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DRUG METABOLISM AND TRANSPORT |
From the Department of Biopharmaceutical Sciences, School of Pharmacy (Dr Putnam, Dr Benet); Genomics Core Facility, Department of Biochemistry and Biophysics (Mr Woo); and Drug Studies Unit, School of Pharmacy (Dr Huang), University of California, San Francisco.
Address for reprints: Leslie Z. Benet, PhD, Department of Biopharmaceutical Sciences, University of California, San Francisco, 513 Parnassus Avenue, Room U-68, San Francisco, CA 94143-0446.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: MDR1 variant • P-glycoprotein • dicloxacillin • pharmacokinetics
Recently, more than 50 polymorphisms in the MDR1 gene have been identified that could potentially affect the pharmacokinetics and pharmacodynamics of drugs that are P-glycoprotein substrates.12-17 Several investigators have studied the clinical effects of a synonymous C3435T variant in the MDR1 gene, reporting conflicting results. Hoffmeyer et al13 reported that individuals with the TT genotype at position 3435 had more than 2-fold lower duodenal P-glycoprotein expression levels and higher plasma concentrations of the probe P-glycoprotein substrate, digoxin, relative to individuals with the reference CC genotype. Shon et al18 observed a similar trend using fexofenadine as a P-glycoprotein substrate, whereas Drescher et al19 found no effect of the C3435T variant on fexofenadine disposition. In contrast, Kim et al15 and Sakaeda et al20 reported lower plasma concentrations of fexofenadine and digoxin, respectively, in healthy individuals with the TT genotype. One explanation for the discrepancy between these genotype-phenotype relationships may be that haplotypes, combinations of single-nucleotide polymorphisms (SNPs) on the same allele, are responsible for phenotype, not an individual SNP.
Identifying genetic variants that are responsible for differences in drug response may allow clinicians to optimize drug therapy, provided that the genotype-phenotype relationship is stable. For example, after administering a drug to a patient, concentrations of parent drug and metabolite may be measured in urine or plasma, often at a single time point, to determine the patient's phenotype. However, although phenotype generally correlates well with genotype in healthy volunteers, this may not be the case in disease states or under conditions of induction or inhibition. Discordances between genotype-phenotype relationships have been reported for metabolizing enzymes, such as CYP2C19,21 and may also occur for transporters. A previous study showed that patients with HIV-1 express a functionally defective form of P-glycoprotein that appeared to increase as the infection progressed.22 Thus, the effects of disease states or drug interactions on transporter expression or activity may affect the individual's phenotype.
The present study investigated the stability of MDR1 genotype-phenotype relationships after inducing P-glycoprotein by administration of rifampin. The study tested the hypotheses that the C3435T variant in the MDR1 gene governs interindividual differences in the pharmacokinetics of a P-glycoprotein substrate, dicloxacillin, and that P-glycoprotein induction compensates for differences in pharmacokinetics due to the variant. Dicloxacillin was used as a model compound because it is a P-glycoprotein substrate23 that is only partially metabolized.24,25 The results from this study would suggest whether genotyping individuals for the C3435T variant is a useful tool for predicting drug pharmacokinetics, particularly under conditions that induce the protein. Furthermore, the study might improve our understanding of the circumstances in which genotypic differences in transporters or enzymes may affect drug disposition and dosing requirements.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Study Design
The study was approved by the Committee on Human Research and the General Clinical Research Center at the University of California, San Francisco. All subjects gave their written informed consent before enrolling and abstained from alcohol and nonstudy drugs during the study. Two individuals (subjects 12 and 13), who were homozygous for the C3435T variant, withdrew from the study due to adverse effects, which included skin rash, fever, headache, and diarrhea, possibly from rifampin dosing. The data obtained from subject 12 prior to rifampin treatment were included in the pharmacokinetic analysis; however, the data from subject 13 were excluded because this subject tested positive for barbiturates.
A repeated-measures study was conducted in 2 periods: period 1 (study day 1) investigated the effect of the C3435T variant on the pharmacokinetics of dicloxacillin, whereas period 2 (study days 2-12) investigated the additional effects of rifampin dosing on dicloxacillin pharmacokinetics. The 2 hospital visits on study days 1 and 12 were conducted at the General Clinical Research Center, University of California, San Francisco (UCSF). On these days, subjects were given 3 low-fat, low-caffeine meals, with breakfast served 3 hours after drug dosing. Study drugs were obtained from the Department of Pharmaceutical Services at the UCSF Medical Center.
On the first day of the study, subjects received two 500-mg dicloxacillin sodium capsules following an overnight fast of at least 8 hours. Venous blood samples (7 mL) were drawn before dicloxacillin dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, and 6 hours after dosing. To minimize drug degradation, the blood samples were centrifuged immediately, and the plasma was separated and frozen at -80°C. Subjects also provided a baseline urine sample and collected urine in 3-hour intervals for 12 hours after dosing. To increase urine output, subjects drank an 8-ounce glass of water along with the dicloxacillin dose and every 3 hours afterwards. The urine volume from each collection was measured, and a 5-mL aliquot was frozen at -80°C until analysis. The first period of the study ended after the last urine collection.
In the second period of the study, subjects took a dose (600 mg) of rifampin at home each morning for 10 days. Subjects were required to fast for at least 8 hours before taking the rifampin dose and then to wait 3 hours before eating breakfast. Rifampin compliance was monitored by requiring subjects to contact the study investigator following each rifampin dose. On the 12th day of the study, subjects returned to the General Clinical Research Center for another 1-g dose of dicloxacillin, followed by a dose of rifampin (600 mg) 1 hour later. Venous blood samples (7 mL) were drawn before dicloxacillin dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, and 9 hours after dosing.
The 9-hour sample was taken in period 2 only because we expected that induction of P-glycoprotein might increase the time required for drug absorption, and we wanted to ensure that a sufficient number of blood samples would be collected in the terminal phase to calculate the elimination half-life. We subsequently chose not to use the 9-hour data, however, because we were able to obtain accurate values using the 0- to 6-hour data, and we wanted to analyze both study periods over the same time interval.
As in the first visit, urine was collected prior to dosing and for 12 hours after dosing in 3-hour intervals. At the end of day 12, each subject was given an exit evaluation that included a physical examination and blood and urine tests.
Identification of MDR1 Polymorphisms Using SNaPshot Assay and Sequencing
DNA was extracted from blood samples by standard methods with a Puregene DNA Purification kit (Gentra Systems, Minneapolis, Minn) and stored in aliquots (5 µg/30 µL) at 4°C. The regions of interest in the MDR1 gene were amplified by polymerase chain reaction. The primer sequences for this reaction are described at http://www.pharmacogenetics.ucsf.edu:8001 and http://pharmgkb.org. Approximately 50 ng of DNA was amplified with AmpliTaq Gold Master Mix (Applied Biosystems, Foster City, Calif) and 10 pmole of each primer.
The SNPs of interest were genotyped by a single base extension method (Applied Biosystems SnaPshot) using primers designed for each SNP of interest. Table I shows the primer sequences for the SNPs that were detected in the study subjects. The primers (2-4 pmol/µL) were pooled together to form an SNP primer mixture, which was amplified at the specified conditions after mixing with the pooled template and SNaPshot Multiplex Ready Reaction Mix. The final reaction products were analyzed with an automated ABIPrism 3700 DNA Analyzer (Applied Biosystems) using Genotyper (Applied Biosystems).
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To determine if 3 additional SNPs (intron 9(-44) A>G; intron 13 (+24)C>T, and intron 14 (+38)A>G) in the MDR1 gene were present, the regions of interest were amplified using polymerase chain reaction and sequenced by a chain termination and fluorescence detection method. The sequencing products were analyzed with an automated ABIPrism 3700 DNA Analyzer (Applied Biosystems), and the SNP alleles were identified with Sequencher (Gene Codes, Ann Arbor, Mich).
Liquid Chromatography/Tandem Mass Spectrometry Analysis of Dicloxacillin and Its Metabolites in Plasma and Urine
Concentrations of dicloxacillin and its metabolites in plasma and urine were quantified using a liquid chromatography/tandem mass spectrometry (LC/MS/MS) system, consisting of a 717plus autosampler (Waters, Milford, Mass), an LC-10AD pump (Shimadzu, Kyoto, Japan), and a Quattro LC (Micromass, Manchester, UK) detector. Plasma samples were prepared for injection by adding cloxacillin as an internal standard, adding acetonitrile to precipitate the protein, mixing well, centrifuging for 10 minutes at 1380g in a model 228 centrifuge (Fisher Scientific Co, Hampton, NH), and transferring the supernatant into an autosampler vial. Urine samples were prepared by adding internal standard and diluting with water.
The samples were injected at a flow rate of 0.8 mL/min onto a 50 x 4.6-mm analytical column (Keystone Scientific Inc, Bellafonte, Pa) packed with Hypersil BDS C18 material of 5 µ particle size. The mobile phase consisted of a mixture of acetonitrile, water, and formic acid in the ratio of 45:55:0.1 (v/v). After passing through the analytical column, 25% of the flow was directed into a mass system.
Sample detection used the following transitions in electrospray ionization positive ion mode: dicloxacillin, m/z 470-311; cloxacillin (internal standard), m/z 436-277; 5-hydroxymethyl metabolite of dicloxacillin, m/z 486-327; and penicilloic acid, m/z 488-444. The sample cone voltage and the collision energy for dicloxacillin and the internal standard were fixed at 22 V and 11 eV, respectively. Calculations were performed with MassLynx 3.5 software (Micromass, Manchester, UK).
Because standards were not available for the 5-hydroxymethyl and penicilloic acid metabolites, their concentrations were estimated by comparing the metabolite/dicloxacillin peak area ratio of a reference sample measured with UV detection to that measured with LC/MS/MS. A response factor was calculated for each metabolite, which was defined as the metabolite/dicloxacillin peak area ratio measured with UV detection divided by the corresponding ratio obtained with LC/MS/MS. Metabolite concentrations were determined using the dicloxacillin calibration curve by correcting the MS metabolite/dicloxacillin peak area ratios by the appropriate response factor.
The methods were validated from 0.5 to 50 µg/mL for plasma and 5 to 300 µg/mL for urine. The intraday (n = 6) and interday (n = 12) coefficient of variations were less than 10.8%; the accuracy was 90.3% to 110.1%. Stability was demonstrated for freeze/thaw, bench-top, and processed samples for up to 12 days. Variation and accuracy in sample reinjection were acceptable. Six sources of human plasma and urine were tested, and no matrix effect for the parent drug was observed.
Pharmacokinetic Analysis
The maximum plasma concentration (Cmax) and the time at which it occurred (tmax) were observed. Pharmacokinetic parameters were estimated from plasma concentration data via noncompartmental analysis using WinNonlin Professional software, version 2.1 (Pharsight Corp, Mountain View, Calif). The elimination half-life (t1/2
z) was calculated from the terminal log-linear data points irrespective of multiple peaks in the profiles. Mean residence time (MRT) was estimated as the inverse of the terminal elimination rate constant, which assumes that the disposition of dicloxacillin is reasonably approximated by a 1-compartment body model. The area under the plasma concentration-time curve (AUC) was estimated using the linear trapezoidal method up to the last measured concentration. The mean absorption time (MAT) was calculated as the difference between AUMC/AUC and MRT, where AUMC was defined as the area under the moment versus time curve. AUC and AUMC values were extrapolated to infinite time from the last measured concentration. Oral clearance (CL/F) was calculated as Dose/AUC. Varea/F was calculated as the product of CL/F and t1/2z divided by the natural logarithm of 2.
Urine and plasma data were used to calculate renal and formation clearances. The renal clearance (CLR,0-6) of dicloxacillin was calculated by dividing the amount of drug eliminated in the urine unchanged (Aeu) in 6 hours by the AUC from 0 to 6 hours. Renal clearance of the 5-hydroxymethyl metabolite of dicloxacillin was calculated by dividing the amount of the 5-hydroxymethyl metabolite excreted in the urine in 6 hours by the AUC of the metabolite from 0 to 6 hours. Clearance of formation (CLf) of the 5-hydroxymethyl metabolite was calculated by dividing the amount of the metabolite excreted in the urine in 6 hours by the AUC of the parent drug, dicloxacillin, from 0 to 6 hours. This calculation assumes that all of the 5-hydroxymethyl metabolite is renally excreted, which is reasonable given that the metabolite is hydrophilic. However, the calculated CLf may underestimate the actual value if the metabolite is susceptible to further biodegradation.24
Statistical Analysis
Whether the C3435T variant significantly affected the plasma or urine data was determined by running analysis of variance tests on the mean pharmacokinetic parameters across genotypes in either period 1 or period 2. If no statistically significant differences between genotypes were observed, the mean for the entire study population for that period was calculated from the pharmacokinetic parameters obtained from each subject. Paired t tests were used to analyze for differences across periods 1 and 2.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Haplotypes were assigned to the study subjects according to statistically inferred haplotypes as described by Kroetz et al.17 The MDR1*1 haplotype is the reference haplotype found at a frequency of 15% in Caucasians and African Americans.17 A second major haplotype, MDR1*13, differs from the reference sequence at 6 positions: 1236C>T, 2677G>T (Ala893Ser), 3435C>T, intron 9 (-44)A>G, intron 13(+24)C>T, and intron 14(+38)A>G. The haplotype frequency of MDR1*13 is 32% in Caucasians and 5% in African Americans.17
Figure 1 shows the MDR1 haplotypes for each subject. Because we did not genotype for all of the known MDR1 variants, it was not possible to assign the haplotypes with absolute certainty. At least 9 distinct haplotypes were found in this study population. For 7 subjects, more than 1 haplotype pair could be assigned to the genotyping data. However, in each case, 1 of the possible haplotypes was MDR1*1 or MDR1*13, which was assigned based on the high probability that these subjects carried these common haplotypes. One subject (subject 19) could not be assigned haplotypes from genotyping data alone.
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With 1 exception (subject 19), all of the subjects who were homozygous for the 3435C>T variant also were homozygous for the other 5 SNPs found in MDR1*13. Likewise, for subjects with the CC genotype at position 3435, all except subjects 1 and 4 had the reference genotype at the other variant sites in MDR1*13. These results are consistent with the linkage reported between the 6 variant sites in the MDR1*13 haplotype.17 Three of the subjects in the 3435TT group also had a MDR1 variant leading to an Asn21Asp change in P-glycoprotein.
Effect of Induction Conditions and C3435T Variant on the Pharmacokinetics of Dicloxacillin
Figure 2 shows the concentration profiles of dicloxacillin before and after rifampin dosing for subjects with the CC, CT, and TT genotypes at position 3435 in exon 26 of the MDR1 gene. Many of the subjects exhibited a second or third peak in their plasma concentration profiles, particularly after rifampin treatment.
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The mean pharmacokinetic parameters for each of the 3 genotypes before and after rifampin dosing are shown in Table III. Because the C3435T variant did not significantly affect any of the pharmacokinetic parameters, it was reasonable to combine the data from all of the subjects to calculate mean values for each period. Rifampin dosing significantly reduced the mean Cmax and AUC by 27% (P < .05) and 23% (P < .001), respectively, and increased CL/F by 26% (P < .001) and Varea/F by 17%. Rifampin dosing also significantly reduced the amount of drug excreted unchanged in urine by 19% (P < .05).
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Effect of Induction Conditions and C3435T Variant on the Pharmacokinetics of Dicloxacillin Metabolites
In addition to dicloxacillin, concentrations of 2 of its metabolites were quantitated in plasma and urine: the active 5-hydroxymethyl metabolite of dicloxacillin (Figure 3) and a hydrolysis product, penicilloic acid. In both study periods, the metabolite concentrations were lower than the parent drug; however, the ratio of the 5-hydroxymethyl metabolite to the parent drug increased 3-fold after rifampin dosing. The maximum concentrations of penicilloic acid decreased from 2.7 to 1.5 µg/mL between periods 1 and 2, suggesting that the formation of this metabolite had not increased. Concentration profiles for penicilloic acid are not shown because the levels of this metabolite were very low and may have included penicilloic acid formed from the parent drug during sample processing.
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Because we did not have a reference standard for the 5-hydroxymethyl metabolite, the mean pharmacokinetic parameters for the metabolite were calculated using data from all of the subjects irrespective of genotype (Table IV). The renal clearance of the 5-hydroxymethyl metabolite in period 1 was almost 11-fold greater than its formation clearance, indicating that the metabolite kinetics is formation-rate limited (ie, the metabolite is eliminated as rapidly as it is formed). In addition to Cmax, rifampin dosing significantly affected the formation clearance of the 5-hydroxymethyl metabolite, the AUC, and the amount of the metabolite that was excreted in the urine. Like the parent drug, the renal clearance of the 5-hydroxymethyl metabolite was not affected by rifampin dosing, suggesting that P-glycoprotein in the kidney had not been induced or did not contribute to renal elimination of the metabolite.
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The combined amount of unchanged drug and 5-hydroxymethyl metabolite excreted in the urine was 481 ± 106 mg prior to and 480 ± 79 mg after rifampin dosing, suggesting that the extent of absorption of dicloxacillin was unaffected by rifampin treatment. In period 1, 38.2% ± 9.5% of the dose was excreted as dicloxacillin unchanged, whereas 9.6% ± 2.6% was excreted as the 5-hydroxymethyl metabolite. Following rifampin treatment in period 2, we observed a decrease in the percentage of unchanged drug to 30.8% ± 6.1%, with a corresponding increase in the percentage of 5-hydroxymethyl metabolite to 16.6% ± 4.6%.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Modulators of the efflux transporter, P-glycoprotein, may influence the stability of MDR1 genotype-phenotype relationships. Hoffmeyer et al13 previously correlated the C3435T variant in the MDR1 gene to lower duodenal expression of P-glycoprotein and higher steady-state digoxin plasma concentrations. Consistent with these results, Kurata et al26 reported an increase in digoxin bioavailability and reduced digoxin renal clearance in subjects with the C3435T variant. When digoxin was coadministered with clarithromycin, however, digoxin bioavailability was similar between subjects with the CC and TT genotypes, although the effect of the variant on renal clearance was still observed.
The present study investigated the hypothesis that induction of P-glycoprotein would reduce the effects of the MDR1 C3435T variant on the pharmacokinetics of the P-glycoprotein substrate, dicloxacillin. Hoffmeyer et al13 reported a correlation between digoxin AUC and genotype in the induced state, with the lowest mean AUC observed in individuals with the CC genotype. However, as Dresser27 previously noted, the Hoffmeyer et al study13 did not thoroughly address the effect of genotype under induction conditions. Although 8 subjects received rifampin treatment, only 1 of these individuals had the TT variant at position 3435. Furthermore, the authors did not determine the effect of genotype on the extent of P-glycoprotein induction, which in turn could affect the stability of genotype-phenotype relationships.
In the present study, rifampin significantly changed the pharmacokinetics of dicloxacillin, as reflected in several parameters. The higher mean MAT following rifampin treatment suggests that rifampin decreased the absorption rate of dicloxacillin. The mean Cmax and AUC significantly decreased in parallel (27% and 23%, respectively) following rifampin dosing, whereas the CL/F and Varea/F both appeared to increase in parallel (26% and 17%, respectively). Considering intrasubject variability, these results likely suggest a decrease in F, rather than an increase in CL. The fact that half-life did not decrease significantly following rifampin treatment further supports our belief that CL did not increase. The increases in CLf and AUC of the 5-hydroxymethyl metabolite following rifampin treatment suggest that dicloxacillin metabolism increased in the liver or the intestine. Rifampin may have induced monooxygenases in the liver, which likely catalyze hydroxylation of the 5-methyl group of isoxazolylpenicillins.28
Our results suggest that the MDR1 C3435T variant had no effect on the pharmacokinetics of dicloxacillin. Although we had initially expected subjects with this variant to have higher plasma concentrations, recent studies have produced conflicting results. In studies of digoxin,13,26,29-31 fexofenadine,15,18,19 cyclosporine,32-34 and tacrolimus,35,36 some investigators reported increased absorption13,18,26,29,30,33,35 and others reported reduced absorption15,34 in the presence of the C3435T variant. Our results are consistent with studies by Drescher et al,19 Gerloff et al,31 von Ahsen et al,32 Goto et al,36 and Pauli-Magnus et al,37 which observed no effect of the MDR1 C3435T variant on drug concentration levels.
The absence of a genotype effect in our study may be explained by confounding factors. In particular, organic anion and peptide transporters may have contributed to dicloxacillin transport, mitigating the effect of the C3435T variant. In vitro studies22 suggested that dicloxacillin transport was not inhibited by para-aminohippurate, a typical substrate of organic anion transporters. However, dicloxacillin inhibits uptake by Npt1, an organic anion transporter in the liver,38 and penicillins are reported substrates of intestinal and renal peptide transporters.39
The difference in haplotypes between our study subjects was another confounding factor in our study. We screened the subjects for a single SNP, the C3435T variant, but a post hoc analysis showed that the subjects actually represented 9 different haplotypes. As expected, all but 1 of the subjects in the 3435TT group were also homozygous for the other 5 SNPs in MDR1*13, consistent with the linkage reported between these 6 variants.17 However, even when we compared the data from subjects with similar haplotypes, we did not see any consistent trends or any obvious effects of individual SNPs on the pharmacokinetics of dicloxacillin.
In conclusion, we have demonstrated that rifampin treatment significantly increased the oral clearance and the mean absorption time of the P-glycoprotein substrate, dicloxacillin, and reduced its Cmax. Rifampin also increased the formation clearance and the AUC for the 5-hydroxymethyl metabolite of dicloxacillin. These results suggest that rifampin induced intestinal P-glycoprotein as well as dicloxacillin metabolism. We did not observe a correlation between the MDR1 C3435T variant and the pharmacokinetics of dicloxacillin. Thus, future studies are needed to address the stability of MDR1 genotype-phenotype relationships.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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