase considerably in humans if propafenone is given simultaneously. However, it has not been investigated in detail whether propafenone and its metabolites are substrates and/or inhibitors of human P-glycoprotein. The aim of this study, therefore, was to investigate the P-glycoprotein-mediated transport and inhibition properties of propafenone and its major metabolites 5-hydroxypropafenone and N-desalkylpropafenone in Caco-2 cell monolayers. Inhibition of P-glycoprotein-mediated transport by propafenone and its metabolites was determined using digoxin as a P-glycoprotein substrate. No polarised transport was observed for propafenone and N-desalkylpropafenone in Caco-2 cell monolayers. However, 5-hydroxypropafenone translocation was significantly greater from basal-to-apical compared with apical-to-basal (P(app) basal-apical vs. P(app) apical-basal, 10.21+/-2.63 x 10(-6) vs. 4.34+/-1.84 x 10(-6) cm/s; P<0.01). Moreover, propafenone, 5-hydroxypropafenone and N-desalkylpropafenone inhibited P-glycoprotein-mediated digoxin transport with IC(50) values of 6.8, 19.9, and 21.3 microM, respectively. In summary, whereas propafenone and N-desalkylpropafenone are not substrates of P-glycoprotein, 5-hydroxypropafenone is translocated by human P-glycoprotein across cell monolayers. In addition, propafenone and its two major metabolites 5-hydroxypropafenone and N-desalkylpropafenone are inhibitors of human P-glycoprotein and therefore contribute to the digoxin-propafenone interaction observed in humans.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor.

Artemisinin drugs are of utmost importance in the treatment of malaria, because they represent the sole class of therapeutically used antimalarial drugs to which malaria parasites have not yet developed resistance. The major disadvantage of these medicines is the comparatively high recrudescence rate, which has been attributed to the remarkable decrease of artemisinin plasma concentrations during multiple dosing. Autoinduction of CYP2B6-mediated metabolism has been implicated as the underlying mechanism. So far, the molecular mechanism of induction by artemisinin has not been resolved. Because the xenosensors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) have been shown to mediate induction of drug-metabolizing enzymes and drug transporters, we investigated the hypothesis that artemisinin induces cytochrome P450 expression by activating PXR and/or CAR. By combining in vitro transfection methods and quantitative analyses of gene expression in cell lines and primary human hepatocytes, we here show that artemisinin drugs activate human PXR as well as human and mouse CAR and induce the expression of CYP2B6, CYP3A4, and MDR1 in primary human hepatocytes and in the human intestinal cell line LS174T. Furthermore, we demonstrate that artemisinin acts as a ligand of both nuclear receptors, because it modulates the interaction of the receptors with coregulators. In conclusion, activation of PXR and CAR and especially the resulting induction of CYP3A4 and MDR1 demonstrate that artemisinin has a higher risk of potential drug interactions than anticipated previously.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Simultaneous determination of oxycodone and its major metabolite, noroxycodone, in human plasma by high-performance liquid chromatography.

Oxycodone (14-hydroxy-7,8-dihydrocodeinone) is a potent opioid receptor agonist. In the present study, a liquid-liquid extraction-based reversed-phase HPLC method with UV detection was validated and applied for the analysis of oxycodone and its major metabolite, noroxycodone, in human plasma. The analytes were separated using a mobile phase, consisting of acetonitrile and phosphate buffer (8:92, v/v) at a flow rate of 1 mL/min, and UV detection at 205 nm. The retention times for oxycodone, noroxycodone and codein (internal standard) were 14.7, 13.8 and 10.2 min, respectively. The validated quantitation range of the method was 2-100 ng/mL for oxycodone and 10-100 ng/mL for noroxycodone. The developed procedure was applied to assess the pharmacokinetics of oxycodone and its metabolite following administration of a single 20 mg oral dose of oxycodone hydrochloride to one healthy male volunteer.

Adult↗
PubMed2005

Grapefruit juice ingestion significantly reduces talinolol bioavailability.

OBJECTIVES: Our objectives were to evaluate the effect of single and repeated grapefruit juice ingestion relative to water on the oral pharmacokinetics of the nonmetabolized and P-glycoprotein-transported drug talinolol in humans and to assess the potential impact of grapefruit juice ingestion on P-glycoprotein and intestinal uptake transporters. METHODS: The oral pharmacokinetics of 50 mg talinolol was determined with water, with 1 glass of grapefruit juice (300 mL), and after 6 days of repeated grapefruit juice ingestion (900 mL/d) in 24 healthy white volunteers. MDR1 messenger ribonucleic acid and P-glycoprotein levels were measured in duodenal biopsy specimens obtained from 3 individuals before and after ingestion of grapefruit juice. Three commonly occurring polymorphisms in the MDR1 gene were also assessed. RESULTS: A single glass of grapefruit juice decreased the talinolol area under the serum concentration-time curve (AUC), peak serum drug concentration (Cmax), and urinary excretion values to 56% (P < .001), 57% (P < .001), and 56% (P < .001), respectively, of those with water. Repeated ingestion of grapefruit juice had a similar effect (44% to 65% reduction; P < .01). Single or repeated juice ingestion did not affect renal clearance, elimination half-life, or time to reach Cmax (tmax). MDR1 messenger ribonucleic acid and P-glycoprotein levels in duodenal biopsy specimens were not affected by grapefruit juice. MDR1 genotypes (C1236T, G2677T/A, and C3435T) were not associated with altered talinolol pharmacokinetics. CONCLUSION: Because both single and repeated ingestion of grapefruit juice lowered rather than increased talinolol AUC, our findings suggest that constituents in grapefruit juice preferentially inhibited an intestinal uptake process rather than P-glycoprotein. Moreover, grapefruit juice did not alter intestinal P-glycoprotein expression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

CYP3A5 genotype is associated with elevated blood pressure.

The present study aimed to determine whether a polymorphism in CYP3A5, encoding the major CYP3A enzyme in the human kidney, is associated with blood pressure in Caucasians. A homogenous group of 115 young, white male students with normal or mildly elevated, but untreated blood pressure was included. Blood pressure was recorded by ambulatory 24-h blood pressure-monitoring and compared between individuals with high (*1/*3) and low CYP3A5 expression (*3/*3). Moreover, genotype-dependent differences in parameters associated with the renin-angiotensin-aldosterone system were evaluated. Twenty-four hour diastolic blood pressure values were not significantly different between the two groups. However, individuals with the CYP3A5*3/*3 genotype had significantly higher 24-h ambulatory systolic blood pressure values compared to subjects with the CYP3A5*1/*3 genotype (129+/-10 versus 124+/-9, P < 0.05). There was no association of CYP3A5 genotype with angiotensin II plasma concentrations, renal plasma flow, glomerular filtration rate, urinary sodium excretion and parameters determined by echocardiography, but the *3/*3 group had significantly lower serum aldosterone concentrations compared to the individuals with the *1/*3 genotype (101+/-29 versus 117+/-29 pg/ml, P < 0.05). These data, as generated with a homogenous population of young Caucasians, indicate that the CYP3A5 genotype affects blood pressure in humans possibly by genotype-dependent differences in renal, CYP3A5-mediated metabolism of cortisol and/or aldosterone. We interpret the lower serum aldosterone concentration in the genotype group with the elevated systolic blood pressure as a counter-regulatory mechanism to attenuate the increased blood pressure associated with the CYP3A5*3/*3 genotype.

Adult↗
PubMed2005

CYP3A5 genotype is associated with diagnosis of hypertension in elderly patients: data from the DEBATE Study.

OBJECTIVE: The aim of this study was to address the presently controversial question of whether cytochrome P450 (CYP) 3A5 polymorphism is associated with hypertension. METHOD: We studied 373 elderly (age > or =75 years) Finnish (Caucasian) patients from the ongoing DEBATE (Drugs and Evidence Based Medicine in the Elderly) trial. The patients were classified into those with a history of hypertension (n = 229) and those without a history of hypertension (n = 144) on the basis of a detailed questionnaire on each patient's medical history and an interview. The patients were genotyped for the CYP3A5 6986A/G single nucleotide polymorphism (SNP) [CYP3A5*1/*3 alleles]. RESULTS: The proportion of individuals with the CYP3A5*1/*3 genotype, i.e. CYP3A5 expressors, was significantly higher among patients with a diagnosis of hypertension than among patients without (18.3% vs 9.0%, p = 0.016). The corresponding odds ratio was 2.26 (95% CI 1.17, 4.38). The allele and genotype frequencies for the two control SNPs, ABCB1 (MDR1) 3435C/T and SLCO1B1 521T/C, did not differ between the two groups. CONCLUSION: This work lends support to the theory that the polymorphic CYP3A5 enzyme may be involved in regulation of blood pressure. The possible role of CYP3A5 as a genetic contributor to hypertension susceptibility warrants further study.

Aged↗
PubMed2004

Characterisation of cerivastatin as a P-glycoprotein substrate: studies in P-glycoprotein-expressing cell monolayers and mdr1a/b knock-out mice.

The aim of this study was to characterise the role of the efflux transporter P-glycoprotein in the disposition of cerivastatin. We investigated directional transport characteristics of [14C]cerivastatin across cell monolayers expressing P-glycoprotein (Caco-2 and L-MDR1) and disposition of cerivastatin in mice with disrupted mdr1a and mdr1b genes. The mice were given orally 1 mg/kg cerivastatin and plasma and tissue samples for analysis of cerivastatin were obtained 10, 20, or 30 min after drug administration. Four knock-out mice and four wild-type mice were studied at each time point. In addition, the hypothesis that gemfibrozil-mediated inhibition of P-glycoprotein contributes to the interaction between gemfibrozil and cerivastatin was tested in Caco-2 cells. The apparent permeability coefficient (P(app)) value for the basal-to-apical transport of cerivastatin in Caco-2 and L-MDR1 cell monolayers was 2.4 times (P<0.001) and 3.8 times (P<0.001) as high as the apical-to-basal P(app) value respectively. The P-glycoprotein inhibitor PSC-833 (1 microM) inhibited the net basal-to-apical transport of cerivastatin in Caco-2 monolayers by 35% (P<0.01) and the MRP inhibitor MK-571 (10 microM) by 50% (P<0.01). At concentrations up to 250 microM, gemfibrozil showed no significant effects on the net transport of cerivastatin in Caco-2 cells. The concentration of cerivastatin in the brain at 30 min was 3.1 times higher in the knock-out mice than in the wild-type mice (P<0.05). The brain-to-plasma cerivastatin concentration ratio at 20 min and 30 min was 2.1 (P<0.05) and 3.6 times (P<0.05) higher respectively in the knock-out animals compared with the wild-type animals. Collectively, these results indicate that cerivastatin is a P-glycoprotein substrate, although other transporters probably contribute to cerivastatin transport in humans. As several statins are P-glycoprotein substrates, beneficial as well as adverse effects of the statins might be affected by interindividual differences in P-glycoprotein expression or function caused by, e.g., the MDR1 polymorphism.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2004

Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens.

OBJECTIVES: Our objectives were to determine the content of cytochrome P450 (CYP) 3A4, CYP3A5, and P-glycoprotein and to measure CYP3A4-dependent catalytic activity in paired human small intestinal and liver specimens. METHODS: Samples of duodenum or proximal jejunum and liver wedge biopsy specimens were obtained from 15 patients undergoing a gastrointestinal operation. Enterocytes were isolated from the intestinal samples. The contents of CYP3A4, CYP3A5, and P-glycoprotein and CYP3A4-mediated catalytic activities were determined in homogenized enterocyte and liver samples. RESULTS: The CYP3A4 protein content was about 3 times (P <.01) and the P-glycoprotein content about 7 times (P <.0001) higher in the enterocyte homogenates than in the liver homogenates. CYP3A5 protein was detected in all samples, but the levels were too low in most cases to allow quantification. The 2 cases with a quantifiable hepatic CYP3A5 content had the CYP3A5*1/*3 genotype; all other cases were homozygous for the CYP3A5*3 allele. No intraindividual correlations between the intestine and liver with respect to CYP3A4 content, P-glycoprotein content, or the measured catalytic activities were present. Values for the maximum rate of metabolism (V(max)) of verapamil N-dealkylation (formation of D-617) and N-demethylation (formation of norverapamil) activities correlated with the CYP3A4 protein content in both organs. CONCLUSIONS: This work demonstrated a much higher content of both CYP3A4 protein and P-glycoprotein in enterocytes isolated from human duodenal or jejunal mucosa than in paired specimens of liver tissue. These results lend support to the view that biotransformation in the gut wall substantially contributes to the overall first-pass metabolism of many CYP3A4 substrates. Furthermore, the high content of P-glycoprotein on the apical surface of enterocytes supports the theory that this efflux transporter may act in concert with CYP3A4 to limit oral drug bioavailability. Finally, these results indicate that neither CYP3A4 nor MDR1 (P-glycoprotein) is coordinately regulated in the liver and intestine.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Impact of concentration and rate of intraluminal drug delivery on absorption and gut wall metabolism of verapamil in humans.

BACKGROUND AND AIMS: In humans gut wall metabolism can be quantitatively as important as hepatic drug metabolism in limiting the systemic exposure to drugs after oral administration. However, it has been proposed that the role of gut wall metabolism might be overemphasized, because high luminal drug concentrations would lead to a saturation of gut wall metabolism. Therefore we investigated the impact of concentration and rate of intraluminal drug delivery on absorption (F(abs)) and gastrointestinal extraction (E(GI)) of a luminally administered cytochrome P450 (CYP) 3A4 substrate (verapamil) using a multilumen perfusion catheter in combination with a stable isotope technique. METHODS: Two 20-cm-long, adjacent jejunal segments were isolated with the multilumen perfusion catheter in 7 subjects. In this study 80 mg of unlabeled verapamil (d0-verapamil 15 min) was infused into one segment over a 15-minute period, 80 mg of 3-fold deuterated verapamil (d3-verapamil 240 min) was administered over a 240-minute period into the other segment, and simultaneously, 5 mg of 7-fold deuterated verapamil (d7-verapamil) was injected intravenously over a 15-minute period. RESULTS: The rate of intraluminal drug delivery had only a modest effect on bioavailability of the verapamil isotopes (after correction for F abs ) (F/F abs d3-verapamil 240 min versus d0-verapamil 15 min, 0.24 +/- 0.10 versus 0.20 +/- 0.09; P <.05). Accordingly, the E GI value for d3-verapamil 240 min was 0.50 +/- 0.18 compared with 0.59 +/- 0.14 for d0 -verapamil 15 min ( P <.05). In vivo, E GI (d0-verapamil 15 min ) correlated strongly with E GI (d3-verapamil 240 min ) (r = 0.94, P <.005). Moreover, intrinsic clearance of CYP3A4-mediated verapamil metabolism in homogenates of simultaneously collected shed enterocytes correlated with in vivo E GI of d0-verapamil 15 min /d3-verapamil 240 min (r = 0.62, P =.03). CONCLUSIONS: Substantial gut wall metabolism of verapamil occurs in humans and can be predicted from ex vivo data by use of shed enterocytes. The different intraluminal concentrations and rates of intraluminal drug delivery did not lead to a pronounced saturation of intestinal drug metabolism.

Adult↗
PubMed2004

Importance of P-glycoprotein at blood-tissue barriers.

P-glycoprotein is the product of the ABCB1 [also known as multidrug resistance 1 (MDR1)] gene. It translocates a broad variety of xenobiotics out of cells. P-glycoprotein was first described in tumor cells that were resistant to various anticancer agents as a result of P-glycoprotein overexpression. P-glycoprotein is not only expressed in tumor cells but also in a broad variety of normal tissues with excretory function (small intestine, liver and kidney) and at blood-tissue barriers (blood-brain barrier, blood-testis barrier and placenta). In particular, following the generation of P-glycoprotein-deficient mice it became clear that this efflux transporter limits the absorption of orally administered drugs, promotes drug elimination into bile and urine, and protects various tissues (e.g. brain, testis and fetus) from potentially toxic xenobiotics. In humans, a considerable interindividual variability in P-glycoprotein tissue expression is observed, and current research is focused on the potential role of ABCB1 polymorphisms and haplotypes that affect P-glycoprotein tissue expression, plasma concentrations of drugs, the frequency of adverse drug reactions and treatment outcome.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Clinical aspects of the MDR1 (ABCB1) gene polymorphism.

Transporter proteins, in particular P-glycoprotein (Pgp), are important determinants in absorption, tissue targeting, and elimination of drugs. In addition to physiological and environmental factors, its expression and function are modified by genetic polymorphisms of the MDR1 gene. So far, several MDR1 SNPs have been identified, and mutations at positions 2677 and 3435 were associated with alteration of Pgp expression and/or function. In contrast to drug-metabolizing enzymes (eg, CYP2D6), for which loss of function mutations or gene amplification manifests as distinct phenotypes in the population, the impact of MDR1 polymorphisms on pharmacokinetics and pharmacodynamics of Pgp substrates is moderate. Clinical studies on the effects of the C3435T polymorphism and drug treatment with cardiac glycosides, the immunosuppressants cyclosporine and tacrolimus, HIV protease inhibitors, and tricyclic antidepressants are discussed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗