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Biomedical subjects

M Eichelbaum

Publications and source records attributed to M Eichelbaum.

At least 37 records · Page 2Linked to original sources
PubMed2001

The C3435T mutation in the human MDR1 gene is associated with altered efflux of the P-glycoprotein substrate rhodamine 123 from CD56+ natural killer cells.

P-glycoprotein (PGP) is a membrane protein which determines drug disposition in humans (e.g. digoxin). It is also expressed in various leukocyte lineages with highest expression in CD56+ natural killer cells. Recently, a polymorphism in exon 26 (C3435T) of this gene was shown to correlate with intestinal PGP expression and function in humans. Carriers homozygous for this polymorphism (TT) showed more than two-fold lower PGP expression and higher digoxin plasma concentrations compared to the CC group. However, it is not known whether this mutation in the MDR1 gene is also associated with altered PGP function in peripheral blood cells. We therefore assessed efflux of the PGP-substrate rhodamine 123 from CD56+ natural killer cells. Leukocytes were isolated from whole blood of 10 CC, 10 CT and 11 TT healthy Caucasian individuals. Using flow cytometry, rhodamine fluorescence was determined in CD56+ cells. Moreover, MDRI mRNA was quantified in leukocytes by real-time polymerase chain reaction. Subjects with CC genotype revealed a significantly lower rhodamine fluorescence (i.e. higher PGP function) compared to individuals with TT genotype (51.1 +/- 11.4% versus 67.5 +/- 9.5%, p < 0.01). Heterozygous individuals had an intermediate rhodamine fluorescence (61.4 +/- 6.3%). MDR1 mRNA normalized for cyclophilin was lowest in the TT population (1.29 +/- 1.01), intermediate in heterozygous subjects (1.60 +/- 0.76) and highest in the CC group (1.91 +/- 0.94; not significant). In summary, subjects being homozygous for C in position 3435 of the MDR1 gene have a more pronounced efflux of rhodamine from CD56+ natural killer cells and a higher MDR1 mRNA expression in leukocytes than subjects with the TT genotype. Measurement of rhodamine efflux using flow-cytometry from peripheral blood cells allows assessment of genetically determined differences in P-glycoprotein function.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver.

The human cytochrome P450, CYP2B6, is involved in the metabolism of several therapeutically important drugs and environmental or abused toxicants. In this study, we present the first systematic investigation of genetic polymorphism in the CYP2B6 gene on chromosome 19. A specific direct sequencing strategy was developed based on CYP2B6 and CYP2B7 genomic sequence information and DNA from 35 subjects was completely analysed for mutations throughout all nine exons and their exon-intron boundaries. A total of nine novel point mutations were identified, of which five result in amino acid substitutions in exon 1 (C64T, Arg22Cys), exon 4 (G516T, Gln172His), exon 5 (C777A, Ser259Arg and A785G, Lys262Arg) and exon 9 (C1459T, Arg487Cys) and four are silent mutations (C78T, G216C, G714A and C732T). Polymerase chain reaction-restriction fragment length polymorphism tests were developed to detect each of the five nonsynonymous mutations in genomic DNA. By screening a population of 215 subjects the C64T, G516T, C777A, A785G and C1459T mutations were found at frequencies of 5.3%, 28.6%, 0.5%, 32.6% and 14.0%, respectively. Haplotype analysis revealed six different mutant alleles termed CYP2B6*2 (C64T), *3 (C777A), *4 (A785G), *5 (C1459T), *6 (G516T and A785G) and *7 (G516T, A785G and C1459T). By analysing a large number of human liver samples, significantly reduced CYP2B6 protein expression and S-mephenytoin N-demethylase activity were found in carriers of the C1459T (R487C) mutation (alleles *5 and *7). These data demonstrate that the extensive interindividual variability of CYP2B6 expression and function is not only due to regulatory phenomena, but also caused by a common genetic polymorphism.

Aryl Hydrocarbon Hydroxylases↗
PubMed2001

Comprehensive analysis of the genetic factors determining expression and function of hepatic CYP2D6.

Variable expression and function of the cytochrome P4502D6 (CYP2D6) leads to distinct phenotypes termed ultrarapid (UM), extensive (EM), intermediate (IM) and poor metabolizer (PM). Whereas the PM phenotype is known to be caused by two null-alleles leading to absence of functional CYP2D6 protein, the large variability among individuals with functional alleles remained largely unexplained. In this study, we systematically investigated 76 liver biopsies from individuals with known sparteine metabolic ratios (MRS) for the relationships between CYP2D6 genotype, microsomal protein expression, bufuralol 1'-hydroxylase activity and in-vivo phenotype. Average CYP2D6 protein levels ranged from undetectable in PMs (MRS > 20) to 2.6 +/- 2.7 pmol/mg microsomal protein in IMs (1.2 < MRS< 20), 7.6 +/- 4.7 in EMs (0.2 < MRS < 1.2) and 23.8 +/- 7.7 in UMs (MRS < 0.2), respectively. Analysis with respect to genotype demonstrated gradually increased expression and function for individuals with no, one, two or three functional gene copies per genome. The recently discovered -1584 C/G promoter polymorphism was identified as another major factor for expression and function with the mutant [-1584G] promoter type being consistently associated with significantly higher expression than [-1584C]. To investigate functional differences between the detected variant protein forms CYP2D6.1, 2D6.2, 2D6.9 and 2D6.10, we expressed them recombinantly in insect cells. The most significant difference was a decrease in the relative P450 holoprotein content of all allelic forms, including the common functional variant 2D6.2, in comparison to 2D6.1, whereas only modest Km changes were observed. Taken together, these data provide further insight into the complex mechanisms that govern the highly variable expression and function of CYP2D6.

Cytochrome P-450 CYP2D6↗
PubMed2001

High-throughput genotyping of thiopurine S-methyltransferase by denaturing HPLC.

BACKGROUND: The thiopurine S:-methyltransferase (TPMT) genetic polymorphism has a significant clinical impact on the toxicity of thiopurine drugs, which are used in the treatment of leukemia and as immunosuppressants. To date, 10 mutant alleles are known that are associated with intermediate or low TPMT activity. To facilitate rapid screening of clinically relevant TPMT mutations, we developed a strategy of high-throughput genotyping by applying denaturing HPLC (DHPLC). METHODS: To test the specificity and efficiency of the DHPLC method, 98 DNA samples from a selected population of patients receiving thiopurine therapy or with previous thiopurine withdrawal were analyzed for the most frequent mutant TPMT alleles, *2 and *3A, which contain key mutations in exons 5, 7, and 10 to identify clearly different elution profiles. All fragments were examined by direct sequencing. Additionally, to test the sensitivity of DHPLC analysis, genotyping for the *2 and *3A alleles of all 98 DNA samples was performed by PCR-based methods (PCR-restriction fragment polymorphism analysis and allele-specific PCR). RESULTS: The presence of mutations discriminating for alleles *2, *3A, *3C, and *3D, as well as various silent and intron mutations, were correctly predicted by DHPLC in 100% of the samples as confirmed by direct sequencing. Comparison with PCR-based methods for alleles *2 and *3 produced an agreement of 100% with no false-negative signals. CONCLUSIONS: DHPLC offers a highly sensitive, rapid, and efficient method for genotyping of the relevant TPMT mutations, discriminating at least for alleles *2 and *3, in clinical and laboratory practice. Additionally, DHPLC allows a simultaneous screening for novel genetic variability in the TPMT gene.

Antimetabolites, Antineoplastic↗
PubMed2001

Natural protein variants of pregnane X receptor with altered transactivation activity toward CYP3A4.

Between 45 and 60% of all drugs currently used are metabolized by the CYP3A4 protein. CYP3A4 expression in liver varies up to 60-fold in the general population, which can lead to ineffective drug therapy (high CYP3A4) or, on the other hand, to harmful drug reactions (low CYP3A4). Most of this variability has been attributed to genetic factors, but to date their identity remains unknown. Recently, it was shown that CYP3A expression is largely controlled by the pregnane X receptor (PXR). We, therefore, hypothesized that polymorphisms in PXR may contribute to CYP3A4 variability. The presence of PXR variants was investigated in two ethnic groups, Caucasians and Africans. Six missense mutations leading to variant PXR proteins were identified, and their consequences on CYP3A4 expression were analyzed. Expressed in LS174T cells, three protein variants, V140M, D163G, and A370T, exhibited altered basal and/or induced transactivation of CYP3A promoter reporter genes. Thus, these natural PXR protein variants may play a role in the observed interindividual variability of CYP3A4 expression and may be involved in rare, atypical responses to drugs or altered sensitivities to carcinogens.

Black People↗
PubMed2000

Determination of propafenone and its phase I and phase II metabolites in plasma and urine by high-performance liquid chromatography-electrospray ionization mass spectrometry.

A sensitive method was developed to determine propafenone, 5-hydroxypropafenone, N-despropylpropafenone and propafenone glucuronides in human plasma and urine by HPLC-electrospray ionization mass spectrometry with the respective deuterated analogues as internal standards. The analytes were extracted by a single solid-phase extraction, collecting two fractions, one containing the glucuronides and the other propafenone and the phase I metabolites 5-hydroxypropafenone and N-despropylpropafenone. The mobile phases used for HPLC were: (A) 5 mM ammonium acetate in water and (B) 5 mM ammonium acetate in methanol-tetrahydrofuran (50:50, v/v). Separation of the diastereoisomeric propafenone glucuronides was achieved on a Spherisorb ODS 2 column (150 x 2.0 mm I.D., particle size 5 microm) at a flow-rate of 0.3 ml/min using a linear gradient from 20% B to 50% B in 15 min. For separation of propafenone, 5-hydroxypropafenone and N-desalkylpropafenone a linear gradient from 50% B to 80% B in 10 min was employed. The mass spectrometer was operated in the selected ion monitoring mode using the respective MH+ ions for quantification. The limits of quantification achieved with this method were 10 pmol/ml for propafenone, 5-hydroxypropafenone, R- and S-propafenone glucuronide and 20 pmol/ml for N-desalkylpropafenone using 0.5 ml of plasma. Reproducibility and accuracy was below 12% for each analyte over the whole concentration range measured. The method was applied to a pharmacokinetic study assessing the influence of rifampicin on propafenone disposition.

Chromatography, High Pressure Liquid↗
PubMed2000

Morphine-related metabolites differentially activate adenylyl cyclase isozymes after acute and chronic administration.

Morphine-3- and morphine-6-glucuronide are morphine's major metabolites. As morphine-6-glucuronide produces stronger analgesia than morphine, we investigated the effects of acute and chronic morphine glucuronides on adenylyl cyclase (AC) activity. Using COS-7 cells cotransfected with representatives of the nine cloned AC isozymes, we show that AC-I and V are inhibited by acute morphine and morphine-6-glucuronide, and undergo superactivation upon chronic exposure, while AC-II is stimulated by acute and inhibited by chronic treatment. Morphine-3-glucuronide had no effect. The weak opiate agonists codeine and dihydrocodeine are also addictive. These opiates, in contrast to their 3-O-demethylated metabolites morphine and dihydromorphine (formed by cytochrome P450 2D6), demonstrated neither acute inhibition nor chronic-induced superactivation. These results suggest that metabolites of morphine (morphine-6-glucuronide) and codeine/dihydrocodeine (morphine/dihydromorphine) may contribute to the development of opiate addiction.

Adenylyl Cyclase Inhibitors↗
PubMed2000

Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.

To evaluate whether alterations in the multidrug-resistance (MDR)-1 gene correlate with intestinal MDR-1 expression and uptake of orally administered P-glycoprotein (PGP) substrates, we analyzed the MDR-1 sequence in 21 volunteers whose PGP expression and function in the duodenum had been determined by Western blots and quantitative immunohistology (n = 21) or by plasma concentrations after orally administered digoxin (n = 8 + 14). We observed a significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function of MDR-1. Individuals homozygous for this polymorphism had significantly lower duodenal MDR-1 expression and the highest digoxin plasma levels. Homozygosity for this variant was observed in 24% of our sample population (n = 188). This polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of MDR-1.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Rapid and highly sensitive method for the determination of verapamil, [2H7]verapamil and metabolites in biological fluids by liquid chromatography-mass spectrometry.

A rapid and highly sensitive method for the determination of verapamil [2,8-bis-(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6-azaoctanitrile+ ++] and [2H7]verapamil and their primary metabolites D-617 [2-(3,4-dimethoxyphenyl)-5-methylamino-2-isopropylvaleronitrile], D-703 [2-(4-hydroxy-3-methoxyphenyl)-8-(3,4-dimethoxy-phenyl)-6-methyl-2-iso-p ropyl-6-azaoctanitrile], D-702 [2-(3,4-dimethoxy-phenyl)-8-(4-hydroxy-3-methoxyphenyl)-6-methyl-2-isopr opyl-6-azaoctanitrile], norverapamil [2,8-bis-(3,4-dimethoxyphenyl)-2-isopropyl-6-azaoctanitrile] and secondary metabolites D-620 [2-(3,4-dimethoxyphenyl)-5-amino-2-isopropylvaleronitrile], D-717 [2-(4-hydroxy-3-methoxyphenyl)-5-amino-2-isopropylvaleronitrile], and D-715 [2-(4-hydroxy-3-methoxyphenyl)-8-(3,4-dimethoxy-phenyl)-2-isopropyl-6-++ +azaoctanitrile] has been developed using high-performance liquid chromatography-electrospray mass spectrometry. D-832, the gallopamil analogue of D-617 and [2H3]norverapamil were used as internal standards. The analytes were extracted automatically from plasma and intestinal perfusate using end-capped CN- and C2 solid-phase extraction cartridges. Separation of the eight analytes was achieved on a LUNA C8 analytical column (150x2 mm I.D., 5 microm particle size) with 5 mM ammonium acetate-acetonitrile as the mobile phase run with a gradient from 70:30 to 40:60 and run times of 15 min. With the mass spectrometer operated in the selected-ion monitoring mode, the limits of quantification in plasma and intestinal perfusate were 1 pmol/ml for D-620, D-617, D-702, D-703, norverapamil, verapamil, and [2H7]verapamil and 2.5 pmol/ml for D-717 and D-715 using a sample size of 1 ml plasma and intestinal perfusate. The method described was successfully applied to the determination of verapamil, [2H7]verapamil and their metabolites in human plasma and intestinal fluid in pharmacokinetic studies.

Body Fluids↗
PubMed2000

Psychotropic drug use, falls and hip fracture in the elderly.

The use of benzodiazepines (BZD) or other psychotropic agents is an established risk factor for falls and hip fractures. The evidence supporting this association has been based solely on history and/or prescription data. In a case-control study we monitored the intake of BZD, tricyclic antidepressants (TCA) and barbiturates in patients with hip fracture by serum analysis, and compared this measurement with drug history and prescription records. The serum was BZD positive in 41% of 82 community-dwelling patients; an equivalent by history and/or prescription records, however, was detected in only 18% (p < 0.0001). In contrast, in 82 age- and gender-matched community-dwelling control patients, there was only a minor discrepancy (3%) in BZD use between anamnestic (N = 19) and analytical (N = 21) data. In 23 patients admitted from nursing homes, a similar trend was visible (39% serum positive for BZD vs 26% by drug history). Barbiturate use (N = 2) could be neglected, and TCA intake was minor (N = 7); in each case both assessments were in accordance. In conclusion, in patients with hip fracture, BZD use is substantially more frequent than reported and previously assumed, pointing to an underestimated risk factor for this injury.

Accidental Falls↗
PubMed2000

Variability of cyclophosphamide uptake into human bronchial carcinoma: consequences for local bioactivation.

PURPOSE: The alkylating cytostatic prodrug cyclophosphamide is bioactivated by the human cytochrome P450 enzyme system. Since these enzymes are not only expressed in human liver, but also in extrahepatic tissue, local bioactivation of this drug may play an important role in its antineoplastic effects, e.g., chemotherapy of lung tumors. This would require uptake of significant amounts of cyclophosphamide into tumor tissue, which has not yet been demonstrated. METHODS: We used a recently developed, ex vivo isolated, ventilated and perfused human lung model to study cyclophosphamide uptake into bronchial carcinoma and healthy lung tissue. Following a standard lobectomy, lung samples containing the tumor were perfused with buffer containing 2 mM cyclophosphamide for 2 h. Cyclophosphamide concentrations in perfusate and healthy peripheral tissue were measured during the perfusion and in tumors at the end of perfusion. RESULTS: In all tissue samples, cyclophosphamide uptake was relatively poor, indicated by a tissue to perfusate ratio of 0.021. Moreover, in tumor samples, cyclophosphamide concentrations were significantly lower (P < 0.05) than in healthy lung tissue and showed pronounced interindividual variability. Median concentrations were 36.8 microg/g (26.9 44.2 microg/g) in healthy tissue and 5.1 microg/g (0.0-26.8 microg/g) in tumor samples. Tumor cyclophosphamide concentrations varied between 0 and 75% of those reached in healthy tissue. CONCLUSIONS: Our results indicate that CP tumor concentrations are modulated by factors different from dose and that expression of bioactivating enzymes in human lung or transfection of genes encoding these enzymes into tumor cells does not necessarily lead to local bioactivation of cyclophosphamide.

Aged↗
PubMed2000

The effect of rifampin treatment on intestinal expression of human MRP transporters.

The importance of the ATP-dependent transporter P-glycoprotein, which is expressed in the brush border membrane of enterocytes and in other tissues with excretory function, for overall drug disposition is well recognized. For example, induction of intestinal P-glycoprotein by rifampin appears to be the underlying mechanism of decreased plasma concentrations of P-glycoprotein substrates such as digoxin with concomitant rifampin therapy. The contribution of transporter proteins other than P-glycoprotein to drug interactions in humans has not been elucidated. Therefore, we tested in this study the hypothesis whether the conjugate export pump MRP2 (cMOAT), which is another member of the ABC transporter family, is inducible by rifampin in humans. Duodenal biopsies were obtained from 16 healthy subjects before and after nine days of oral treatment with 600 mg rifampin/day. MRP2 mRNA and protein were determined by reverse transcription-polymerase chain reaction and immunohistochemistry. Rifampin induced duodenal MRP2 mRNA in 14 out of 16 individuals. Moreover, MRP2 protein, which was expressed in the apical membrane of enterocytes, was significantly induced by rifampin in 10 out of 16 subjects. In summary, rifampin induces MRP2 mRNA and protein in human duodenum. Increased elimination of MRP2 substrates (eg, drug conjugates) into the lumen of the gastrointestinal tract during treatment with rifampin could be a new mechanism of drug interactions.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2000

Pharmacokinetics and pharmacodynamics of R- and S-gallopamil during multiple dosing.

AIMS: Using a stable isotope technique we investigated the pharmacokinetics and pharmacodynamics of gallopamil after administration of 50 mg pseudoracemic gallopamil every 12 h for 7 doses (72 h). METHODS: Six male healthy volunteers were studied. After the seventh dose the pharmacokinetics and pharmacodynamics were assessed. Serum levels of gallopamil were measured by gas chromatography/mass spectrometry. Effects of gallopamil were measured by ECG recording. RESULTS: The apparent oral clearances (R: 4.8 l min-1 (95% CI: 2.9-6.8); S: 5.5 l min-1 (95% CI: 2.5-8.5)) and half-lives (R: 6.2 h; S: 7.2 h) of R- and S-gallopamil were similar (P >0.05). The serum protein binding (fu R: 0.035 (95% CI: 0.026-0. 045); S: 0.051 (95% CI: 0.033-0.069)) and the renal elimination (% of dose R: 0.49%; S: 0.71%) were enantioselective. Gallopamil had a potent effect on the PR interval (% prolongation 35.7% (95% CI: 14. 0-57.3)). No changes in other electrocardiographic or cardiovascular parameters were observed. CONCLUSIONS: The pharmacokinetics and bioavailability of the racemic drug gallopamil are not stereoselective at steady-state and are therefore not substantially altered compared with the single dose administration of gallopamil.

Area Under Curve↗
PubMed2000

Disposition of propafenone in a poor metabolizer of CYP2D6 with Gilbert's syndrome.

Gilbert's syndrome, a genetic deficiency in bilirubin UDP-glucuronosyltransferase (UGT1A1), may dispose to increased toxicity of propafenone in poor metabolizers (PMs) of cytochrome P4502D6 because glucuronidation of propafenone is the major metabolic pathway for drug elimination in PMs. A patient with Gilbert's syndrome who is also PM participated in an interaction study with propafenone and rifampicin along with five otherwise healthy PMs. Using stable isotope techniques, the pharmacokinetics of single doses of 140 mg propafenone i.v. (unlabelled) and 300 mg propafenone p.o. (labelled) were compared between the index patient and the five healthy controls. Propafenone did not accumulate in the plasma of the index patient either before or during induction: AUC(0-infinity) of propafenone in the index patient was within the 95% confidence interval of controls; AUC(0-infinity) of propafenone glucuronide and amount of urinary excretion of propafenone glucuronide in the patient were within or even greater than the 95% confidence intervals of controls. Therefore, individuals with Gilbert's syndrome who also have a PM phenotype appear to be at no higher risk for toxicity of propafenone than otherwise healthy PMs. An indirect conclusion from these in vivo data might be that propafenone is not a substrate of the UGT1A1 isoform.

Adult↗
PubMed2000

Elucidation of the genetic basis of the common 'intermediate metabolizer' phenotype for drug oxidation by CYP2D6.

A subgroup of 10-15% of Caucasians are termed phenotypical 'intermediate metabolizers' of drug substrates of CYP2D6 because they have severely impaired yet residual in-vivo function of this cytochrome P450. Genotyping based on the currently known CYP2D6 alleles does not predict this phenotype satisfactorily. A systematic sequencing strategy through 1.6 kb of the CYP2D6 5'-flanking sequence revealed six mutations of which three were exclusively associated with the functional CYP2D6*2 allele (-1496 C to G; -652 C to T; and -590 G to A), two were associated with the nonfunctional *4 and with the functional *10-alleles (-1338 C to T and -912 G to A) and one (-1147 A to G) was seen in all *2, *4 and *10-alleles investigated. The -1496 C to G mutation was found to be polymorphic within CYP2D6*2 alleles. In a family study, the wild-type CYP2D6 *2[-1496 C] and the novel variant [-1496 G] allele co-segregated with lower and higher CYP2D6 in-vivo function, respectively, as shown by phenotyping using sparteine as probe drug. In a representative population sample selected for genotypes comprising one CYP2D6*2 and one non-functional allele, the median urinary metabolic ratio (MRs) for sparteine oxidation was 4.4-fold reduced in individuals with the variant allele (*2[-1496 G], MRs = 0.53, n = 27) compared with individuals lacking the mutation (*2[-1496 C], MRs = 2.33, n = 12; P < 0.0001). The mutation -1496 C to G has an estimated frequency of approximately 20% in the general population and allows establishment of a genotype for the identification of over 60% of intermediate metabolizers in Caucasian populations.

Base Sequence↗
PubMed2000

Characterization of the major metabolites of verapamil as substrates and inhibitors of P-glycoprotein.

Verapamil is subject to extensive oxidative metabolism mediated by cytochrome P450 enzymes with less than 5% of an oral dose being excreted unchanged in urine. Furthermore, verapamil is known to be a potent inhibitor of P-glycoprotein function. There is evidence from in vivo investigations that some verapamil metabolites might be actively transported. The aim of the present study was to investigate P-glycoprotein-mediated transport and inhibition properties of verapamil and its metabolites norverapamil, D-620, D-617, and D-703. Polarized transport of these compounds was assessed in P-glycoprotein-expressing Caco-2 and L-MDR1 cells (LLC-PK1 cells stably transfected with human MDR1-P-glycoprotein). Inhibition of P-glycoprotein-mediated transport by these compounds was determined using digoxin as P-glycoprotein substrate. At concentrations of 5 microM, significant differences between basal-to-apical and apical-to-basal apparent permeability coefficients were observed for D-617 and D-620 in all P-glycoprotein-expressing cell monolayers, indicating that both are P-glycoprotein substrates. In contrast, no P-glycoprotein-dependent transport was found for verapamil, norverapamil, and D-703 in Caco-2 cells and for D-703 in L-MDR1 cells. Moreover, verapamil, norverapamil, and D-703 inhibited P-glycoprotein-mediated digoxin transport with IC(50) values of 1.1, 0.3, and 1.6 microM, respectively, whereas D-617 and D-620 did not (at concentrations up to 100 microM). We conclude that verapamil phase I metabolites exhibit different P-glycoprotein substrate and inhibition characteristics, with the N-dealkylated metabolites D-617 and D-620 being P-glycoprotein substrates and norverapamil and D-703 being inhibitors of P-glycoprotein function, which may influence P-glycoprotein-dependent drug disposition and elimination.

ATP Binding Cassette Transporter, Subfamily B, Mem↗