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BRIEF REPORTS/DRUG METABOLISM AND TRANSPORT |
From Clinical Pharmacology, Pharmacia. Current affiliations: Pfizer, Inc, Sandwich, United Kingdom (Dr Xie); Pfizer, Inc, Singapore (Dr Tan); CV Therapeutics, Palo Alto, California (Dr Gordi); Clinical PK/PD, Pfizer, Inc, Groton, Connecticut (Dr Sharma); Pfizer, Inc, San Diego, California (Mr Nickens); Pfizer Japan, Inc, Tokyo, Japan (Ms Arakawa); and Jasper Clinic, Kalamazoo, Michigan (Mr Knuth, Dr Antal).
Address for reprints: Rujia Xie, PhD, Global Research & Development, Sandwich Laboratories, Pfizer Limited, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom.
Key Words: cytochrome P450 3A • P-glycoprotein • induction • ethnicity
It has been reported that St. John's Wort (SJW) may have inducing effects on the cytochrome P450 enzyme system, specifically the CYP3A4 isoform (CYP3A4)1,2 and the intestinal P-glycoprotein (Pgp) efflux membrane transporter.1,3 This may have profound implications on patients taking medications that are substrates for Pgp and/or CYP3A4. Ethnic difference is an important factor to determine drug metabolism and response. Varying results have been reported in studies evaluating ethnic differences in the pharmacokinetic disposition of Pgp/CYP3A4 substrates and suggest that these differences may be attributed to ethnically associated differences in intestinal Pgp and CYP3A4 activity.4-8
Fexofenadine and midazolam have been widely used as probes for intestinal and hepatic Pgp transporter and CYP3A enzyme activities in human interaction studies.6,9-11 In vivo studies examining SJW induction on CYP3A4 and Pgp substrates' pharmacokinetic (PK) parameters and its relationship among various ethnic groups have not been examined extensively. The purpose of the current study was to investigate whether any differences in the inducibility of Pgp and CYP3A by SJW are present among 6 ethnic groups in healthy volunteers using fexofenadine and midazolam as probes.
METHODS
Subjects and Treatment
Thirty subjects, who signed written informed consent, completed the trial. They were Caucasians, African Americans, Hispanics, Chinese, Indians, and Malays (5 per group). All subjects met the inclusion and exclusion criteria written in the study protocol, which was approved by the Bronson Center for Clinical and Community Research Institutional Review Board (Kalamazoo, Mich) and the Ethics Committee of Singapore General Hospital (Singapore). Every subject provided a family history of ethnic heritage going back 2 generations and of all family members. Subjects who received any known enzyme-altering drugs or herbal preparations within 30 days prior to the first dosing were excluded from the study.
Each subject received a single dose of 60 mg of fexofenadine, 5 mg of midazolam syrup, and 2 mg of midazolam intravenous infusion (6 hours after the oral dose of midazolam) on study days 1 and 11. All subjects took 300 mg of SJW 3 times a day, starting on day 2 through day 11. Plasma and urine samples were taken for PK analyses of fexofenadine and midazolam. One blood sample was taken for the genotyping of CYP3A4, CYP3A5, Pgp, and Pregnane X Receptor (PXR) analyses.
Sample Analysis
Fexofenadine and midazolam concentrations in plasma and urine samples were analyzed using validated high-performance liquid chromatographic (HPLC)/tandem mass spectrometric (LC-MS-MS) methods at Cedra Corporation (Austin, Tex). Genomic DNA samples were analyzed using a combination of TagMan-based assays and ABI PRISM-based sequencing at EPIDAUROS Biotechnologie AG (Bernried, Germany).
Pharmacokinetic Analysis
Pharmacokinetic parameters of midazolam and fexofenadine for day 1 (D1) and day 11 (D11) were calculated by the standard method for noncompartmental analysis using a nonlinear regression program, Kinetica (Innaphase, Pa). The blood-to-plasma concentration ratio of midazolam is 0.812; therefore, blood clearance of midazolam was equal to 1.25 · systemic clearance. It was assumed that systemic blood clearance of midazolam was equivalent to hepatic blood clearance, and hepatic availability (FH) was expressed as
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Statistical Analysis
Statistical analysis of PK parameters was performed by 1-way analysis of variance (ANOVA). Point estimates and 95% confidence intervals (95% CIs) were calculated for the ratio of PK parameters for day 11 to day 1. The Bonferroni/Dunn test was used to perform unpaired comparisons between ethnic groups for PK parameters and ratios of parameters at an overall significance level of 5% (with the individual unpaired significance level being less than .0033) for independent groups. Within each ethnic group and for combined data, a 1-sample t test was used to evaluate the mean ratio, and the hypothesized mean was set equal to 1.
RESULTS
Subjects
Twenty-two male and 8 female subjects completed the study. The average age of subjects was 30 ± 8 years (range, 19-51 years), and the mean body mass index was 25 ± 3kg/m2 (range, 20-30 kg/m2). The mean body weight of subjects was 70 ± 9 kg (range, 53-91 kg), and there were no statistically significant differences for the demographics among the 6 ethnic groups.
Fexofenadine
The plasma concentrations of fexofenadine on day 11 decreased in all groups compared to day 1. Caucasians had the lowest plasma concentrations of fexofenadine on both day 1 and day 11 at all time points among the 6 ethnic groups (data not shown). After SJW treatment, mean oral clearance (CLoral) and apparent volume of distribution at steady state (Vss,oral) of fexofenadine increased in all groups, about 2 times higher than those of day 1 based on all subjects (Table I). Significant increases of fexofenadine's CLoral on day 11 were observed for Caucasians and Hispanics, whereas nonsignificant but substantial changes were observed for the other ethnic groups (Table I). SJW exhibited no significant effect on terminal half-lives (t
) (5.2 hours, day 1 vs 5.3 hours, day 11; P = .3580) and renal clearance (CLR) of fexofenadine (4.0 L/h, day 1 vs 4.2 L/h, day 11; P = .1816) based on all subjects. Among the groups, CLoral means were comparable for day 1 and day 11, as well as CLoral and Vss,oral ratios of day 11 to day 1 (Table I).
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Midazolam
Midazolam plasma concentrations were lower on day 11 compared to those on day 1 in all subjects. Caucasians showed the lowest plasma concentrations among the populations for both day 1 and day 11 (data not shown). After SJW treatment, significant increases of midazolam systemic clearance (CLIV) and CLoral were observed in all groups (Table I). Caucasians had the highest mean CLIV on day 1 and day 11 compared to other populations; it was significantly higher than that of Hispanics, Chinese, and Indians on day 1 and that of Chinese on day 11 (Table I). However, CLIV ratios of day 11 to day 1 were similar among the 6 ethnic groups. Midazolam CLoral with SJW was about 3 times higher than that of midazolam alone based on all subjects. Caucasians' CLoral was approximately 2 times higher than that of Hispanics, Chinese, and Indians before SJW administration, whereas the only significant difference was observed between Caucasians and Chinese on day 11. The CLoral ratios of day 11 to day 1 were not different among the ethnic groups. Midazolam F on day 11 was only 55% of that on day 1 (Table I), in which FH decreased by 19% and FG decreased by 32% with SJW based on all subjects. Mean FH was about2-to4-fold higher than FG before and after SJW for all subjects. Six ethnic populations showed similarity of midazolam FandFG for both day 1 and day 11. Caucasians' FH was significantly lower than that of Chinese, Hispanics, and Indians on day 1 and also significantly lower than that of Chinese on day 11. Nevertheless, there were no significant differences among the ethnic groups for the ratios of day 11 to day 1 for F, FH, and FG.
Genotype-Phenotype Association
The genes and alleles tested for all subjects were CYP3A4 (*2 to *19), CYP3A5 (1, *3, *4, *6, and *7), Pgp (G3435T-exon26, G2677T, and G2677A-exon21), and PXR (G1108A, G418A, A488G, G52A, C79T (*2), G106A (*3), and G365A (*4)). All Asian subjects had 1 or 2 variant alleles in G2677T; only 20% non-Asians were wild-type G2677T, whereas 13% non-Asians and 46% Asians were wild-type G3435T. All subjects were wild-type CYP3A4, except 1 within CYP3A4*10. Three Asian subjects had heterozygous PXR variants. None of the individual genotypes was significantly correlated with fexofenadine or midazolam PK parameters.
DISCUSSION
In the current study, fexofenadine CLoral was approximately doubled based on all subjects after a 10-day treatment with SJW. Although the CLoral substantially increased in all ethnic groups, a statistical significance was not always observed mainly due to considerable interindividual variability and small sample size. Fexofenadine t and CLR were not influenced by SJW. This may be due to the fact that SJW can induce intestinal Pgp,1 which in turn can decrease the bioavailability of fexofenadine but not its systemic clearance. Our observations are similar to recent reports of fexofenadine and SJW interaction studies.10,11
Caucasians showed higher mean CLoral of fexofenadine than in Asian populations both before and after SJW treatment. However, there were large overlaps for individual values across the 6 ethnic groups, resulting in no significant differences in fexofenadine CLoral among studied groups. These results indicate that interindividual variability within the group is comparable to interethnic variability and imply that Pgp activity is not likely to be significantly different among these ethnic groups. Moreover, because the ratios (D11/D1) of PK parameters of fexofenadine were similar, the degree of induction of Pgp by SJW appears to be comparable among the ethnic groups evaluated.
Midazolam CLIV and CLoral significantly increased by SJW in the 6 ethnic groups, without change in Vss.Both FH and FG significantly decreased after SJW treatment. These results support the premise that SJW increases first-pass elimination of midazolam in both the intestine and liver due to the induction of intestinal and hepatic CYP3A4 enzyme activities.11 Our study results demonstrate a larger decrease in FG compared to the decrease in FH, providing evidence that CYP3A4 enzyme activity was induced to a greater extent in the intestinal tract. Higher hepatic availability in comparison with intestinal availability was found, indicating that oral first-pass elimination played an important and determining role in midazolam disposition.13-15 It has been found that the intestine is a major site of interaction between midazolam and clarithromycin.16
Our results suggest that Caucasians have significantly higher clearances (CLIV and CLoral) and lower midazolam FH than those of Chinese, Hispanics, and Indians prior to enzyme induction. The reason might be that Caucasians have higher intrinsically hepatic CYP3A4 enzyme activity. Ethnic differences of CYP3A4 activity have been studied in different populations for different CYP3A4 substrates, 6,17 and different results were reported.8,18,19 Therefore, ethnic differences in hepatic metabolism seem to be unpredictable by race and specific enzyme, and ethnic variation caused by CYP3A4 activity may be dependent on the substrates evaluated. Midazolam CL and FH ratios were similar among the 6 ethnic groups, indicating that hepatic CYP3A4 enzyme inducibility was comparable. The results also demonstrated that F and FG of midazolam with and without SJW were comparable among the evaluated 6 ethnic groups, further supporting that inducibility of CYP3A4 enzyme activity was similar.
In conclusion, this study showed that the coadministration of SJW resulted in a significant increase in the clearances of a Pgp substrate (fexofenadine) and a CYP3A substrate (midazolam) in 6 ethnic groups. Both intestinal and hepatic CYP3A4 activities are induced. However, the induction of intestinal CYP3A4 activity was significantly higher than that of hepatic CYP3A4 activity. There is an indication that the extent of Pgp and CYP3A4 induction was comparable among the 6 evaluated ethnic groups.
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FOOTNOTES |
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This study was supported by Pharmacia Corporation.
Submitted for publication February 3, 2004; Revised version accepted November 15, 2004.
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