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Journal of Clinical Pharmacology, 2004; 44:1398-1404
© 2004 the American College of Clinical Pharmacology

METHODS

Assessment of In Vivo CYP2D6 Activity: Differential Sensitivity of Commonly Used Probes to Urine pH

Mahmut Özdemir, Kim H. Crewe, Geoffrey T. Tucker and Amin Rostami-Hodjegan

From the Department of Pharmacology, Faculty of Medicine, Osmangazi University, Eskisehir, Turkey (M. Özdemir) and Molecular Pharmacology and Pharmacogenetics, University of Sheffield, United Kingdom (K. H. Crewe, G. T. Tucker, A. Rostami-Hodjegan).

Address for reprints: Dr Amin Rostami-Hodjegan, Department of Molecular Pharmacology and Pharmacogenetics, University of Sheffield, L Floor, Medicine & Pharmacology, The Royal Hallamshire Hospital, Sheffield S10 2JF UK.


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Drug/metabolite ratios (MRs) are used as in vivo markers of enzyme activity. The ratios are potentially confounded by the renal clearance of the drug (urine-based MRs) or metabolite (plasma-based MRs). The authors have investigated the relative sensitivity of urinary MR of 3 in vivo probe substrates of CYP2D6 debrisoquine (DB), dextromethorphan (DM), and metoprolol (MP) to changes in urine pH. Three groups of healthy volunteers each comprising 12 individuals were given DB (10 mg), DM (25 mg), or MP (100 mg) on 3 occasions. In 1 study arm, urine was acidified by the oral intake of ammonium chloride; in another, it was alkalinized by intake of sodium bicarbonate; and in the third, urine pH was uncontrolled. Urinary MP/{alpha}-hydroxy-MP, DM/dextrorphan, and DB/4-hydroxy-DB ratios were calculated. The meangeo MR for DB was not significantly different in any of the study arms, whereas those for MP and DM were significantly different under acidified and alkalinized urine conditions compared to uncontrolled urine pH (P < .01) and were correlated with urine pH (P < .001). Without control of urine pH, in vivo estimates of CYP2D6 metabolic activity are likely to be less precise using DM or MP as probe substrates compared to DB. Although this is unlikely to cause any problem in distinguishing the large functional differences in CYP2D6 in poor metabolizer (PM) and extensive metabolizer (EM) phenotypes, this may contribute to difficulties in differentiating in vivo metabolic activity among allelic variants within the overall CYP2D6 EM phenotype using MP or DM. However, because DB is not available in many countries (eg, United States), alternative in vivo markers of CYP2D6 with low sensitivity to urine pH should be sought.

Key Words: CYP2D6 • phenotyping • phenotype-genotype correlation • debrisoquine • dextromethorphan • metoprolol • urine pH • metabolic ratio

In vivo drug-metabolizing enzyme activity is defined by unbound partial metabolic clearances of CYP isoform-specific substrates.1,2 However, in practice, indirect measures (eg, elimination rate, MR in plasma or urine) following the administration of specific CYP probe compounds are used in population studies.2 A prerequisite of the use of these indirect measures of enzyme activity is an understanding of their pharmacokinetic basis and specificity.1,2 In particular, drug/metabolite ratios (MRs) are confounded by the effect of renal function on the excretion of the drug (urine-based MRs) or metabolite (plasma-based MRs).1-3

Debrisoquine (DB), metoprolol (MP), and dextromethorphan (DM) are commonly used probe substrates for the assessment of in vivo CYP2D6 activity.4 However, they have different ionization characteristics, with their pKa values being 11.9, 9.7, and 8.3, respectively.5 Urine pH ranges from 4.5 to 8.5 (average 6.2).6-8 This can have profound effects on the passive renal tubular reabsorption of lipid-soluble basic drugs with pKa values between 6 and 12.9 Accordingly, such drugs should show significant urine pH-dependent renal clearance, which, in turn, will add variability to the estimation of enzyme activity using MRs.

Labbe et al10 noted that variation in urine pH could explain between 20% and 80% of the intraindividual variability in MR for DM and MP, and they called for a prospective study to evaluate this further. Thus, the aims of the current study were (1) to assess the relative sensitivity of MR values for 3 common CYP2D6 probe substrates to changes in urine pH and (2) to investigate whether a correction method can be applied to eliminate or reduce the impact of variable urine pH when using such ratios to assign in vivo enzyme activity in an individual.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects
Thirty-six healthy subjects (27 male, 9 female, aged 18-50 years) were included in the study. The protocol was approved by the ethics committee of the Medical Faculty of Osmangazi University (Eskisehir, Turkey). All subjects gave written informed consent. The results of clinical laboratory tests, including liver and renal function tests, were within normal limits. All subjects were nonsmokers and were not taking any medication. Intake of alcohol and xanthine-containing beverages was not allowed during the study period.

Drugs
Subjects were given oral doses of either DM hydrobromide (25 mg) (Robitussin Dry Cough Medicine, Whitehall Laboratories, England), DB hemisuccinate (10 mg) (Cambridge Laboratories, England), or MP tartrate (100 mg) (Lopressor tablets, Novartis Laboratories, Turkey). Urine pH was perturbed by oral administration of enteric-coated ammonium chloride tablets (Chlorammonic 500 mg, Chiesi S.A., France) and sodium bicarbonate (3 g in 60 mL water, food grade, Merck, Germany), as described in the Study Design.

Study Design
The study was open, randomized, and crossover. The 36 subjects were divided into 3 groups of 12, each of which was given 1 of the probe drugs (DB, DM, or MP) on 3 occasions: (1) when the urine was acidified by taking ammonium chloride, (2) when the urine was alkalinized by taking sodium bicarbonate, and (3) when urine pH was uncontrolled. Each of these study arms was separated by a 10-day interval: a summary of the protocols for arms 1 and 2 is shown in Figure 1. The protocols for alkalization and acidification of urine were adapted from those described by Beckett and Tucker.11 Urine was collected in 2 samples from 0900 to 1700 hours, and the pH of cumulated urine was measured immediately after final sampling using a Jenway 3071 pH-meter (Jenway, Dunmow, England). A 10-mL aliquot was stored at -20°C. The frozen samples were subsequently transported by air to the Unit of Molecular Pharmacology and Pharmacogenetics at the University of Sheffield for analysis.



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  		Figure 1. Dosing and sampling schemes: (a) "acidified urine" study arm and (b) "alkalinized urine" study arm.

 

Drug and Metabolite Assays
Metroprolol and {alpha}-hydroxy-MP were measured by high-performance liquid chromatography (HPLC) with fluorescence detection.12 The limits of detection were 50 ng/mL for MP and 10 ng/mL for {alpha}-hydroxy-MP. Intra-assay coefficients of variation were less than 5%. DB and 4-hydroxy-DB were measured by gas liquid chromatography (GLC) with nitrogen-selective detection.13 Intra-assay coefficients of variation were 2% and 4%, respectively, at 1 µg/mL. Detection limits were 20 ng/mL for DB and 50 ng/mL for 4-hydroxy-DB. The HPLC method of Chen et al14 was used to assay DM and dextrorphan after hydrolysis with ß-glucuronidase. Intra-assay coefficients of variation were between 6% and 13% at 2.5 ng/mL, with a detection limit of 0.2 ng/mL.

Statistical Analysis
Differences between log-transformed MR values (8-hour collection) in the study arms were assessed using the paired t test, and the Spearman rank test was used to assess correlations between MR values and urine pH. Once the correlations were established, different linear and nonlinear models were fitted to data to describe the trend (Solver, Microsoft Excel).


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Mean MR and urine pH values for each study arm are shown in Table I. The protocols for alkalization and acidification of urine resulted in significant increases and decreases, respectively, in measured urine pH when compared to uncontrolled study arms (P < .001). Of 108 measured samples, 23 had pH values outside the extremes reported in the literature (ie, <4.5 and >8.5).6-8 Because there was a storage delay between collection of the first and last urine samples, values are likely to be artifactually high.15 We did not include samples with pH values outside the literature range when correlating MR and urine pH.


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  		Table I Mean Values of Metabolic Ratios (MRs) and Urine pH and Confidence Intervals (CIs) for the Differences Between Study Arms

 

The MR for DB was not significantly different in any of the study arms, whereas the corresponding values for MP and DM were significantly different for acid and alkaline urine conditions compared to uncontrolled urine pH. Figure 2 shows individual fold changes in log MR values for each drug relative to uncontrolled urine pH conditions. Correlations were observed between inverse MR values for DM and MP and urine pH (Spearman rank correlation: r = 0.81, P < .05 and r = 0.6, P < .05, respectively) but not for DB. Exponential trend lines were fitted to plots of 1/MR against pH for DM and MP (Figure 3). Because average urine pH is reported to be 6.2,6-8 the values of all MRs were estimated at pH 6.2 (as the reference point) by correcting the observed value according to the following equation:



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  		Figure 2. Effect of extreme urine pH on fold changes in log metabolic ratios: (a) dextromethorphan (DM)/dextrorphan, (b) metoprolol (MP)/{alpha}-OH MP, and (c) debrisoquine (DB)/4-OH DB.

 


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  		Figure 3. Relationships between inverse metabolic ratio (MR) values of (a) dextromethorphan and (b) metoprolol and urine pH. Study arms: alkalinized (open circles), acidified (open diamonds), and uncontrolled urine pH (solid squares).

 

where MR(individual) refers to the value in an individual subject, and MR(population) refers to the value obtained from the trend line fitted to all the data (Figure 3). Assuming an exponential relationship between MR and pH, the above equation could be simplified as follows:


where B was 0.96 and 0.60 for DM and MP, respectively. Similar calculations could be carried out to obtain the MR at any given values of pH (eg, average values of 6.5 or 6.7 observed in this study, Table I) and to reduce the MR variation caused by variable pH in different individuals.

After application of the correction, there were no significant differences in MR values between any of the study arms (Table II).


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  		Table II Comparisons of Metabolic Ratio (MR) Values Corrected to pH 6.2

 


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
Our findings support and extend those of Labbe et al16 in illustrating the importance of variable urine pH in obscuring the ability to estimate in vivo enzyme activity accurately using MRs of lipid-soluble, partially ionized substrate probes. On this basis, DB would be the probe of choice rather than DM or MP because its relatively high pKa value and polarity preclude urine pH-sensitive renal clearance.17 Unfortunately, DB is not available for human use in many countries. A greater sensitivity to pH observed with DM compared to MP is consistent with their relative pKa values.

Application of the correction for urine pH requires further validation. Collection of urine under oil is used in clinical practice for studies involving urine pH evaluation to prevent changes in pH during storage.15 Although this was not the case in this study, it should be noted that some researchers have found no appreciable difference in measured pH between samples under paraffin or in capped plastic containers over 24 hours.18 Thus, considering the short storage of the first urine sample (ie, 3-5 hours) and immediate measurement of pH after the second sample, it can be argued that the overall pH was not affected significantly. Moreover, if any change had occurred, it could be considered as a "shift" in all samples and could not affect the slope values for pH correction.

Failure to take account of variability in urine pH may explain some of the discrepancies observed when using MRs to compare enzyme activity across racial groups. For example, although strong correlations have been observed between enzyme activity assessed using different CYP2D6 probes in Caucasians10,19-25 and Orientals,24,26 consistency between the probes has been less in black Africans22,24,25,27-31 and Arabs.32,33 This may be explained partly by genetic variants of CYP2D6 that influence the relative docking of substrates at the active enzyme site25 and that occur at different frequencies in different racial groups.24,34-39 However, racial differences in renal excretion40 and dietary differences41 may also contribute, to the extent that they may influence urine pH variations and hence MR values.

The use of MRs based on pH-sensitive probes may also obscure the ability to correlate genotype with enzyme activity. Although this is unlikely to be a problem in distinguishing the large functional differences in CYP2D6 in poor metabolizer (PM) and extensive metabolizer (EM) phenotypes, as evident from a number of reports, it could contribute to difficulty in relating genotypes for the large number of allelic variants within the EM distribution to in vivo enzyme function25,35,36,42-44 (see Figure 4). In this regard, it is relevant that the data of Sachse et al42 (Figure 4) and others25,37,44,45 indicate less variability of the DB MR for each allelic variant compared to the variability of the DM MR (100-fold variation in MR for intermediate metabolizer [IM]/EM genotype using DB vs >400-fold variation using DM). Establishing a clear relationship between different genotypes and enzyme activity of CYP2D6 may help with dose individualization if there is robust evidence that pharmacological or toxic effects are related to variation in enzyme activity. Currently, there is sparse clinical evidence to support the benefit of genotyping for dosage adjustment of CYP2D6 substrates.46,47 Also, current CYP2D6 genotyping information only helps to discriminate discrete groups of PMs, IMs, EMs, and ultra-rapid metabolizers (UMs).48,49 Some of the variation in the in vivo enzyme activity within these groups is related to biological factors unrelated to CYP2D6, such as liver size,50-53 hepatocellularity and microsomal protein content,54,55 the effects of underlying diseases,3,56 and the modulating effects of endobiotics and xenobiotics that affect enzyme activity.45,57-60 Also, part of this apparent variability could be related to measurement errors and the confounding effects of variables such as urine pH on MR. If the latter can be obviated by the use of less sensitive probe substrates or corrected for, the task of relating genotype to enzyme activity may be facilitated.



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  		Figure 4. The relationship between different allelic variants of CYP2D6 gene and apparent CYP2D6 enzyme activity, as measured by metabolic ratios (MRs) of (a) dextromethorphan and (b) debrisoquine. MR values are shown such that the antimode between extensive metabolizers and poor metabolizers is aligned for each probe, and the scales are normalized on the basis of fold variation from the antimode. Adapted from Sachse et al42 with permission of the publisher.

 


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
We greatly appreciate the efforts of Ms Claire Martin in the preparation of the manuscript.


   FOOTNOTES
 
DOI: 10.1177/0091270004269582

Submitted for publication May 26, 2004; Revised version accepted July 27, 2004.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

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