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Pharmacokinetic drug interaction between fexofenadine and fluvastatin mediated by organic anion-transporting polypeptides in rats
European Journal of Pharmaceutical Sciences 37 (2009) 413–417
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European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps
Pharmacokinetic drug interaction between fexofenadine and fluvastatin mediated by organic anion-transporting polypeptides in rats Fu Qiang a , Beom-Jin Lee b , Wonjae Lee a , Hyo-Kyung Han a,∗ a b
BK21 Project Team, College of Pharmacy, Chosun University, 375 Seosuk-dong, Dong-Gu, Gwangju 501-752, Republic of Korea Bioavailability Control Laboratory, College of Pharmacy, Kangwon National University, Chuncheon 200-701, Republic of Korea
a r t i c l e
i n f o
Article history: Received 2 January 2009 Received in revised form 17 March 2009 Accepted 22 March 2009 Available online 1 April 2009 Keywords: Fexofenadine Fluvastatin Organic anion-transporting polypeptides Drug interaction Rat
a b s t r a c t This study aimed to examine the transporter-mediated drug interaction between fexofenadine and fluvastatin in rats. Compared to the control group given fluvastatin alone, the concurrent use of fexofenadine (10 or 20 mg/kg) prior to the oral administration of fluvastatin (5 mg/kg) decreased the systemic exposure of fluvastatin by 17–51% in rats. Consequently, the bioavailability of oral fluvastatin was significantly lower (p < 0.05) in the presence of fexofenadine compared to that from the control group. Furthermore, the intravenous pharmacokinetics of fluvastatin (2 mg/kg) was significantly altered by the pretreatment with fexofenadine (20 mg/kg, p.o.). The plasma clearance of fluvastatin was reduced by 44% in the presence of fexofenadine. The effect of fluvastatin on the pharmacokinetics of fexofenadine was also investigated in rats. The pretreatment with fluvastatin (5 or 10 mg/kg) decreased AUC and Cmax of oral fexofenadine (10 mg/kg) by 47–53% and 28–60%, respectively, while it did not affect the intravenous pharmacokinetics of fexofenadine. Given that both fluvastatin and fexofenadine can interact with organic anion-transporting polypeptides (OATPs) expressed in intestine and liver, the present results suggest the potential drug interaction between fluvastatin and fexofenadine via the competition for the OATP-mediated cellular transport pathway during intestinal absorption and/or hepatic uptake of drugs. © 2009 Elsevier B.V. All rights reserved.
1. Introduction Drug transporters play an important role in the absorption and elimination of many endogenous and exogenous compounds. Among various drug transporters expressed in intestine and liver, organic anion-transporting polypeptides (OATPs) form a superfamily of the sodium-independent transport system for a wide range of amphipathic organic compounds including organic dyes, steroid conjugates, anionic oligopeptides and numerous pharmaceutical drugs [1–3]. Since OATPs involved in the cellular transport of many drugs and the multiple prescriptions are increasingly common in current medical practice, there might be high potential for the OATP-mediated drug–drug interactions (DDIs). However, the preclinical and clinical significance of OATP-mediated drug interactions has not been clearly defined yet while metabolic drug interactions or P-gp mediated drug interactions have been extensively examined [4,5]. Fexofenadine is a non-sedating histamine H1-receptor antagonist and effective for the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria [6]. After an oral administration
∗ Corresponding author. Tel.: +82 62 230 6364; fax: +82 62 222 5414. E-mail address: [email protected] (H.-K. Han). 0928-0987/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2009.03.012
of fexofenadine, the majority of the dose (>85%) was recovered as the unchanged form in urine and feces while the metabolism of fexofenadine was insignificant in vivo [7,8]. Fexofenadine is a wellknown substrate of the OATP-A (OATP1A2) and OATP-B (OATP2B1) as well as P-gp [9–12]. Therefore, the modulation of those transporter activities could result in the altered pharmacokinetics of fexofenadine. In fact, the fruit juice decreased the oral bioavailability of fexofenadine by inhibiting the OATPs in both rat and humans [13–15]. Fluvastatin is a lipid-lowering agent and a potent inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the ratelimiting enzyme in cholesterol biosynthesis [16,17]. Fluvastatin is readily and extensively absorbed from the gastrointestinal tract following an oral administration, but it undergoes the extensive first-pass metabolism [18,19]. Previous studies have indicated the OATP1B1-, OATP2B1-, and OATP1B3-mediated fluvastatin transport [20,21]. Since both fexofenadine and fluvastatin can interact with OATPs expressed in intestine and liver, the coadministration of both drugs may change the systemic exposure of each drug via the competition for the common cellular transport pathways and consequently alters the therapeutic risk–benefit ratio of each drug. As a result, the drug interaction potential between fexofenadine and fluvastatin is of great importance for the clinical safety of both drugs but so far it has not been evaluated yet. Therefore, the present
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study investigated the potential pharmacokinetic drug interaction between fluvastatin and fexofenadine after the concomitant use of those drugs in rats. 2. Materials and methods 2.1. Materials Fluvastatin sodium was purchased from Biocon Chemical Co. (Electronic city, Bangalore, India). Fexofenadine, atorvastatin, piroxicam were obtained from Sigma Chemical Co. (St. Louis, MO, USA). Triethylamine was obtained from Junsei Chemical Co. (Tokyo, Japan). Acetonitrile, methanol, ethanol and acetic acid were obtained from Merck Co. (Darmstadt, Germany). All other chemicals were of analytical grade and all solvents were of HPLC grade.
2.3.2. Fluvastatin Plasma concentration of fluvastatin was determined by the HPLC method as follows. Briefly, 15 l of atorvastatin (10 g/ml) as an internal standard was added to 85 l of each plasma sample and then the sample was deproteinized by adding 200 l of acetonitrile. After centrifugation of the samples at 13,000 × g for 10 min, the supernatant was evaporated and the residue was reconstituted with 200 l of the mobile phase, and then 50 l of aliquots were injected directly into the HPLC system (Perkin Elmer Series 200, USA). An octadecylsilane column (Gemini C18, 4.6 mm × 250 mm, 5 m; Phenomenex, Torrance, CA, USA) was eluted with the mobile phase of 0.1 M acetic acid:acetonitrile:methanol (34.5:4.0:61.5, v/v/v%) at a flow rate of 1.0 ml/min. The UV detector set at 235 nm. The calibration curve from the standard samples was linear over the concentration range of 0.01–1 g/ml. The detection limit of fluvastatin was 0.01 g/ml.
2.2. Animal studies
2.4. Pharmacokinetic data analysis
Male Sprague–Dawley rats (280–300 g) were purchased from Samtako Bio Co. (Osan, Korea). All animal studies were performed in accordance with the “Guiding Principles in the Use of Animals in Toxicology” adopted by the Society of Toxicology (USA). Rats were divided into ten groups (n = 6 per each group). Groups 1–3: 10 mg/kg of fexofenadine (p.o.) + 0, 5 or 10 mg/kg of fluvastatin (p.o., 15 min prior to fexofenadine administration), Groups 4 and 5: 5 mg/kg of fexofenadine (i.v.) + 0 or 10 mg/kg of fluvastatin (p.o., 15 min prior to fexofenadine administration), Groups 6–8: 5 mg/kg of fluvastatin (p.o.) + 0, 10 or 20 mg/kg of fexofenadine (p.o., 15 min prior to fluvastatin administration) and Groups 9 and 10: 2 mg/kg of fluvastatin (i.v.) + 0 or 20 mg/kg of fexofenadine (p.o., 15 min prior to fluvastatin administration). A single dose of approximately 10 mg/kg fexofenadine is comparable to the clinical dose of 120 mg in humans [14,15]. Also, the doses for fluvastatin used in the present study were selected based on the previous report [22] as well as assay sensitivity. Fexofenadine was dissolved in ethanol and water (1:10) for oral administration and in saline (0.9%) for i.v. administration. Fluvastatin was dissolved in the distilled water for oral administration and in saline (0.9%) for i.v. administration. Blood samples were collected from the femoral artery at 0, 0.05, 0.16, 0.25, 0.5, 1, 2, 4, 8, 12, 24 h following an intravenous administration. Blood samples were also collected from the femoral artery at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12, 24 h following an oral administration. Blood samples were centrifuged and the obtained plasma was stored at −70 ◦ C until analyzed.
Noncompartmental pharmacokinetic analysis was performed using the WinNonlin® version 5.2 (Pharsight Corporation, Mountain View, CA, USA). The elimination rate constant (Kel ) was estimated from the slope of the terminal phase of the log plasma concentration–time points fitted by the method of least-squares and the terminal half-life (T1/2 ) was calculated by 0.693/Kel . The peak concentration (Cmax ) and the time to reach peak concentration (Tmax ) of drug in plasma were obtained by visual inspection of the data from the concentration–time curve. The area under the plasma concentration–time curve (AUC0–t ) from time zero to the time of last measured concentration (Clast ) was calculated by the linear trapezoidal rule. The AUC from time zero to infinite (AUC0–∞ ) was obtained by the addition of AUC0–t and the extrapolated area determined by Clast /Kel . Total plasma clearance (CL) was calculated by dose/AUC. The absolute bioavailability (A.B.) of drug was calculated by AUCp.o. /AUCi.v. × dosei.v. /dosep.o. × 100. The relative bioavailability (R.B.) of fexofenadine was estimated by AUCfexofenadine with fluvastatin /AUC fexofenadine × 100 and the R.B. of fluvastatin was estimated by AUCfluvastatin with fexofenadine / AUCfluvastatin × 100. 2.5. Statistical analysis All mean values were presented with their standard deviation (mean ± S.D.). Statistical analysis was conducted using a one-way ANOVA followed by a posteriori testing with Dunnett correction. A p value less than 0.05 was considered statistically significant.
2.3. HPLC assay 3. Results 2.3.1. Fexofenadine Plasma concentration of fexofenadine was determined by the HPLC method described as follows. In brief, 10 l of piroxicam (10 g/ml) as an internal standard was added to 90 l of each plasma sample and then the mixture was deproteinized by adding 200 l of acetonitrile. After centrifugation of the samples at 13,000 × g for 10 min, the supernatant was evaporated and the residue was reconstituted with 120 l of the mobile phase, and then 50 l of aliquots were injected directly into the HPLC system (Perkin Elmer Series 200; Waltham, MA, USA). The octadecylsilane column (Gemini C18, 4.6 mm × 150 mm, 5 m; Phenomenex, Torrance, CA, USA) was eluted with the mobile phase consisting of 0.1 M triethylamine:acetonitrile:methanol (61:19.5:19.5, v/v/v%, pH 4.4 adjusted with phosphoric acid) at a flow rate of 1.0 ml/min. The UV detector set at 195 nm. The calibration curve from the standard samples was linear over the concentration range of 0.01–0.5 g/ml. The detection limit of fexofenadine was 0.01 g/ml.
3.1. Altered pharmacokinetics of fexofenadine in the presence of fluvastatin The mean plasma concentration–time profiles of fexofenadine in the presence and the absence of fluvastatin were characterized in rats and illustrated in Figs. 1 and 2. The mean pharmacokinetic parameters of fexofenadine were also summarized in Tables 1 and 2. As shown in Table 1, the pretreatment with fluvastatin (5 or 10 mg/kg) significantly altered the oral exposure of fexofenadine compared to the control group given fexofenadine alone. The Cmax and AUC of fexofenadine decreased by 28–60% and 47–53%, respectively via the concurrent use of 5 or 10 mg/kg of fluvastatin. Consequently, the absolute and relative bioavailability values of fexofenadine decreased significantly (p < 0.05) under the pretreatment with fluvastatin. However, there was no significant change in Tmax and terminal plasma half-life (T1/2 ) of fexofenadine in the presence
F. Qiang et al. / European Journal of Pharmaceutical Sciences 37 (2009) 413–417
Fig. 1. Mean plasma concentration–time profiles of fexofenadine following an oral administration of fexofenadine (10 mg/kg) to rats in the presence and the absence of fluvastatin (5 or 10 mg/kg) (mean ± S.D., n = 6). () fexofenadine alone, () pretreatment with 5 mg/kg of fluvastatin, () pretreatment with 10 mg/kg of fluvastatin.
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Fig. 2. Mean plasma concentration–time profiles of fexofenadine following an intravenous administration of fexofenadine (5 mg/kg) to rats in the presence and the absence of fluvastatin (10 mg/kg, p.o.) (mean ± S.D., n = 6). () fexofenadine alone, () pretreatment with 10 mg/kg of oral fluvastatin.
of fluvastatin (Table 1). The intravenous pharmacokinetic profiles of fexofenadine were also evaluated in the presence and the absence of fluvastatin in rats (Table 2 and Fig. 2). In contrast to oral fexofenadine, fluvastatin had no effect on the pharmacokinetic profiles of intravenous fexofenadine.
pharmacokinetics of intravenous fluvastatin was also significantly altered by the pretreatment with fexofenadine. Plasma clearance of fluvastatin was reduced by 44% under the pretreatment with fexofenadine, leading to the increased systemic exposure of fluvastatin in the presence of fexofenadine. Collectively, the concurrent use of fexofenadine significantly altered the intravenous as well as oral pharmacokinetics of fluvastatin in rats.
3.2. Pharmacokinetic characteristics of fluvastatin in the presence of fexofenadine Mean plasma concentration–time profiles of fluvastatin following an oral administration of fluvastatin in the presence and the absence of fexofenadine were shown in Figs. 3 and 4. The mean pharmacokinetic parameters were also summarized in Tables 1 and 2. The oral exposure of fluvastatin decreased by 17–51% in the presence of fexofenadine. As a result, the relative bioavailability of fluvastatin was decreased to 49–83% after the concomitant use of fexofenadine. The effect of fexofenadine reducing the oral exposure of fluvastatin was dose proportional over the dose range of 10–20 mg/kg. Furthermore, as summarized in Fig. 4 and Table 2, the
4. Discussion Combination therapies are widely used for drugs in many different therapeutic classes and this co-medication increases the risk for significant drug–drug interactions. Therefore, it is important to address potential DDI risks relevant for the respective patient population by using appropriate in vitro/in vivo studies to guide clinical interaction studies. While transporter-mediated DDIs are clinically
Table 1 Pharmacokinetic parameters of fexofenadine and fluvastatin after an oral administration of fexofenadine (10 mg/kg) or fluvastatin (5 mg/kg) to rats (mean ± S.D., n = 6). Fexofenadine (10 mg/kg) Alone
a *
Pretreatment with fluvastatin
0.25 ± 0.27 0.7 ± 0.6 0.70 ± 0.40 6.4 ± 2.3 4.6 ± 3.1 100
Cmax (g/ml) Tmax (h) AUClast (g h/ml)a T1/2 (h) A.B. (%) R.B. (%)
Fluvastatin (5 mg/kg)
5 mg/kg
10 mg/kg
0.18 ± 0.07 0.3 ± 0.2 0.37 ± 0.19 4.5 ± 1.3 2.4 ± 1.4 51
0.10 ± 0.04 0.5 ± 0.2 0.33 ± 0.10* 5.7 ± 2.4 2.1 ± 1.2* 45
Alone
Pretreatment with fexofenadine
2.08 ± 1.10 0.8 ± 0.4 9.95 ± 3.10 8.7 ± 2.5 86.4 ± 23.7 100
10 mg/kg
20 mg/kg
2.06 ± 0.99 0.6 ± 0.2 8.22 ± 2.18 12 ± 4.2 73.8 ± 27.6 83
1.52 ± 0.50 0.6 ± 0.2 4.89 ± 0.60* 11 ± 4.0 43.2 ± 9.0* 49
AUClast : fexofenadine–AUC0–12 , fluvastatin–AUC0–24 . p < 0.05, compared to the control group given fexofenadine or fluvastatin alone.
Table 2 Pharmacokinetic parameters of fexofenadine and fluvastatin after an intravenous administration of fexofenadine (5 mg/kg) or fluvastatin (2 mg/kg) to rats (mean ± S.D., n = 6).
T1/2 (h) CL (l/(h kg)) Vdss (l/kg) AUC0−∞ (g h/ml)* *
Fexofenadine (5 mg/kg)
Fluvastatin (2 mg/kg)
Alone
Alone
11.3 0.62 1.39 7.97
± ± ± ±
Pretreatment with fluvastatin (10 mg/kg, p.o.) 6.3 0.07 0.87 0.90
10.7 0.66 1.96 7.33
± ± ± ±
3.9 0.08 0.37 0.8
p < 0.05, compared to the control group given fluvastatin alone.
9.6 1.23 15.9 4.66
± ± ± ±
Pretreatment with fexofenadine (20 mg/kg, p.o.) 3.3 0.31 3.08 0.96
13.1 0.69 13.1 7.30
± ± ± ±
7.9 0.03* 8.76 1.50*
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Fig. 3. Mean plasma concentration–time profiles of fluvastatin following an oral administration of fluvastatin (5 mg/kg) to rats in the presence and the absence of fexofenadine (10 or 20 mg/kg) (mean ± S.D., n = 6). () fluvastatin alone, () pretreatment with 10 mg/kg of fexofenadine, () pretreatment with 20 mg/kg of fexofenadine.
significant in addition to metabolizing enzyme-mediated DDIs, broad overlap in the substrate specificity between transporters and metabolic enzymes makes it difficult to determine the relative contribution of transporters or enzymes to overall drug interaction of certain drugs. In that sense, fexofenadine can be an ideal probe to study transporter-mediated drug interactions, given that it is a substrate of some transporters such as P-gp and OATPs [9–12] but its metabolism is insignificant [7,8]. Therefore, the present study was focused on the transporter-mediated drug interactions between fexofenadine and fluvastatin, particularly potential drug interaction mediated by OATPs in the consideration that both drugs can interact with OATPs. Kamath et al. [15] have reported that coadministration of orange juice or apple juice with fexofenadine caused a decrease in the oral exposure (AUC and Cmax ) of fexofenadine in rats, suggesting the preferential inhibition of OATPs over P-gp by the components of fruit juice. This observation in rats also appeared to be consistent with the findings in humans by Dresser et al. [14], although the extent of decrease in the oral bioavailability in rats was not as great as that observed in humans [14,15]. The dose of 10 mg/kg
Fig. 4. Mean plasma concentration–time profiles of fluvastatin following an intravenous administration of fluvastatin (2 mg/kg) to rats in the presence and the absence of fexofenadine (20 mg/kg, p.o.) (mean ± S.D., n = 6). () fluvastatin alone, () pretreatment with 20 mg/kg of oral fexofenadine.
used in their rat study corresponded to the 120 mg human dose [14,15]. Therefore, the present study was performed in rats by using 10 mg/kg dose of fexofenadine to evaluate the potential drug interaction mediated by the inhibition of organic anion-transporting polypeptides. As shown in Tables 1 and 2, the concurrent use of fluvastatin significantly reduced the oral exposure of fexofenadine while it did not affect the intravenous pharmacokinetics of fexofenadine. The marked decrease in oral AUC and Cmax values of fexofenadine with no change in Tmax and T1/2 under the pretreatment with fluvastatin should be mainly due to the reduced intestinal absorption of fexofenadine rather than the enhanced systemic elimination. Fexofenadine is a substrate of P-gp expressed in intestine but Pgp is unlikely to play a role in this interaction since the inhibition of P-gp should increase the intestinal absorption of drugs. Fexofenadine is a substrate of organic anion-transporting polypeptides such as human OATP1A2, OATP2B1, and OATP1B3 and rat oatp1, oatp2, and oapt3, which have involved in the hepatic and intestinal uptake of fexofenadine [11,12,14,23]. Considering that (i) fluvastatin would be at higher concentrations in small intestine than in liver because of extensive presystemic extraction; (ii) the inhibition of drug uptake in liver immediately after drug absorption would act to increase, rather than decrease, the plasma concentrations of fexofenadine; (iii) the intravenous pharmacokinetics of fexofenadine was not affected by the concomitant use of fluvastatin in contrast to oral fexofenadine, the primary mechanism for the decreased oral exposure of fexofenadine is most likely the inhibition of OATPs-mediated intestinal absorption of fexofenadine in the presence of fluvastatin. This is also supported by the previous findings reported by Dresser et al. [14] and Kamath et al. [15]. In their studies, the bioavailability of fexofenadine was greatly reduced by coadministration of grapefruit, orange, and apple juices via the inhibition of OATP-mediated intestinal absorption of fexofenadine in humans and rats [14,15]. Taken together, both fluvastatin and fruit juice exhibited similar inhibition effect on the OATP-mediated oral absorption of fexofenadine. The effect of combination therapy on the pharmacokinetics of fluvastatin was also examined as summarized in Tables 1 and 2. The pretreatment with fexofenadine significantly altered the pharmacokinetics of oral and intravenous fluvastatin compared to the control group given fluvastatin alone. The oral exposure of fluvastatin was significantly reduced by the concurrent use of fexofenadine, implying the competition between two drugs for the OATP-mediated intestinal absorption (Fig. 3). Moreover, the higher fexofenadine concentrations in intestine from higher doses of fexofenadine seemed to affect OATP-mediated intestinal absorption of fluvastatin to a greater extent and thus exhibited an increased inhibition effect on fluvastatin pharmacokinetics (Table 1 and Fig. 3). Active uptake of many statins, such as cerivastatin, fluvastatin, pravastatin, pitavastatin, and rosuvastatin, by OATPs into the liver has been demonstrated in many recent publications [20,21]. Therefore, blocking the active hepatic uptake of fluvastatin mediated by OATPs could cause the significant increase of systemic exposure of fluvastatin. This is strongly supported by the results from the present study. There was marked decrease in plasma clearance of fluvastatin, implying the inhibition of OATPs-mediated hepatic uptake of fluvastatin in the presence of fexofenadine (Table 2). Consequently, the pretreatment with fexofenadine significantly enhanced the systemic exposure of intravenous fluvastatin as illustrated in Fig. 4. Therefore, fexofenadine significantly altered both intravenous and oral pharmacokinetics of fluvastatin probably via the competition for OATPs-mediated intestinal absorption as well as hepatic uptake in rats. Fluvastatin is metabolized by several enzymes including CYP2C9, CYP3A4 and CYP2C8, with CYP2C9 as the major one
F. Qiang et al. / European Journal of Pharmaceutical Sciences 37 (2009) 413–417
while the role of transporters such as P-gp might not be significant in the disposition of fluvastatin [24,25]. So far the drug interactions affecting fluvastatin disposition have been limited to metabolic interactions, however, clinical observations indicated that the involvement of multiple enzymes in the metabolism of fluvastatin should minimize the effect, in case a coadministered drug inhibits one enzyme [26–28]. In contrast to minimal metabolic interactions, our present findings raised the awareness on the significance of OATPs-mediated drug interaction in the pharmacokinetics of fluvastatin. Given that statins are widely used in clinics to treat dyslipidemia and an increase in the plasma concentration of many of the currently used statins can cause severe side effects [29], our present study also suggests that the clinical evaluation of drug interaction potential mediated by OATPs with statins is of great importance for the clinical safety. In summary, the concurrent use of fexofenadine and fluvastatin changed the systemic exposure of each drug significantly (p < 0.05) via the inhibition of OATPs in rats. The affinity and capacity of fexofenadine and fluvastatin for OATPs could be different in rat and human. Therefore, the clinical implication of current findings should be further investigated in clinical studies in order to confirm whether their concomitant use should need medical supervision or not. 5. Conclusion The present study suggests that there might be potential drug interaction between fluvastatin and fexofenadine mediated by organic anion-transporting polypeptides expressed in small intestine and liver. Acknowledgement This study was supported by the research grant from Chosun University (2008). References Hagenbuch, B., Gui, C., 2008. Xenobiotic transporters of the human organic anion transporting polypeptides (OATP) family. Xenobiotica 38, 778–801. Niemi, M., 2007. Role of OATP transporters in the disposition of drugs. Pharmacogenomics 8, 787–802. Mikkaichi, T., Suzuki, T., Tanemoto, M., Ito, S., Abe, T., 2004. The organic anion transporter (OATP) family. Drug Metab. Pharmacokinet. 19, 171–179. Leucuta, S.E., Vlase, L., 2006. Pharmacokinetics and metabolic drug interactions. Curr. Clin. Pharmacol. 1, 5–20. Pal, D., Mitra, A.K., 2006. MDR-and CYP3A4-mediated drug–drug interactions. J. Neuroimmun. Pharmacol. 1, 323–339. Simpson, K., Jarvis, B., 2000. Fexofenadine: a review of its use in the management of seasonal allergic rhinitis and chronic idiopathic urticaria. Drugs 59, 301–321. Devillier, P., Roche, N., Faisy, C., 2008. Clinical pharmacokinetics and pharmacodynamics of desloratadine, fexofenadine and levocetirizine: a comparative review. Clin. Pharmacokinet. 47, 217–230.
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Pharmacokinetic drug interaction between fexofenadine and fluvastatin mediated by organic anion-transporting polypeptides in rats Fu Qiang a , Beom-Jin Lee b , Wonjae Lee a , Hyo-Kyung Han a,∗ a b
BK21 Project Team, College of Pharmacy, Chosun University, 375 Seosuk-dong, Dong-Gu, Gwangju 501-752, Republic of Korea Bioavailability Control Laboratory, College of Pharmacy, Kangwon National University, Chuncheon 200-701, Republic of Korea
a r t i c l e
i n f o
Article history: Received 2 January 2009 Received in revised form 17 March 2009 Accepted 22 March 2009 Available online 1 April 2009 Keywords: Fexofenadine Fluvastatin Organic anion-transporting polypeptides Drug interaction Rat
a b s t r a c t This study aimed to examine the transporter-mediated drug interaction between fexofenadine and fluvastatin in rats. Compared to the control group given fluvastatin alone, the concurrent use of fexofenadine (10 or 20 mg/kg) prior to the oral administration of fluvastatin (5 mg/kg) decreased the systemic exposure of fluvastatin by 17–51% in rats. Consequently, the bioavailability of oral fluvastatin was significantly lower (p < 0.05) in the presence of fexofenadine compared to that from the control group. Furthermore, the intravenous pharmacokinetics of fluvastatin (2 mg/kg) was significantly altered by the pretreatment with fexofenadine (20 mg/kg, p.o.). The plasma clearance of fluvastatin was reduced by 44% in the presence of fexofenadine. The effect of fluvastatin on the pharmacokinetics of fexofenadine was also investigated in rats. The pretreatment with fluvastatin (5 or 10 mg/kg) decreased AUC and Cmax of oral fexofenadine (10 mg/kg) by 47–53% and 28–60%, respectively, while it did not affect the intravenous pharmacokinetics of fexofenadine. Given that both fluvastatin and fexofenadine can interact with organic anion-transporting polypeptides (OATPs) expressed in intestine and liver, the present results suggest the potential drug interaction between fluvastatin and fexofenadine via the competition for the OATP-mediated cellular transport pathway during intestinal absorption and/or hepatic uptake of drugs. © 2009 Elsevier B.V. All rights reserved.
1. Introduction Drug transporters play an important role in the absorption and elimination of many endogenous and exogenous compounds. Among various drug transporters expressed in intestine and liver, organic anion-transporting polypeptides (OATPs) form a superfamily of the sodium-independent transport system for a wide range of amphipathic organic compounds including organic dyes, steroid conjugates, anionic oligopeptides and numerous pharmaceutical drugs [1–3]. Since OATPs involved in the cellular transport of many drugs and the multiple prescriptions are increasingly common in current medical practice, there might be high potential for the OATP-mediated drug–drug interactions (DDIs). However, the preclinical and clinical significance of OATP-mediated drug interactions has not been clearly defined yet while metabolic drug interactions or P-gp mediated drug interactions have been extensively examined [4,5]. Fexofenadine is a non-sedating histamine H1-receptor antagonist and effective for the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria [6]. After an oral administration
∗ Corresponding author. Tel.: +82 62 230 6364; fax: +82 62 222 5414. E-mail address: [email protected] (H.-K. Han). 0928-0987/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2009.03.012
of fexofenadine, the majority of the dose (>85%) was recovered as the unchanged form in urine and feces while the metabolism of fexofenadine was insignificant in vivo [7,8]. Fexofenadine is a wellknown substrate of the OATP-A (OATP1A2) and OATP-B (OATP2B1) as well as P-gp [9–12]. Therefore, the modulation of those transporter activities could result in the altered pharmacokinetics of fexofenadine. In fact, the fruit juice decreased the oral bioavailability of fexofenadine by inhibiting the OATPs in both rat and humans [13–15]. Fluvastatin is a lipid-lowering agent and a potent inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the ratelimiting enzyme in cholesterol biosynthesis [16,17]. Fluvastatin is readily and extensively absorbed from the gastrointestinal tract following an oral administration, but it undergoes the extensive first-pass metabolism [18,19]. Previous studies have indicated the OATP1B1-, OATP2B1-, and OATP1B3-mediated fluvastatin transport [20,21]. Since both fexofenadine and fluvastatin can interact with OATPs expressed in intestine and liver, the coadministration of both drugs may change the systemic exposure of each drug via the competition for the common cellular transport pathways and consequently alters the therapeutic risk–benefit ratio of each drug. As a result, the drug interaction potential between fexofenadine and fluvastatin is of great importance for the clinical safety of both drugs but so far it has not been evaluated yet. Therefore, the present
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study investigated the potential pharmacokinetic drug interaction between fluvastatin and fexofenadine after the concomitant use of those drugs in rats. 2. Materials and methods 2.1. Materials Fluvastatin sodium was purchased from Biocon Chemical Co. (Electronic city, Bangalore, India). Fexofenadine, atorvastatin, piroxicam were obtained from Sigma Chemical Co. (St. Louis, MO, USA). Triethylamine was obtained from Junsei Chemical Co. (Tokyo, Japan). Acetonitrile, methanol, ethanol and acetic acid were obtained from Merck Co. (Darmstadt, Germany). All other chemicals were of analytical grade and all solvents were of HPLC grade.
2.3.2. Fluvastatin Plasma concentration of fluvastatin was determined by the HPLC method as follows. Briefly, 15 l of atorvastatin (10 g/ml) as an internal standard was added to 85 l of each plasma sample and then the sample was deproteinized by adding 200 l of acetonitrile. After centrifugation of the samples at 13,000 × g for 10 min, the supernatant was evaporated and the residue was reconstituted with 200 l of the mobile phase, and then 50 l of aliquots were injected directly into the HPLC system (Perkin Elmer Series 200, USA). An octadecylsilane column (Gemini C18, 4.6 mm × 250 mm, 5 m; Phenomenex, Torrance, CA, USA) was eluted with the mobile phase of 0.1 M acetic acid:acetonitrile:methanol (34.5:4.0:61.5, v/v/v%) at a flow rate of 1.0 ml/min. The UV detector set at 235 nm. The calibration curve from the standard samples was linear over the concentration range of 0.01–1 g/ml. The detection limit of fluvastatin was 0.01 g/ml.
2.2. Animal studies
2.4. Pharmacokinetic data analysis
Male Sprague–Dawley rats (280–300 g) were purchased from Samtako Bio Co. (Osan, Korea). All animal studies were performed in accordance with the “Guiding Principles in the Use of Animals in Toxicology” adopted by the Society of Toxicology (USA). Rats were divided into ten groups (n = 6 per each group). Groups 1–3: 10 mg/kg of fexofenadine (p.o.) + 0, 5 or 10 mg/kg of fluvastatin (p.o., 15 min prior to fexofenadine administration), Groups 4 and 5: 5 mg/kg of fexofenadine (i.v.) + 0 or 10 mg/kg of fluvastatin (p.o., 15 min prior to fexofenadine administration), Groups 6–8: 5 mg/kg of fluvastatin (p.o.) + 0, 10 or 20 mg/kg of fexofenadine (p.o., 15 min prior to fluvastatin administration) and Groups 9 and 10: 2 mg/kg of fluvastatin (i.v.) + 0 or 20 mg/kg of fexofenadine (p.o., 15 min prior to fluvastatin administration). A single dose of approximately 10 mg/kg fexofenadine is comparable to the clinical dose of 120 mg in humans [14,15]. Also, the doses for fluvastatin used in the present study were selected based on the previous report [22] as well as assay sensitivity. Fexofenadine was dissolved in ethanol and water (1:10) for oral administration and in saline (0.9%) for i.v. administration. Fluvastatin was dissolved in the distilled water for oral administration and in saline (0.9%) for i.v. administration. Blood samples were collected from the femoral artery at 0, 0.05, 0.16, 0.25, 0.5, 1, 2, 4, 8, 12, 24 h following an intravenous administration. Blood samples were also collected from the femoral artery at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12, 24 h following an oral administration. Blood samples were centrifuged and the obtained plasma was stored at −70 ◦ C until analyzed.
Noncompartmental pharmacokinetic analysis was performed using the WinNonlin® version 5.2 (Pharsight Corporation, Mountain View, CA, USA). The elimination rate constant (Kel ) was estimated from the slope of the terminal phase of the log plasma concentration–time points fitted by the method of least-squares and the terminal half-life (T1/2 ) was calculated by 0.693/Kel . The peak concentration (Cmax ) and the time to reach peak concentration (Tmax ) of drug in plasma were obtained by visual inspection of the data from the concentration–time curve. The area under the plasma concentration–time curve (AUC0–t ) from time zero to the time of last measured concentration (Clast ) was calculated by the linear trapezoidal rule. The AUC from time zero to infinite (AUC0–∞ ) was obtained by the addition of AUC0–t and the extrapolated area determined by Clast /Kel . Total plasma clearance (CL) was calculated by dose/AUC. The absolute bioavailability (A.B.) of drug was calculated by AUCp.o. /AUCi.v. × dosei.v. /dosep.o. × 100. The relative bioavailability (R.B.) of fexofenadine was estimated by AUCfexofenadine with fluvastatin /AUC fexofenadine × 100 and the R.B. of fluvastatin was estimated by AUCfluvastatin with fexofenadine / AUCfluvastatin × 100. 2.5. Statistical analysis All mean values were presented with their standard deviation (mean ± S.D.). Statistical analysis was conducted using a one-way ANOVA followed by a posteriori testing with Dunnett correction. A p value less than 0.05 was considered statistically significant.
2.3. HPLC assay 3. Results 2.3.1. Fexofenadine Plasma concentration of fexofenadine was determined by the HPLC method described as follows. In brief, 10 l of piroxicam (10 g/ml) as an internal standard was added to 90 l of each plasma sample and then the mixture was deproteinized by adding 200 l of acetonitrile. After centrifugation of the samples at 13,000 × g for 10 min, the supernatant was evaporated and the residue was reconstituted with 120 l of the mobile phase, and then 50 l of aliquots were injected directly into the HPLC system (Perkin Elmer Series 200; Waltham, MA, USA). The octadecylsilane column (Gemini C18, 4.6 mm × 150 mm, 5 m; Phenomenex, Torrance, CA, USA) was eluted with the mobile phase consisting of 0.1 M triethylamine:acetonitrile:methanol (61:19.5:19.5, v/v/v%, pH 4.4 adjusted with phosphoric acid) at a flow rate of 1.0 ml/min. The UV detector set at 195 nm. The calibration curve from the standard samples was linear over the concentration range of 0.01–0.5 g/ml. The detection limit of fexofenadine was 0.01 g/ml.
3.1. Altered pharmacokinetics of fexofenadine in the presence of fluvastatin The mean plasma concentration–time profiles of fexofenadine in the presence and the absence of fluvastatin were characterized in rats and illustrated in Figs. 1 and 2. The mean pharmacokinetic parameters of fexofenadine were also summarized in Tables 1 and 2. As shown in Table 1, the pretreatment with fluvastatin (5 or 10 mg/kg) significantly altered the oral exposure of fexofenadine compared to the control group given fexofenadine alone. The Cmax and AUC of fexofenadine decreased by 28–60% and 47–53%, respectively via the concurrent use of 5 or 10 mg/kg of fluvastatin. Consequently, the absolute and relative bioavailability values of fexofenadine decreased significantly (p < 0.05) under the pretreatment with fluvastatin. However, there was no significant change in Tmax and terminal plasma half-life (T1/2 ) of fexofenadine in the presence
F. Qiang et al. / European Journal of Pharmaceutical Sciences 37 (2009) 413–417
Fig. 1. Mean plasma concentration–time profiles of fexofenadine following an oral administration of fexofenadine (10 mg/kg) to rats in the presence and the absence of fluvastatin (5 or 10 mg/kg) (mean ± S.D., n = 6). () fexofenadine alone, () pretreatment with 5 mg/kg of fluvastatin, () pretreatment with 10 mg/kg of fluvastatin.
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Fig. 2. Mean plasma concentration–time profiles of fexofenadine following an intravenous administration of fexofenadine (5 mg/kg) to rats in the presence and the absence of fluvastatin (10 mg/kg, p.o.) (mean ± S.D., n = 6). () fexofenadine alone, () pretreatment with 10 mg/kg of oral fluvastatin.
of fluvastatin (Table 1). The intravenous pharmacokinetic profiles of fexofenadine were also evaluated in the presence and the absence of fluvastatin in rats (Table 2 and Fig. 2). In contrast to oral fexofenadine, fluvastatin had no effect on the pharmacokinetic profiles of intravenous fexofenadine.
pharmacokinetics of intravenous fluvastatin was also significantly altered by the pretreatment with fexofenadine. Plasma clearance of fluvastatin was reduced by 44% under the pretreatment with fexofenadine, leading to the increased systemic exposure of fluvastatin in the presence of fexofenadine. Collectively, the concurrent use of fexofenadine significantly altered the intravenous as well as oral pharmacokinetics of fluvastatin in rats.
3.2. Pharmacokinetic characteristics of fluvastatin in the presence of fexofenadine Mean plasma concentration–time profiles of fluvastatin following an oral administration of fluvastatin in the presence and the absence of fexofenadine were shown in Figs. 3 and 4. The mean pharmacokinetic parameters were also summarized in Tables 1 and 2. The oral exposure of fluvastatin decreased by 17–51% in the presence of fexofenadine. As a result, the relative bioavailability of fluvastatin was decreased to 49–83% after the concomitant use of fexofenadine. The effect of fexofenadine reducing the oral exposure of fluvastatin was dose proportional over the dose range of 10–20 mg/kg. Furthermore, as summarized in Fig. 4 and Table 2, the
4. Discussion Combination therapies are widely used for drugs in many different therapeutic classes and this co-medication increases the risk for significant drug–drug interactions. Therefore, it is important to address potential DDI risks relevant for the respective patient population by using appropriate in vitro/in vivo studies to guide clinical interaction studies. While transporter-mediated DDIs are clinically
Table 1 Pharmacokinetic parameters of fexofenadine and fluvastatin after an oral administration of fexofenadine (10 mg/kg) or fluvastatin (5 mg/kg) to rats (mean ± S.D., n = 6). Fexofenadine (10 mg/kg) Alone
a *
Pretreatment with fluvastatin
0.25 ± 0.27 0.7 ± 0.6 0.70 ± 0.40 6.4 ± 2.3 4.6 ± 3.1 100
Cmax (g/ml) Tmax (h) AUClast (g h/ml)a T1/2 (h) A.B. (%) R.B. (%)
Fluvastatin (5 mg/kg)
5 mg/kg
10 mg/kg
0.18 ± 0.07 0.3 ± 0.2 0.37 ± 0.19 4.5 ± 1.3 2.4 ± 1.4 51
0.10 ± 0.04 0.5 ± 0.2 0.33 ± 0.10* 5.7 ± 2.4 2.1 ± 1.2* 45
Alone
Pretreatment with fexofenadine
2.08 ± 1.10 0.8 ± 0.4 9.95 ± 3.10 8.7 ± 2.5 86.4 ± 23.7 100
10 mg/kg
20 mg/kg
2.06 ± 0.99 0.6 ± 0.2 8.22 ± 2.18 12 ± 4.2 73.8 ± 27.6 83
1.52 ± 0.50 0.6 ± 0.2 4.89 ± 0.60* 11 ± 4.0 43.2 ± 9.0* 49
AUClast : fexofenadine–AUC0–12 , fluvastatin–AUC0–24 . p < 0.05, compared to the control group given fexofenadine or fluvastatin alone.
Table 2 Pharmacokinetic parameters of fexofenadine and fluvastatin after an intravenous administration of fexofenadine (5 mg/kg) or fluvastatin (2 mg/kg) to rats (mean ± S.D., n = 6).
T1/2 (h) CL (l/(h kg)) Vdss (l/kg) AUC0−∞ (g h/ml)* *
Fexofenadine (5 mg/kg)
Fluvastatin (2 mg/kg)
Alone
Alone
11.3 0.62 1.39 7.97
± ± ± ±
Pretreatment with fluvastatin (10 mg/kg, p.o.) 6.3 0.07 0.87 0.90
10.7 0.66 1.96 7.33
± ± ± ±
3.9 0.08 0.37 0.8
p < 0.05, compared to the control group given fluvastatin alone.
9.6 1.23 15.9 4.66
± ± ± ±
Pretreatment with fexofenadine (20 mg/kg, p.o.) 3.3 0.31 3.08 0.96
13.1 0.69 13.1 7.30
± ± ± ±
7.9 0.03* 8.76 1.50*
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Fig. 3. Mean plasma concentration–time profiles of fluvastatin following an oral administration of fluvastatin (5 mg/kg) to rats in the presence and the absence of fexofenadine (10 or 20 mg/kg) (mean ± S.D., n = 6). () fluvastatin alone, () pretreatment with 10 mg/kg of fexofenadine, () pretreatment with 20 mg/kg of fexofenadine.
significant in addition to metabolizing enzyme-mediated DDIs, broad overlap in the substrate specificity between transporters and metabolic enzymes makes it difficult to determine the relative contribution of transporters or enzymes to overall drug interaction of certain drugs. In that sense, fexofenadine can be an ideal probe to study transporter-mediated drug interactions, given that it is a substrate of some transporters such as P-gp and OATPs [9–12] but its metabolism is insignificant [7,8]. Therefore, the present study was focused on the transporter-mediated drug interactions between fexofenadine and fluvastatin, particularly potential drug interaction mediated by OATPs in the consideration that both drugs can interact with OATPs. Kamath et al. [15] have reported that coadministration of orange juice or apple juice with fexofenadine caused a decrease in the oral exposure (AUC and Cmax ) of fexofenadine in rats, suggesting the preferential inhibition of OATPs over P-gp by the components of fruit juice. This observation in rats also appeared to be consistent with the findings in humans by Dresser et al. [14], although the extent of decrease in the oral bioavailability in rats was not as great as that observed in humans [14,15]. The dose of 10 mg/kg
Fig. 4. Mean plasma concentration–time profiles of fluvastatin following an intravenous administration of fluvastatin (2 mg/kg) to rats in the presence and the absence of fexofenadine (20 mg/kg, p.o.) (mean ± S.D., n = 6). () fluvastatin alone, () pretreatment with 20 mg/kg of oral fexofenadine.
used in their rat study corresponded to the 120 mg human dose [14,15]. Therefore, the present study was performed in rats by using 10 mg/kg dose of fexofenadine to evaluate the potential drug interaction mediated by the inhibition of organic anion-transporting polypeptides. As shown in Tables 1 and 2, the concurrent use of fluvastatin significantly reduced the oral exposure of fexofenadine while it did not affect the intravenous pharmacokinetics of fexofenadine. The marked decrease in oral AUC and Cmax values of fexofenadine with no change in Tmax and T1/2 under the pretreatment with fluvastatin should be mainly due to the reduced intestinal absorption of fexofenadine rather than the enhanced systemic elimination. Fexofenadine is a substrate of P-gp expressed in intestine but Pgp is unlikely to play a role in this interaction since the inhibition of P-gp should increase the intestinal absorption of drugs. Fexofenadine is a substrate of organic anion-transporting polypeptides such as human OATP1A2, OATP2B1, and OATP1B3 and rat oatp1, oatp2, and oapt3, which have involved in the hepatic and intestinal uptake of fexofenadine [11,12,14,23]. Considering that (i) fluvastatin would be at higher concentrations in small intestine than in liver because of extensive presystemic extraction; (ii) the inhibition of drug uptake in liver immediately after drug absorption would act to increase, rather than decrease, the plasma concentrations of fexofenadine; (iii) the intravenous pharmacokinetics of fexofenadine was not affected by the concomitant use of fluvastatin in contrast to oral fexofenadine, the primary mechanism for the decreased oral exposure of fexofenadine is most likely the inhibition of OATPs-mediated intestinal absorption of fexofenadine in the presence of fluvastatin. This is also supported by the previous findings reported by Dresser et al. [14] and Kamath et al. [15]. In their studies, the bioavailability of fexofenadine was greatly reduced by coadministration of grapefruit, orange, and apple juices via the inhibition of OATP-mediated intestinal absorption of fexofenadine in humans and rats [14,15]. Taken together, both fluvastatin and fruit juice exhibited similar inhibition effect on the OATP-mediated oral absorption of fexofenadine. The effect of combination therapy on the pharmacokinetics of fluvastatin was also examined as summarized in Tables 1 and 2. The pretreatment with fexofenadine significantly altered the pharmacokinetics of oral and intravenous fluvastatin compared to the control group given fluvastatin alone. The oral exposure of fluvastatin was significantly reduced by the concurrent use of fexofenadine, implying the competition between two drugs for the OATP-mediated intestinal absorption (Fig. 3). Moreover, the higher fexofenadine concentrations in intestine from higher doses of fexofenadine seemed to affect OATP-mediated intestinal absorption of fluvastatin to a greater extent and thus exhibited an increased inhibition effect on fluvastatin pharmacokinetics (Table 1 and Fig. 3). Active uptake of many statins, such as cerivastatin, fluvastatin, pravastatin, pitavastatin, and rosuvastatin, by OATPs into the liver has been demonstrated in many recent publications [20,21]. Therefore, blocking the active hepatic uptake of fluvastatin mediated by OATPs could cause the significant increase of systemic exposure of fluvastatin. This is strongly supported by the results from the present study. There was marked decrease in plasma clearance of fluvastatin, implying the inhibition of OATPs-mediated hepatic uptake of fluvastatin in the presence of fexofenadine (Table 2). Consequently, the pretreatment with fexofenadine significantly enhanced the systemic exposure of intravenous fluvastatin as illustrated in Fig. 4. Therefore, fexofenadine significantly altered both intravenous and oral pharmacokinetics of fluvastatin probably via the competition for OATPs-mediated intestinal absorption as well as hepatic uptake in rats. Fluvastatin is metabolized by several enzymes including CYP2C9, CYP3A4 and CYP2C8, with CYP2C9 as the major one
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while the role of transporters such as P-gp might not be significant in the disposition of fluvastatin [24,25]. So far the drug interactions affecting fluvastatin disposition have been limited to metabolic interactions, however, clinical observations indicated that the involvement of multiple enzymes in the metabolism of fluvastatin should minimize the effect, in case a coadministered drug inhibits one enzyme [26–28]. In contrast to minimal metabolic interactions, our present findings raised the awareness on the significance of OATPs-mediated drug interaction in the pharmacokinetics of fluvastatin. Given that statins are widely used in clinics to treat dyslipidemia and an increase in the plasma concentration of many of the currently used statins can cause severe side effects [29], our present study also suggests that the clinical evaluation of drug interaction potential mediated by OATPs with statins is of great importance for the clinical safety. In summary, the concurrent use of fexofenadine and fluvastatin changed the systemic exposure of each drug significantly (p < 0.05) via the inhibition of OATPs in rats. The affinity and capacity of fexofenadine and fluvastatin for OATPs could be different in rat and human. Therefore, the clinical implication of current findings should be further investigated in clinical studies in order to confirm whether their concomitant use should need medical supervision or not. 5. Conclusion The present study suggests that there might be potential drug interaction between fluvastatin and fexofenadine mediated by organic anion-transporting polypeptides expressed in small intestine and liver. Acknowledgement This study was supported by the research grant from Chosun University (2008). References Hagenbuch, B., Gui, C., 2008. Xenobiotic transporters of the human organic anion transporting polypeptides (OATP) family. Xenobiotica 38, 778–801. Niemi, M., 2007. Role of OATP transporters in the disposition of drugs. Pharmacogenomics 8, 787–802. Mikkaichi, T., Suzuki, T., Tanemoto, M., Ito, S., Abe, T., 2004. The organic anion transporter (OATP) family. Drug Metab. Pharmacokinet. 19, 171–179. Leucuta, S.E., Vlase, L., 2006. Pharmacokinetics and metabolic drug interactions. Curr. Clin. Pharmacol. 1, 5–20. Pal, D., Mitra, A.K., 2006. MDR-and CYP3A4-mediated drug–drug interactions. J. Neuroimmun. Pharmacol. 1, 323–339. Simpson, K., Jarvis, B., 2000. Fexofenadine: a review of its use in the management of seasonal allergic rhinitis and chronic idiopathic urticaria. Drugs 59, 301–321. Devillier, P., Roche, N., Faisy, C., 2008. Clinical pharmacokinetics and pharmacodynamics of desloratadine, fexofenadine and levocetirizine: a comparative review. Clin. Pharmacokinet. 47, 217–230.
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