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Journal of Clinical Pharmacology, 2004; 44:1412-1417
© 2004 the American College of Clinical Pharmacology

DRUG METABOLISM

Interindividual and Intraindividual Variability of the Urinary 6ß-Hydroxycortisol/Cortisol Ratio in Chinese Subjects: Implications of Its Use for Evaluating CYP3A Activity

Ophelia Q. P. Yin, PhD, Xiaojin Shi, BSc, Brian Tomlinson, MD, FCP and Moses S. S. Chow, PharmD, FCP

From the School of Pharmacy, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, New Territories, Hong Kong (Dr Yin, Dr Chow); Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China (X. Shi); and Department of Medicine and Therapeutics, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, New Territories, Hong Kong (Dr Tomlinson).

Address for reprints: Ophelia Q. P. Yin, PhD, School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The present study determined the interindividual and intrandividual variability of the urinary 6ß-hydroxycortisol/cortisol ratio, a useful marker for CYP3A induction and inhibition in Chinese subjects. The study consisted of 2 parts. In part I, 82 healthy male Chinese subjects underwent 3 study sessions, each separated by a 1-week interval. In part II, 20 subjects who initially completed part I underwent another 3 sessions over a period of 3 to 4 months. During each session, a first-morning urine specimen was collected from each subject for the quantification of urinary concentrations of cortisol and 6ß-hydroxycortisol. There were no significant differences in the mean 6ß-hydroxycortisol/cortisol ratios among the 3 sessions (P > .05, 1-way analysis of variance) for both part I and part II of the study. A normal distribution of the 6ß-hydroxycortisol/cortisol ratio was observed (P = .849, Kolmogorov-Smirnov test). This ratio varied 30-fold (range, 0.76-23.23) among the study subjects. The mean intraindividual variabilities during the short (3-week) and long (3- to 4-month) periods were 30.9% ± 17.5% and 32.2% ± 17.1%, respectively. The genetic fraction contributing to the observed variability in the 6ß-hydroxycortisol/cortisol ratio was estimated to be 0.91. The genetic component is likely to contribute significantly to the variability of the 6ß-hydroxycortisol/cortisol ratio, and such variability should be considered when the ratio is used to evaluate CYP3A induction or inhibition in a given ethnic population.

Key Words: CYP3A • interindividual variability • intraindividual variability

Cytochrome P4503A (CYP3A) is the most abundant CYP enzyme in humans. It is involved in the metabolism of approximately 50% of marketed drugs that undergo phase I metabolism.1 The CYP3A subfamily is composed of 4 forms: CYP3A4, 3A5, 3A7, and 3A43. Among these, CYP3A7 functions primarily as a fetal enzyme, whereas CYP3A43 contributes minimally to CYP3A drug clearance.2,3 CYP3A4 and CYP3A5 are the important isoforms in humans, with CYP3A4 accounting for approximately 30% to 40% of total CYP content in the liver and intestine.4 Compared to CYP3A4, CYP3A5 is normally expressed at a much lower level, although in some individuals, similar levels of CYP3A5 and CYP3A4 can be found.5 Because of the difficulty in distinguishing the contribution of each isoform toward the overall metabolism (CYP3A5 is 85% homologous to CYP3A4), the collective activity of CYP3A4 and CYP3A5 is usually considered as CYP3A activity.

CYP3A activity has been reported to vary more than 20-fold among different individuals within a given population, such as Caucasian,6 Japanese,7 and Chinese8 subjects. On the other hand, the intraindividual variability observed in the Caucasian population has been found to be much less, about 10% to 19% when using midazolam clearance9,10 and 31% to 54% when using the 6ß-hydroxycortisol/cortisol ratio.11,12 The extent of intraindividual variability relative to interindividual variability in the Chinese population, however, is unknown. Because the 6ß-hydroxycortisol/cortisol ratio is a useful biomarker for evaluating CYP3A enzyme induction and inhibition,12-18 we carried out the present study to determine the interindividual and intraindividual variability of this ratio in Chinese subjects.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects
The study protocol was approved by the Clinical Research Ethics Committee of the Chinese University of Hong Kong. Written informed consent was obtained from each subject before participating in the study.

A total of 82 male Hong Kong Chinese subjects aged 19 to 27 years (mean 21.5 ± 1.7 years) and weighing 51.8 to 76.5 kg (mean 64.7 ± 6.4 kg) were recruited. All subjects were nonsmokers and in good health based on medical history, physical examination, electrocardiogram (ECG) evaluation, and routine laboratory tests (blood chemistry, hematology, and urine analysis). The subjects were not taking any regular medications known to induce or inhibit CYP3A and did not take any prescription or nonprescription medication at least 2 weeks before and throughout the study. They were instructed to abstain from alcohol, grapefruit juice, and caffeine-containing beverages for 48 hours before and during the study.

Study Design
The study consisted of 2 parts. In part I, the interindividual variability and "short-term" intraindividual variability of the 6ß-hydroxycortisol/cortisol ratio over a period of 3 weeks were determined. In part II of the study, the "long-term" intraindividual variability over a period of 3 to 4 months was determined.

In part I, all subjects (n = 82) underwent 3 sessions, each separated by a 1-week interval. The first-morning urine specimen was collected on each session, and a 10-mL sample was stored at -80°C until assay.

For part II, 20 subjects who had completed part I underwent another 3 sessions over a period of 3 to 4 months. The urine specimen was collected in a similar manner as in part I.

Determination of Cortisol and 6ß-Hydroxycortisol in Urine
Urine concentrations of cortisol and 6ß-hydroxycortisol were determined by a high-performance liquid chromatography (HPLC) method as previously described,19 with slight modification. Briefly, to a 1.0-mL urine sample, 20 µL of 50 ng/mL internal standard (prednisone) and 1.0 mL of dihydrogen potassium phosphate buffer (pH 9.0) were added. The mixture was loaded onto a Sep-Pak C18 cartridge. After washing with 2.0 mL of dihydrogen potassium phosphate buffer (pH 9.0), 2.0 mL of water, and then 0.1 mL of methanol, the sample was eluted with 3 mL of ethyl acetate. The eluate was subsequently washed by the addition of 0.1 g of sodium sulfate. The organic phase was transferred and evaporated to dryness at 30°C in a water bath under a stream of nitrogen. The residue was reconstituted with 100 µL of methanol/water (50:50, v/v), and 50 µL was injected for HPLC analysis. Separation of the analytes was achieved on a Waters Symmetry C18 column (3.9 x 150 mm, 5 µm), using the mobile phase composed of acetonitrile/tetrahydrofuran/water and eluted with a linear gradient program.

The intraday coefficients of variation (%CV) for cortisol and 6ß-hydroxycortisol were less than 4.3% and 3.5%, respectively. The interday %CV was less than 12.6% for cortisol and less than 11.8% for 6ß-hydroxycortisol. The assay accuracy ranged from 100.1% to 110.0%. The lower limit of quantification was 20 ng/mL for both cortisol and 6ß-hydroxycortisol.

Data Analysis
The mean 6ß-hydroxycortisol/cortisol ratios were compared among different sessions (both part I and part II of the study) using 1-way analysis of variance (ANOVA). A frequency distribution histogram was constructed based on the logarithm of the 6ß-hydroxycortisol/cortisol ratio, and normality of distribution was examined by the Kolmogorov-Smirnov test. Differences in the mean 6ß-hydroxycortisol/cortisol ratio or its intraindividual variability between parts I and II were compared using a Student paired t test. A P value of <.05 was considered statistically significant for all tests. All analyses were performed using the SPSS software (Version 11.5.1, SPSS Inc).


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
There were no significant differences in the mean 6ß-hydroxycortisol/cortisol ratios among the 3 sessions (P > .05, 1-way ANOVA) from part I or part II of the study (Table I). The frequency distribution of the logarithm of the 6ß-hydroxycortisol/cortisol ratio in the 82 subjects is shown in Figure 1. The Kolmogorov-Smirnov test showed that the 6ß-hydroxycortisol/cortisol ratio was normally distributed (P = .849). Of the 82 subjects in part I, the mean 6ß-hydroxycortisol/cortisol ratio was 5.30 ± 4.60 (range, 0.76-23.23), with a 30-fold difference among individuals. The intrasubject CV averaged 31.1% over 3 sessions.


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  		Table I Mean 6ß-Hydroxycortisol/Cortisol Ratio From Different Sessions

 


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  		Figure 1. Frequency distribution histogram of urinary 6ß-hydroxycortisol/cortisol ratio in 82 Chinese subjects (for each subject, the mean value from 3 sessions of the part I study was used).

 

No significant differences (P > .05, paired Student test) in the mean 6ß-hydroxycortisol/cortisol ratio or the intraindividual CV between part I and part II were observed. Of the 20 subjects who completed both parts I and II of the study, the mean "short-term" (over a period of 3 weeks) intrasubject CV was 30.9% ± 17.5%, and the "long-term" (over a period of 3-4 months) intrasubject CV was 32.2% ± 17.1% (Table II).


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  		Table II Intraindividual Variability of the 6ß-Hydroxycortisol/Cortisol Ratio

 


   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
In the present study, we have studied the variability of the urinary 6ß-hydroxycortisol/cortisol ratio, a useful biomarker for evaluating CYP3A enzyme induction and inhibition in human subjects.12-18 This ratio, however, is not a reliable index for the measurement of the actual metabolic activity of CYP3A.20-23 The main reason for this limitation is attributable to the fact that this ratio is influenced not only by the metabolic but also by the renal clearance of cortisol.22 In situations when the renal clearance of cortisol is expected not to change significantly (ie, in CYP3A enzyme induction or inhibition studies, in which each subject serves as his or her own control), this ratio should likely reflect the change in enzyme activity resulting from induction or inhibition.24 Because the use of the urinary 6ß-hydroxycortisol/cortisol ratio is simple and can be easily obtained without the administration of an exogenous substance, this ratio can serve as a useful and practical approach to study CYP3A induction or inhibition and can have advantages over more invasive methods under certain circumstances.

In this study, a wide interindividual variation in the urinary 6ß-hydroxycortisol/cortisol ratio was found, and a normal distribution of this ratio was observed in Chinese subjects. These findings are consistent with previous studies using CYP3A substrates or markers (nifedipine, midazolam, and cortisol).6-8,25,26

Our results on the variability of the 6ß-hydroxycortisol/cortisol ratio show a 30-fold difference among the study subjects. However, the intraindividual variability (31.1%) is significantly smaller than the interindividual variability (P < .05, F test). This suggests that there is a significant genetic variation in the CYP3A activity and/or renal clearance (transport) of cortisol, despite the apparent unimodal distribution of the ratio. Our additional analysis by the genetic component calculation also supports this suggestion. Using the repeated drug administration method proposed by Kalow et al,27 the overall between-subject ({delta}b) and within-subject ({delta}w) variances in the 6ß-hydroxycortisol/cortisol ratio are 24.50 and 2.19, respectively, and the genetic component (rGC), calculated as ({delta}b - {delta}w)/{delta}b, is 0.91 in our study population.

When comparing previous studies14,28,29 in Japanese and Caucasians (with known interindividual and intraindividual variabilities of the 6ß-hydroxycortisol/cortisol ratio), our calculated rGC values for these populations seem to be lower (Table III). This may be attributed to the relatively small sample size (range, 7-11) in the previous studies; consequently, the interindividual variability may be skewed. The wide interindividual variability of the 6ß-hydroxycortisol/cortisol ratio observed in our study is consistent with another study with a large sample size (in which a range of 0.09 to 130.8 was reported in 487 subjects).7


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  		Table III Genetic Component (rGC) for the Urinary 6ß-Hydroxycortisol/Cortisol Ratio in Different Studies

 

Our study was conducted in healthy subjects under "near-basal" conditions without other confounding factors such as disease and comedication. Thus, the estimated rGC value in our study could be a reflection of the genetic contribution to CYP3A activity and/or the renal transport of cortisol. Recently, both CYP3A4 and CYP3A5 have been shown to manifest several polymorphisms. Sata et al30 first reported a rare allele, CYP3A4*3, in a single Chinese subject who had a Met445Thr change in the conserved heme-binding region of P450. Three novel mutations—CYP3A4*4, *5, and *6—were subsequently found to be present in Chinese subjects and associated with lower 6ß-hydroxycortisol/cortisol ratios.31 The CYP3A5 is also polymorphically expressed, with CYP3A5*3 being abundantly present in the Chinese population (allelic frequency of 73%).32 Among the other variants of CYP3A5, CYP3A5*4 and *5 alleles have been found only in Chinese subjects.33 These variations of CYP3A4 and CYP3A5 may explain the high rGC and unimodal distribution of the 6ß-hydroxycortisol/cortisol ratio observed in the present study. However, the contribution of the renal transport of cortisol to genetic variation is unknown at present.

The intersubject and intrasubject variability data and their related genetic component provide insight into the significance of the genetic component contributed by cortisol metabolism and/or renal transport in Chinese subjects. It is unknown whether other ethnic groups show similar variations. Further studies are needed to compare different ethnic groups.

The knowledge of intraindividual variability in the 6ß-hydroxycortisol/cortisol ratio can also provide a basis for power and sample size calculations when this marker is used to evaluate potential drug-drug interactions involving CYP3A. In our study, the mean inter-subject and intrasubject CVs of the 6ß-hydroxycortisol/cortisol ratio were 94% and 31%, respectively, in the Chinese subjects. For Caucasians, the mean intersubject CV was 55% to 76%,14,16-18 and the intrasubject CV was 31% to 54%.9,10 Such data can be helpful in estimating the effect size of drug studies involving a particular population.

A limitation of this study is that only male subjects were recruited. However, the effect of gender on CYP3A activity is not certain and may not be significant. Actually, in a majority of the studies to date, there has been no statistically significant difference in the CYP3A activity (using either the 6ß-hydroxycortisol/cortisol ratio or midazolam clearance as the biomarker) between female and male subjects.9,34,35

In summary, our study demonstrated a wide inter-individual and a lower intraindividual variation in the urinary 6ß-hydroxycortisol/cortisol ratio in healthy Chinese subjects. These data suggest that a genetic component contributes to the variation of CYP3A activity and/or the renal transport of cortisol. These variations should be considered when designing studies involving the urinary 6ß-hydroxycortisol/cortisol ratio for the assessment of CYP3A induction or inhibition in a given ethnic population.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
This study was supported in part by grant ITS/174/00 from the Innovation and Technology Commission of the government of Hong Kong SAR. There were no conflicts of interest directly relevant to the content of this study.


   FOOTNOTES
 
DOI: 10.1177/0091270004269760

Submitted for publication April 21, 2004; Revised version accepted August 2, 2004.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

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