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PHARMACOGENOMICS |
From the Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland and Clinical Pharmacology, TYKSLAB, Health Care District of Southwest Finland (Dr Hilli, Dr Laine); SFINX Drug Interaction Unit, Turku University Hospital, Turku, Finland (Dr Korhonen); Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland and Novamass Analytical Ltd, Oulu, Finland (Dr Turpeinen); and Department of Chemistry, University of Oulu, Oulu, Finland (Mr Hokkanen, Dr Mattila).
Address for reprints: Johanna Hilli, MD, PhD, Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Itäinen Pitkäkatu 4B, 3rd Floor, FIN-20520 Turku, Finland; e-mail: johanna.hilli{at}utu.fi.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: YP1A2 polymorphism • SNP g.-163C>A • melatonin • oral contraceptives • ethinylestradiol
Caffeine clearance has been considered the "gold standard" for assessing CYP1A2 activity.6,7 However, melatonin, which is a quite selective substrate for CYP1A2, can be used as an alternative probe for CYP1A2 enzyme activity.8,9 Exogenous melatonin has been used for the treatment of jet lag, sleep disorders, and in combination therapies of certain types of cancers. In healthy subjects, daytime doses of 0.1 to 10 mg melatonin have produced significant drowsiness, fatigue, and performance decrements, which have been maximal approximately 2 hours after ingestion.10
Caffeine has been shown to increase the oral bioavailability of melatonin, probably due to inhibition of CYP1A2-catalyzed first-pass metabolism of melatonin. In addition, this effect was found to be more pronounced in nonsmoking subjects and in subjects with the CYP1A2*1F*1F genotype.9 Female sex steroids, such as ethinylestradiol, gestodene, and desogestrel, have been shown to have distinctive inhibitory properties on different CYP enzymes in vitro.11-15 In humans, concomitant use of oral contraceptives (OCs) has been found to inhibit the metabolism of several substrates of CYP1A2, CYP2C19, and CYP3A4.16 In fact, impairment of the mainly CYP1A2- and CYP3A4-mediated antipyrine metabolism17,18 by oral contraceptives has been known for more than 30 years, long before the CYP1A2 enzyme itself was discovered.19-21 A study comparing the effect of an ethinylestradiol-containing OC and progestin-only preparation on antipyrine elimination suggested the inhibitory effect to be associated with the estrogen component.22 A triphasic oral contraceptive containing norgestimate and ethinylestradiol has been found to decrease significantly the activity of CYP1A2 and CYP2C19 in vivo.23 Women using ethinylestradiol- and gestodene-containing oral contraceptives have been shown to have a 2.8 times higher caffeine/paraxanthine ratio than the control subjects with no OC use.16 In addition, OC use has been shown to increase plasma concentrations and effects of a skeletal muscle-relaxant tizanidine by inhibiting the CYP1A2 enzyme.16
There are no studies investigating the inhibitory effect of OCs on the metabolism of melatonin in subjects with a different genetic profile of CYP1A2. This study was aimed to investigate the effect of OC use and the CYP1A2 g.-163C>A polymorphism on the pharmacokinetics of melatonin, a probe drug for the CYP1A2 activity.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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This study was an open, single-dose, parallel-group study with 4 study groups, 2 of which included subjects with the variant and 2 with the wild-type genotype. Half of the representatives of both the variant and the wild-type genotype were using an ethinylestradiol-containing OC, whereas the rest had no hormonal contraception. Each of the study groups included at least 7 subjects to obtain at least a 50% difference in the melatonin AUC between OC users and nonusers in the power analysis.
The first study group included OC users with the wild-type genotype (n = 7). Of these 7 women, 3 had an OC preparation containing ethinylestradiol and gestodene (20 µg + 75 µg Meliane and 30 µg + 75 µg Femoden, both Bayer Schering Pharma, Berlin, Germany), 2 had an OC containing 35 µg ethinylestradiol and 2 mg cyproterone acetate (Diane Nova, Bayer Schering Pharma), 1 had an OC with 20 µg ethinylestradiol and 150 µg desogestrel (Mercilon, Oy Organon Ab, Roseland, New Jersey), and 1 had an OC with 30 µg ethinylestradiol and 3 mg drospirenone (Yasmin, Bayer Schering Pharma). The second study group included 6 men and 1 woman of the wild-type genotype with no hormonal contraceptives (n = 7). The third study group consisted of OC users with the variant genotype (n = 7). Of these women, 4 had an OC containing ethinylestradiol and gestodene (Meliane, Bayer Schering Pharma; 20 µg + 75 µg Harmonet, Wyeth, Madison, New Jersey; and 30 µg + 75 µg Minulet, Wyeth), 2 had an OC with ethinylestradiol and drospirenone (Yasmin, Bayer Schering Pharma), and 1 had an OC with ethinylestradiol and desogestrel (Mercilon, Oy Organon Ab). The fourth study group included 6 men and 2 women of the variant genotype with no hormonal contraception (n = 8). The OC users had been using the OC preparation for at least 1 menstrual cycle before the study, and on the study day, they had been taking the OC preparation for 6 to 21 days during the cycle that the study was performed. One male subject in the fourth study group used inhaled budesonide 200 µg/day for exercise-induced asthma. No other medications or natural products were used during and 2 weeks prior to the study.
On the study day, the subjects were kept as inpatients in the unit for the period of blood sampling. A single oral dose of 6 mg melatonin (2 x 3-mg tablets, Yliopiston apteekki, Helsinki, Finland) was ingested with 200 mL water at 9 AM after an overnight fast. The OC users ingested their OC preparation at 8 AM on the study day and during the preceding 6 days. A standard lunch was served 4 hours after melatonin ingestion. Alcohol, methylxanthine-containing food and beverages, and charcoal-grilled food and cruciferous vegetables were forbidden during and 2 days prior to the study. The subjects were advised to refrain from heavy exercise for 24 hours prior to the study. Smoking was forbidden.
Assessments
Blood Sampling
On the study day, each subject had a forearm vein cannulated for blood sampling. Timed venous blood samples for the measurement of melatonin and 6-OH-melatonin concentrations were drawn 1 hour, 0.5 hours, and immediately before melatonin administration as well as 0.5, 1, 1.5, 2, 2.5, 3, 4, and 6 hours after it. Blood samples (10 mL) were taken into ethylenediaminetetraacetic acid (EDTA)–containing tubes. Plasma was separated within 30 minutes and stored at –70°C until measurement of melatonin and 6-OH-melatonin concentrations. The baseline concentrations of melatonin and 6-OH-melatonin were determined as the mean value of all the 3 concentrations measured within an hour before melatonin intake. The baseline value was deducted from the results to study the additional effect of the ingested melatonin on plasma melatonin and 6-OH-melatonin concentrations.
Bioanalytical Assays
Samples were prepared by protein precipitating the plasma with a 3-fold volume of acetonitrile containing phenacetin as the internal standard in Sirocco 96-well protein precipitation plates (Waters Corp, Milford, Massachusetts) according to the manufacturer's instructions. A Waters Quattro II mass spectrometer and Waters Alliance 2690 liquid chromatograph (Waters Corp) were used. A Gemini C18 column (50 x 2.0 mm, 3 µm) and a Phenomenex C18 precolumn (4.0 x 2.0 mm) were used. The eluent A used was 0.1% acetic acid in water, and eluent B was methanol. A linear gradient elution from 5% B to 90% B in 1.5 minutes was used, followed by 1.5-minute isocratic elution with 90% B with a flow rate of 0.4 mL/min and column equilibration for 3 minutes with gradient starting conditions, with a flow rate of 0.5 mL/min. A positive ion mode electrospray ionization was used with a cone voltage of 24 V and a capillary voltage of 3500 V. Collision gas used was argon at 1.7 x 10–3 mbar pressure. Collision energy used was 14 eV for melatonin and 6-hydroxymelatonin and phenacetin. Monitored multiple-reaction monitoring (MRM) transitions were m/z 233
174 for melatonin, m/z 249190 for 6-hydroxymelatonin, and m/z 180110 for phenacetin.
The lower limits of quantification were 0.4 ng/mL and 2.0 ng/mL for melatonin and 6-hydroxymelatonin, respectively. Values greater than 50% of the lower quantification limits were considered reliable and used as such. Interday and intraday coefficients of variation were less than 15% for both compounds through the linear quantification range of 0.4 to 400 ng/mL and 1.6 to 80 ng/mL for melatonin and 6-hydroxymelatonin, respectively.
Assessment of Alertness and Adverse Effects
Adverse events (AEs) were questioned by the same investigator at 0, 3, and 6 hours after melatonin intake using an open question of how the subject was feeling. All reported or otherwise noted adverse effects were recorded and classified as mild, moderate, or severe. In addition, the subject's state of alertness was measured by a visual analog scale (VAS), with alert and tired being the endpoints on the scale. This state of alertness was converted into a percentage where 0% denotes a state of perfectly alert and 100% a state of totally tired.
Pharmacokinetics
Pharmacokinetics were calculated using the WinNonlin Professional program, Version 4.1 (Pharsight Corporation, Mountain View, California). The pharmacokinetics of melatonin and its metabolite 6-OH-melatonin were characterized by peak concentration in plasma (Cmax), time to Cmax (tmax), area under the concentration-time curve (AUC0-
), and elimination half-life (t1/2). The weight-adjusted apparent oral clearance (clearance/weight) was determined for melatonin. Genotyping for CYP1A2 SNP g.-163C>A was done as described in detail in a previous study.24
Statistical Methods
The number of study subjects was based on a power calculation to detect a 50% difference in melatonin AUC between OC users and nonusers using melatonin AUC values from a previous study.9 The pharmacokinetic variables and the state of alertness between the study groups were analyzed using the analysis of variance and the Kruskal-Wallis test. Paired t test was used to analyze changes in the state of alertness, and the Pearson and Spearman rank tests were used for studying the relationship between melatonin pharmacokinetics and the state of alertness. P values of 5% or less were regarded as significant. Logarithmic transformation of pharmacokinetic variables was done prior to analysis, but it did not affect the results. Bonferroni correction was used in all between-group analyses. The data were analyzed using the SAS Enterprise Guide for Windows, Version 3.0 (SAS Institute, Cary, North Carolina).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetics of Melatonin
There was a statistically significant difference in the melatonin AUC (P = .0002), Cmax (P = .0007), and clearance/weight (CL/W, P = .0008) values between the study groups (Kruskal-Wallis test). The tmax (P = .71) and t1/2 (P = .90) values did not differ significantly between the groups. The mean pharmacokinetic values of the groups are shown in Table I and individually illustrated in Figure 2. When the contraceptive users (n = 14) and nonusers (n = 15) were compared as separate groups regardless of the genotype, there was about a 5-fold difference in the AUC (P < .0001), a 4-fold difference in the Cmax (P < .0001), and about an 8-fold difference in the weight-corrected apparent oral clearance of melatonin (P < .0001) values. When the different genotypes were studied as groups regardless of the OC use, there were no statistically significant differences in the pharmacokinetic values of melatonin between representatives of the wild-type (n = 14) and the variant (n = 15) genotypes (P values from .57 to .79). In subjects representing the wild-type genotype, the oral contraceptives caused a 5-fold increase in the AUC of melatonin (P = .0018), and the effect of OCs was similar (4.5-fold) in subjects homozygous for the variant (-163A) allele (P = .0072, Table I). Instead, the AUC of melatonin was equal in the nonusers of OCs of the wild-type and of the variant genotypes (P = .97). Accordingly, the genotype did not affect the magnitude of inhibition of melatonin metabolism. In addition, there was a similar, about 5-fold increase in the Cmax of melatonin by OCs in both the wild-type (P = .0042) and variant (P = .033) allele carriers.
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AUC Ratio
The ratio of the AUC values of 6-OH-melatonin and melatonin depicts the turnover rate of melatonin by CYP1A2. This ratio was about 8-fold higher in non-OC users when compared with OC users (P < .0001, Mann-Whitney U test). CYP1A2 genotype did not affect the AUC ratio in OC users (P = .85, Table I) or nonusers (P = .64).
Alertness and Adverse Effects
The state of alertness assessed by the VAS did not differ between the groups at baseline (mean alertness 45% vs 45% vs 37% vs 35%, P = .65, Kruskal-Wallis test). Also, there was no difference in the alertness at 3 or 6 hours between the groups, between the OC users and nonusers, or between the genotypes (data not shown). The subjects generally felt tired during the study day, especially before noon. The state of alertness was reduced during the first 3 hours after melatonin intake, but there was no statistically significant difference between the baseline and 3-hour values (P = .32), probably due to the fact that the subjects were quite tired already at baseline. The state of alertness was significantly increased at 3 PM when compared with the noon values (mean 14%, 95% confidence interval [CI] 4% to 24%, P = .0079, paired t test), and the trend was similar when compared with the morning values (mean 9%, 95% CI –0.7% to 19%, P = .068, paired t test). The state of alertness did not correlate with the melatonin pharmacokinetic values AUC, Cmax, or clearance/weight. No adverse effects were reported during the study day except for 1 subject having moderate headache.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Although quite considerable changes were seen in melatonin metabolism as a result of CYP1A2 inhibition by oral contraceptives, no changes in 6-OH-melatonin pharmacokinetics were seen between the study groups. This is surprising because the 6-hydroxylation accounts for more than 80% of melatonin clearance.33 However, the AUC ratio of 6-OH-melatonin and melatonin was 8-fold higher in non-OC users than in OC users, suggesting that OCs may also affect the 6-OH-melatonin concentrations because a proportionally smaller amount of melatonin is metabolized into 6-OH-melatonin in the presence of OCs. Also, it is possible that the OC use may induce the further metabolism of 6-OH-melatonin into glucuronide or sulfate conjugates.34 In fact, ethinylestradiol has been shown to increase the in vivo clearance of lamotrigine,35,36 lorazepam, oxazepam,37 propranolol,38 and clofibrate39,40 by enhancing glucuronidation or stimulating the excretion of glucuronides of these drugs. No clinical reports of ethinylestradiol-induced sulfotransferase activity have been published so far, but as a drug undergoing sulfation, ethinylestradiol has the potential to interfere with also sulfate conjugation of other drugs.41
The only difference between the representatives of the wild-type and variant genotypes was seen in the baseline values of the melatonin metabolite 6-OH-melatonin, which were significantly higher in the wild-type subjects. In the literature, carriers of the variant CYP1A2*1F allele have been designated as slow caffeine metabolizers, whereas subjects homozygous for the wild-type CYP1A2*1A allele have been designated as rapid caffeine metabolizers.42 Our finding of the higher 6-OH-melatonin concentrations in the representatives of the wild-type genotype suggests, in fact, faster melatonin turnover by CYP1A2, but otherwise nothing in our results implicates differences in the rate of melatonin metabolism between the genotypes. Although not ideal, male subjects were used in this study because of the difficulty in getting female volunteers with the appropriate genotype and no hormonal contraceptive use. According to literature, men seem to have higher activity of CYP1A2 relative to women.43-45 There were 6 male subjects in both of the non-OC groups. The pharmacokinetic values of the 3 women recruited in this study did not stand out from the male values, as shown in Figure 2. The 2 outliers with the longest elimination half-lives were men, and the subject with the highest AUC ratio in study group 2 was a woman (Figure 2).
Although the AUC and Cmax values of melatonin were significantly higher in OC users than in nonusers, there were no significant differences in the state of alertness of these subjects. The finding that the quite large increase in melatonin exposure did not significantly affect the subjective alertness is in concordance with the quite mild sedative effect that melatonin has shown in the treatment of sleep disorders.46
The combined effect of the SNP g.-163C>A and CYP1A2 inhibition on melatonin metabolism has not been studied before. We studied the SNP g.-163C>A present in many variant alleles of CYP1A2; therefore, direct comparison with the effects of the *1F allele is not possible. In a recent work, CYP1A2 induction was only seen when g.-163C>A appeared alone, and the effect was abolished in the presence of other SNPs.32 We found a clear effect of OC use on CYP1A2 activity, but the genotype did not appear to play a significant additional role. There were no significant differences in the state of alertness between the subjects of different genotypes or OC use. According to our results, the possible effect of the SNP g.-163C>A on CYP1A2 activity appears to be mild and is not likely to cause any clinically significant changes in melatonin pharmacokinetics. The OC use, however, changes significantly the CYP1A2-dependent metabolism of melatonin and alters the results of CYP1A2 phenotyping.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: None declared.
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REFERENCES |
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