Biomedical subjects

Martin F Fromm

Publications and source records attributed to Martin F Fromm.

At least 19 recordsLinked to original sources

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↗

PubMed2004

Genetic polymorphisms in the multidrug resistance-associated protein 3 (ABCC3, MRP3) gene and relationship to its mRNA and protein expression in human liver.

AIMS: To determine the genetic variability of multidrug resistance protein 3 (MRP3). METHODS: Genomic DNA samples from 103 Caucasians were systematically screened for genetic variations to find a potential relationship with hepatic MRP3 expression. Sequencing comprised all 31 exons, approximately 100 bp of the flanking intronic regions and 2 kb of the 5' UTR. RESULTS: In total, 51 mutations were identified. Fifteen SNPs were located in the coding exons of MRP3, six of which are nonsynonymous mutations. SNPs 39G>C (allele frequency: 0.5%, located in exon 1), 202C>T (1.6%, exon 2), 1037C>T (0.5%, exon 9), 1537C>A (0.5%, exon 12), 3890G>A (5.2%, exon 27) and 4267G>A (0.6%, exon 29) resulted in Lys13Asn, His68Tyr, Ser346Phe, Gln513Lys, Arg1297His and Gly1423Arg amino acid substitutions, respectively. A splice site mutation (1339-1G>T) was found at the intron 10-exon 11 boundary. To evaluate, whether mutations in the MRP3 gene correlate with human hepatic MRP3 expression, we analyzed the genetic variants in Caucasian liver samples, whose MRP3 mRNA (n = 84) and protein (n = 50) expression has been determined by real time quantitative PCR and Western Blot, respectively. We found a significant correlation of a polymorphism in the 5' promoter region (-211C>T) of MRP3 with mRNA expression. Individuals homozygous and heterozygous for the -211C>T promoter polymorphism had significantly lower MRP3 transcript levels compared to wild-type individuals (P < 0.05). Accordingly, electrophoretic mobility shift assay demonstrated that -211C>T polymorphism affected the binding of nuclear factors. CONCLUSIONS: Multiple genetic polymorphisms of MRP3 exist in Caucasians. The -211C>T promoter polymorphism appears to be associated with altered hepatic MRP3 mRNA expression.

Alternative Splicing↗

PubMed2004

Variable expression of P-glycoprotein in the human placenta and its association with mutations of the multidrug resistance 1 gene (MDR1, ABCB1).

The MDR1 gene product P-glycoprotein in the human placenta is important for protecting the fetus from unintended, harmful drug exposure, but also for limiting the access of therapeutic drugs to the fetus after maternal drug intake. A polymorphism in exon 26 of the MDR1 gene (C3435T) has previously been shown to be associated with reduced P-glycoprotein expression in the small intestine, kidney and lymphocytes. In the present study, we examined systematically whether MDR1 polymorphisms also have an impact on P-glycoprotein expression in the human placenta. MDR1 mRNA and P-glycoprotein were analysed in 73 full-term human placentas of Caucasians, as well as respective MDR1 genotypes/haplotypes, for the C3435T and G2677T/A polymorphisms of mothers and infants. MDR1 mRNA levels were not different between these genotype groups. However, P-glycoprotein expression was significantly lower when both mother and infant were homozygous for the 3435T allele (TT/tt) compared to maternal and fetal homozygotes for the C-allele (0.40 +/- 0.18 a.u. for TT/tt versus 0.66 +/- 0.30 a.u. for CC/cc, P = 0.01). Moreover, placentas from mothers carrying both polymorphisms (3435T and 2677T; TT/TT) also had a significantly lower P-glycoprotein expression (0.31 +/- 0.12 a.u.) compared to placentas of wild-type individuals (CC/GG, 0.71 +/- 0.31 a.u., P = 0.02). Taken together, the MDR1 polymorphisms C3435T and G2677T are associated with altered P-glycoprotein expression in the human placenta, and may have clinical consequences due to genetically determined, variable drug exposure of the fetus.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Identification of budesonide and prednisone as substrates of the intestinal drug efflux pump P-glycoprotein.

Steroid resistance is a major problem in the management of patients with inflammatory bowel disease. In Crohn disease, poor response to corticosteroids has been related to increased expression of the drug efflux pump, P-glycoprotein. However, it has not been investigated thoroughly whether corticosteroids commonly used for drug therapy in inflammatory bowel disease are substrates of P-glycoprotein. We tested the hypothesis that budesonide and prednisone are substrates of P-glycoprotein thereby possibly contributing to variable therapeutic effects. Polarized, basal to apical transport of [3H]budesonide and [3H]prednisone was studied in monolayers of L-MDR1 cells (LLC-PK1 cells stably transfected with human MDR1 cDNA) and Caco-2 cells, both of which express P-glycoprotein in their apical membrane. Drug transport was measured during 4 hours at substrate concentrations of 5 microM. Net transport rates and permeability coefficients were calculated. Inhibition of P-glycoprotein-mediated transport across Caco-2 monolayers was determined after addition of the P-glycoprotein inhibitor PSC-833. The net transport rate from the basolateral to the apical side was significantly higher in L-MDR1 than in LLC-PK1 cells for both budesonide and prednisone. Apparent permeability coefficients of budesonide and prednisone reflected polarized transport from basal to apical. PSC-833 inhibited the polarized transport of both corticosteroids. In conclusion, budesonide and prednisone were identified as substrates of the intestinal drug efflux pump, P-glycoprotein. Therefore, drug secretion via P-glyco-protein into gut lumen might play a more important role in pharmacokinetics and pharmacodynamics of these corticosteroids than currently appreciated in gastroenterological practice.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1).

This study aimed to characterize possible relationships between polymorphisms in the drug transporter genes organic anion transporting polypeptide-C (OATP-C, SLCO1B1), OATP-B (SLCO2B1), multidrug resistance-associated protein 2 (MRP2, ABCC2) and multidrug resistance transporter (MDR1, ABCB1) and the pharmacokinetics of pravastatin. We studied 41 healthy Caucasian volunteers who had previously participated in pharmacokinetic studies with pravastatin. Six volunteers had a very high pravastatin AUC value and were defined as outliers according to statistical criteria. The OATP-C gene was sequenced completely in all subjects, and they were also genotyped for selected single nucleotide polymorphisms (SNP) in the OATP-B, MDR1 and MRP2 genes. Of the six outliers, five were heterozygous for the OATP-C 521T>C (Val174Ala) SNP (allele frequency 42%) and three were heterozygous for a new SNP in the promoter region of OATP-C (-11187G>A, allele frequency 25%). Among the remaining 35 subjects, two were homozygous and six were heterozygous carriers of the 521T>C SNP (allele frequency 14%, P = 0.0384 versus outliers) and three were heterozygous carriers of the -11187G>A SNP (allele frequency 4%, P = 0.0380 versus outliers). In subjects with the -11187GA or 521TC genotype, the mean pravastatin AUC0-12 was 98% (P = 0.0061) or 106% (P = 0.0034) higher, respectively, compared to subjects with the reference genotype. These results were substantiated by haplotype analysis. In heterozygous carriers of *15B (containing the 388A>G and 521T>C variants), the mean pravastatin AUC0-12 was 93% (P = 0.024) higher compared to non-carriers and, in heterozygous carriers of *17 (containing the -11187G>A, 388A>G and 521T>C variants), it was 130% (P = 0.0053) higher compared to non-carriers. No significant associations were found between OATP-B, MRP2 or MDR1 polymorphisms and the pharmacokinetics of pravastatin. These results suggest that haplotypes are more informative in predicting the OATP-C phenotype than single SNPs.

Adult↗

PubMed2004

Lipid-lowering response to statins is affected by CYP3A5 polymorphism.

Individuals expressing the polymorphic CYP3A5 enzyme might show a more than average efficiency in the metabolism of lovastatin, simvastatin and atorvastatin. We studied whether the expression of CYP3A5 is associated with an impaired lipid-lowering response to statins in 69 Caucasian patients. Lovastatin, simvastatin and atorvastatin were significantly less effective in CYP3A5 expressors than in non-expressors. The mean serum total cholesterol concentration at 1 year was 23% higher (P = 0.0014) and the mean serum low-density lipoprotein cholesterol concentration was 24% higher (P = 0.036) in subjects possessing the CYP3A5*1 allele (CYP3A5 expressors, n = 7) than in subjects homozygous for the CYP3A5*3 allele (non-expressors, n = 39). The mean percentage reduction in serum total cholesterol from baseline was significantly smaller in CYP3A5 expressors than in non-expressors (17% versus 31%, P = 0.026). No association between hypolipidemic efficacy and CYP3A5 polymorphism was observed among 23 subjects taking statins that are not dependent on CYP3A5 (fluvastatin, pravastatin). These findings suggest that CYP3A5 may be a genetic determinant of interindividual differences in response to certain statins.

Aged↗

PubMed2003

Celecoxib inhibits metabolism of cytochrome P450 2D6 substrate metoprolol in humans.

OBJECTIVE: In vitro data have shown that celecoxib inhibits the metabolism of cytochrome P450 (CYP) 2D6 substrates. However, very limited data are available on the influence of cyclooxygenase 2 inhibitors on the disposition of CYP2D6 substrates in humans. Therefore the objective of this study was to examine the effect of celecoxib and rofecoxib on the pharmacokinetics of the clinically relevant CYP2D6 substrate metoprolol. METHODS: An open, randomized, 3-period crossover study was performed in 12 healthy male volunteers. Metoprolol (50 mg) was given in all 3 periods without or after 7 days of pretreatment with celecoxib (200 mg twice daily) or rofecoxib (25 mg daily) to achieve steady-state conditions of cyclooxygenase 2 inhibitors in periods 2 and 3. RESULTS: Celecoxib significantly increased the area under the plasma concentration-time curve of metoprolol from 271 to 414 micro g. h/L (64% +/- 57%, P <.001) and by more than 200% in 1 volunteer. The extent of this drug interaction was more pronounced in volunteers with 2 fully functional alleles compared with volunteers with 1 fully functional allele (103% +/- 75% versus 36% +/- 23%, P <.05). After administration of celecoxib, the area under the plasma concentration-time curve from 0 to 24 hours of alpha-hydroxymetoprolol decreased significantly from 474 to 387 micro g. h/L (P <.01). Rofecoxib caused no significant effects on the pharmacokinetics of metoprolol. CONCLUSION: We conclude that celecoxib inhibits the metabolism of the CYP2D6 substrate metoprolol but that rofecoxib does not. Clinically relevant drug interaction may occur between celecoxib and CYP2D6 substrates, particularly those with a narrow therapeutic index.

Adrenergic beta-Antagonists↗

PubMed2003

Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis.

BACKGROUND & AIMS: The human multidrug resistance 1 (MDR1) gene product P-glycoprotein is highly expressed in intestinal epithelial cells, where it constitutes a barrier against xenobiotics. The finding that mdr1a knockout mice develop a form of colitis that is similar to ulcerative colitis, which can be prevented by antibiotics, indicates a barrier function for P-glycoprotein against the invasion of bacteria or toxins. Because the MDR1 single nucleotide polymorphism C3435T is associated with lower intestinal P-glycoprotein expression, we tested whether this polymorphism predisposes to development of ulcerative colitis. METHODS: Allele frequencies and genotype distributions of the C3435T single nucleotide polymorphism were investigated in 149 patients with ulcerative colitis, 126 patients with Crohn's disease, and sex-matched healthy controls. RESULTS: Significantly increased frequencies of the 3435T allele and the 3435TT genotype were observed in patients with ulcerative colitis compared with controls (3435T: P = 0.049; odds ratio, 1.4; 95% confidence interval, 1.02-1.94; 3435TT: P = 0.045; odds ratio, 2.03; 95% confidence interval, 1.04-3.95). In contrast, frequencies of the T allele and the TT genotype were the same in patients with Crohn's disease as in controls (P = 0.66 and P = 0.59, respectively). In comparison to 998 non-sex-matched controls, the effect for the TT genotype in ulcerative colitis patients was more pronounced (P = 0.0055; odds ratio, 2.1). CONCLUSIONS: The higher frequency of the 3435TT genotype in patients with ulcerative colitis corroborates the findings from the mdr1a knockout mice. The results support the notion that P-glycoprotein plays a major role in the defense against intestinal bacteria or toxins. Impairment of barrier function in 3435TT subjects could render this genotype more susceptible to the development of ulcerative colitis.

Adolescent↗

PubMed2003

P-glycoprotein-mediated intestinal and biliary digoxin transport in humans.

BACKGROUND AND AIMS: Intestinal transport by P-glycoprotein is a recently recognized determinant of drug disposition. However, direct measurements of transporter-mediated drug elimination into isolated segments of human small intestine are lacking. METHODS: Using a recently developed intestinal perfusion catheter, we perfused in healthy volunteers two 20-cm jejunal segments with and without the P-glycoprotein inhibitor quinidine before and during administration of the P-glycoprotein inducer rifampin (INN, rifampicin). RESULTS: Within 3 hours after intravenous administration of digoxin (1 mg), perfusate samples were collected. We found that 0.45% +/- 0.24% and 0.83% +/- 0.60% of the digoxin dose were eliminated into a jejunal segment and into bile, respectively. Perfusion of the isolated segment with quinidine reduced intestinal digoxin elimination (0.23% +/- 0.08%, P =.031). During rifampin, intestinal digoxin elimination was 0.80 +/- 0.59 (P =.383). Enterocyte P-glycoprotein content correlated with the area under the plasma concentration-time curve of digoxin (Spearman nonparametric correlation coefficient [r(S)] = -0.73, P =.003) and digoxin nonrenal clearance (r(S) = 0.52, P =.056), as well as with intraluminal and plasma concentrations of quinidine (r(S) = 0.55, P =.041 and r(S) = -0.67, P =.009, respectively). CONCLUSION: Using segmental intestinal perfusion, we provide direct evidence that intestinal P-glycoprotein mediates substantial drug elimination after intravenous administration from the systemic circulation into the gut lumen and prevents entry of luminally administered P-glycoprotein substrates into the enterocytes. These data also highlight the relative importance of direct intestinal drug secretion in comparison with drug elimination through bile.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Differential expression and function of CYP2C isoforms in human intestine and liver.

This study aimed to characterize the intestinal and hepatic expression and function of CYP2C enzymes in the same set of subjects. CYP2C isoform-specific quantitative reverse transcription-polymerase chain reaction assays, Western immunoblotting and marker reactions of CYP2C8, CYP2C9 and CYP2C19 activities were employed to investigate expression and activity of the CYP2C isoforms in samples of small intestine and liver obtained from 15 patients undergoing gastrectomy or pancreatoduodenectomy. The rank order for CYP2C mRNA expression in the intestine was CYP2C9 = CYP2C18 > CYP2C19 > CYP2C8, whereas that in the liver was CYP2C9 > CYP2C8 > CYP2C18 > CYP2C19. The rank order for expression of CYP2C protein in the intestine was CYP2C9 > CYP2C19 > CYP2C8 (content below limit of quantification) > CYP2C18 (not detected) and that in the liver was CYP2C9 > CYP2C8 > CYP2C19 > CYP2C18 (not detected). The CYP2C9 protein content was approximately 10-fold higher in the liver than in the intestine (P < 0.001). The CLint for the formation of D-703 from verapamil (marker of CYP2C8 activity) was 7.6-fold higher (P < 0.001) and that for the diclofenac 4'-hydroxylation (marker of CYP2C9 activity) was 6.1-fold higher (P < 0.001) in the liver than in the intestine. Apart from a borderline positive correlation (r = 0.58, P = 0.0504) between the intestinal and hepatic CLint for the diclofenac 4'-hydroxylation, no intra-individual relationships between these tissues with respect to expression or activity of different CYP2C isoforms were found. Collectively, these results show that CYP2C8, CYP2C9 and CYP2C19 are expressed as functional enzymes in the human small intestine, and further suggest that CYP2C genes are independently regulated in human intestine and liver. Although, overall, the expression and activity of CYP2C enzymes is lower in the gut than in the liver, the surface area of the proximal small intestine is large and intestinal CYP2C9 and CYP2C19 may well contribute to the first-pass metabolism of their substrate drugs.

Adult↗

PubMed2003

Influence of omeprazole on multidrug resistance protein 3 expression in human liver.

Multidrug resistance protein (MRP) 3 transports bile salts and conjugated xenobiotics from cells (hepatocytes and enterocytes) into the blood. Hepatic MRP3 expression is low under normal conditions but is markedly up-regulated during cholestasis. Since little is known about additional factors increasing human hepatic MRP3 expression, we investigated the variability of MRP3 expression in a large collection of human livers and factors contributing to variable MRP3 expression in liver and HepG2 cells. MRP3 was measured in 62 human livers from patients with and without omeprazole treatment and in HepG2 cells with and without omeprazole or beta-naphthoflavone treatment. Livers of patients treated with omeprazole showed 4.8-fold (P < 0.0001) higher MRP3 protein expression compared with the remainder of the population. Accordingly, MRP3 mRNA and protein were induced 2.4- and 1.8-fold, respectively (P < 0.01 and P < 0.05), in HepG2 cells treated with omeprazole. Finally, MRP3 was induced in HepG2 cells by beta-naphthoflavone. In summary, treatment with omeprazole and beta-naphthoflavone is a determinant of variable human hepatic MRP3 expression.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2003

Pharmacokinetic interactions with rifampicin : clinical relevance.

The antituberculosis drug rifampicin (rifampin) induces a number of drug-metabolising enzymes, having the greatest effects on the expression of cytochrome P450 (CYP) 3A4 in the liver and in the small intestine. In addition, rifampicin induces some drug transporter proteins, such as intestinal and hepatic P-glycoprotein. Full induction of drug-metabolising enzymes is reached in about 1 week after starting rifampicin treatment and the induction dissipates in roughly 2 weeks after discontinuing rifampicin. Rifampicin has its greatest effects on the pharmacokinetics of orally administered drugs that are metabolised by CYP3A4 and/or are transported by P-glycoprotein. Thus, for example, oral midazolam, triazolam, simvastatin, verapamil and most dihydropyridine calcium channel antagonists are ineffective during rifampicin treatment. The plasma concentrations of several anti-infectives, such as the antimycotics itraconazole and ketoconazole and the HIV protease inhibitors indinavir, nelfinavir and saquinavir, are also greatly reduced by rifampicin. The use of rifampicin with these HIV protease inhibitors is contraindicated to avoid treatment failures. Rifampicin can cause acute transplant rejection in patients treated with immunosuppressive drugs, such as cyclosporin. In addition, rifampicin reduces the plasma concentrations of methadone, leading to symptoms of opioid withdrawal in most patients. Rifampicin also induces CYP2C-mediated metabolism and thus reduces the plasma concentrations of, for example, the CYP2C9 substrate (S)-warfarin and the sulfonylurea antidiabetic drugs. In addition, rifampicin can reduce the plasma concentrations of drugs that are not metabolised (e.g. digoxin) by inducing drug transporters such as P-glycoprotein. Thus, the effects of rifampicin on drug metabolism and transport are broad and of established clinical significance. Potential drug interactions should be considered whenever beginning or discontinuing rifampicin treatment. It is particularly important to remember that the concentrations of many of the other drugs used by the patient will increase when rifampicin is discontinued as the induction starts to wear off.

Drug Interactions↗

PubMed2002

Genetically determined differences in P-glycoprotein function: implications for disease risk.

The MDR1 gene product P-glycoprotein does not only contribute to drug resistance during chemotherapy of tumors but it is also expressed in healthy tissues with excretory function (intestine, liver and kidney). It transports a wide range of structurally unrelated compounds out of cells. Intestinal expression of this transporter has been shown to determine bioavailability of orally administered P-glycoprotein substrates such as digoxin. Recently, several mutations were found in the MDR1 gene. Subjects homozygous for the C3435T mutation (24% of Caucasians) have low intestinal P-glycoprotein levels, high plasma concentrations after oral digoxin and a reduced P-glycoprotein function in peripheral blood cells in comparison to the remainder of the population. Potential implications of this reduced mechanism of detoxification will be shown for three selected diseases: (1) association of low intestinal P-glycoprotein expression with development of inflammatory bowel disease; (2) implications for disease risk and therapeutic outcome of HIV; and (3) consequences of this mutation for renal P-glycoprotein expression and risk of renal cell carcinoma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

The influence of MDR1 polymorphisms on P-glycoprotein expression and function in humans.

The MDR1 (ABCB1) gene product P-glycoprotein is a membrane protein, which functions as an ATP-dependent exporter of xenobiotics from cells. Its importance was first recognized because of its role in the development of multidrug resistance (MDR) of cultured tumor cells against various anticancer agents. It is now, however, well established that this transporter is not only expressed in tumor cells, but also in normal tissues with excretory function (intestine, liver, kidney). Since P-glycoprotein has a very broad substrate specificity, it determines disposition of a broad variety of drugs. Moreover, induction and inhibition of P-glycoprotein are new mechanisms for drug interactions in humans. Very recently, systematic screens of the MDR1 gene have identified multiple single nucleotide polymorphisms. Some of those appear to be associated with altered transporter function and expression. This review discusses the currently available data on the influence of MDR1 polymorphisms on P-glycoprotein tissue expression, drug disposition, treatment outcome and disease risk.

ATP Binding Cassette Transporter, Subfamily B, Mem↗