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BACKGROUND AND OBJECTIVES: We aimed to study the impact of size, maturation and cytochrome P450 2D6 (CYP2D6) genotype activity score as predictors of intravenous tramadol disposition.METHODS: Tramadol and O-desmethyl tramadol (M1) observations in 295 human subjects (postmenstrual age 25 weeks to 84.8 years, weight 0.5-186 kg) were pooled. A population pharmacokinetic analysis was performed using a two-compartment model for tramadol and two additional M1 compartments. Covariate analysis included weight, age, sex, disease characteristics (healthy subject or patient) and CYP2D6 genotype activity. A sigmoid maturation model was used to describe age-related changes in tramadol clearance (CLPO), M1 formation clearance (CLPM) and M1 elimination clearance (CLMO). A phenotype-based mixture model was used to identify CLPM polymorphism.RESULTS: Differences in clearances were largely accounted for by maturation and size. The time to reach 50 % of adult clearance (TM50) values was used to describe maturation. CLPM (TM50 39.8 weeks) and CLPO (TM50 39.1 weeks) displayed fast maturation, while CLMO matured slower, similar to glomerular filtration rate (TM50 47 weeks). The phenotype-based mixture model identified a slow and a faster metabolizer group. Slow metabolizers comprised 9.8 % of subjects with 19.4 % of faster metabolizer CLPM. Low CYP2D6 genotype activity was associated with lower (25 %) than faster metabolizer CLPM, but only 32 % of those with low genotype activity were in the slow metabolizer group.CONCLUSIONS: Maturation and size are key predictors of variability. A two-group polymorphism was identified based on phenotypic M1 formation clearance. Maturation of tramadol elimination occurs early (50 % of adult value at term gestation).

Udgivelsesdato: 2009-Apr Oxycodone is O-demethylated by CYP2D6 to oxymorphone which is a potent micro-receptor agonist. The CYP2D6 oxidation polymorphism divides the Caucasian population in two phenotypes: approximately 8% with no enzyme activity, poor metabolizers (PM) and the remainder with preserved CYP2D6 activity, extensive metabolizers (EM). The objective of the study was to determine if the analgesic effect of oxycodone in human experimental pain depends on its metabolism to oxymorphone. The analgesic effect of oxycodone was evaluated in a randomized, placebo-controlled, double-blinded, crossover experiment including 33 (16 EM and 17 PM) healthy volunteers. Pain tests were performed before and 1, 2, 3 and 4 hr after medication and included pain detection and tolerance thresholds to single electrical sural nerve stimulation, pain summation threshold to repetitive electrical sural nerve stimulation and the cold pressor test with rating of discomfort and pain-time area under curve (AUC(0-2 min.)). For single sural nerve stimulation, there was a less pronounced increase in thresholds on oxycodone in pain detection (9% vs. 20%, P = 0.02, a difference of 11%, CI: 2%-20%) and pain tolerance thresholds (15% vs. 26%, P = 0.037, a difference of 10%, CI: 1%-20%) for PM compared with EM. In the cold pressor test, there was less reduction in pain AUC on oxycodone for PM compared with EM (14% vs. 26%, P = 0.012, a difference of 12%, CI: 3%-22%). The plasma oxymorphone/oxycodone ratio was significantly lower in PM compared with EM (P < 0.001). Oxycodone analgesia seems to depend both on oxycodone itself and its metabolite oxymorphone.

OBJECTIVE: The aim of this study was to determine the intrapair similarity in trough steady-state plasma concentrations of metformin in monozygotic and dizygotic twin pairs.METHODS: We included 16 twin pairs (eight monozygotic and eight dizygotic twin pairs) for this study after contacting 524 twin pairs. They were dosed with metformin to steady state (1 g twice daily) for 6 days and on day 7, the trough concentration of metformin was determined 12 h after the last dose.RESULTS: There was no strong intrapair similarity in trough steady-state plasma concentrations of metformin in either dizygotic or monozygotic twin pairs.CONCLUSION: The trough steady-state plasma concentration of metformin does not appear to be tightly genetically regulated. The interpretation of this finding is limited by the small sample size. OBJECTIVE: The aim of this study was to determine the intrapair similarity in trough steady-state plasma concentrations of metformin in monozygotic and dizygotic twin pairs.METHODS: We included 16 twin pairs (eight monozygotic and eight dizygotic twin pairs) for this study after contacting 524 twin pairs. They were dosed with metformin to steady state (1 g twice daily) for 6 days and on day 7, the trough concentration of metformin was determined 12 h after the last dose.RESULTS: There was no strong intrapair similarity in trough steady-state plasma concentrations of metformin in either dizygotic or monozygotic twin pairs.CONCLUSION: The trough steady-state plasma concentration of metformin does not appear to be tightly genetically regulated. The interpretation of this finding is limited by the small sample size.

To describe in detail the intravenous, single oral and multiple oral dose enantioselective pharmacokinetics of tramadol in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs).Eight EMs and eight PMs conducted three phases as an open-label cross-over trial with different formulations; 150 mg single oral tramadol hydrochloride, 50 mg single oral tramadol hydrochloride every 8 h for 48 h (steady state), 100 mg intravenous tramadol hydrochloride. Urine and plasma concentrations of (+/-)-tramadol and (+/-)-M1 were determined for 48 h after administration.In all three phases, there were significant differences between EMs and PMs in AUC and t(1/2) of (+)-tramadol (Por =0.0015), (-)-tramadol (Por =0.0062), (+)-M1 (Por =0.0198) and (-)-M1 (Por =0.0370), and significant differences in C(max) of (+)-M1 (P0.0001) and (-)-M1 (Por =0.0010). In Phase A and C, significant differences in t(max) were seen for (+)-M1 (Por =0.0200). There were no statistical differences between the absolute bioavailability of tramadol in EMs and PMs. The urinary recoveries of (+)-tramadol, (-)-tramadol, (+)-M1 and (-)-M1 were statistically significantly different in EMs and PMs (P0.05). Median antimodes of the urinary metabolic ratios of (+)-tramadol / (+)-M1 and (-)-M1 were 5.0 and 1.5, respectively, hereby clearly separating EMs and PMs in all three phases.The impact of CYP2D6 phenotype on tramadol pharmacokinetics was similar after single oral, multiple oral and intravenous administration displaying significant pharmacokinetic differences between EMs and PMs of (+)-tramadol, (-)-tramadol, -(+)-M1 and (-)-M1. The O-demethylation of tramadol was catalysed stereospecific by CYP2D6 in the way that very little (+)-M1 was produced in PMs.

Background and Objective Polymorphic cytochrome P450 (CYP) 2D6 activity has been shown to be a determinant of the pharmacokinetics and pharmacodynamics of tramadol via hepatic phase I O-demethylation of (+)-tramadol to (+)-O-desmethyltramadol. Our objective was to investigate whether tramadol can be used as a probe for CYP2D6 phenotyping by determining the concordance between the 8-hour tramadol and 12-hour sparteine metabolic urinary ratios. Methods Sparteine phenotyping test was carried out in 278 healthy, white subjects. At a minimum of 2 weeks later, each subject took 50 mg tramadol hydrochloride followed by 8-hour urine collection, and a venous blood sample was drawn from 276 subjects. Urine and plasma concentrations of (+/−)-tramadol and (+/−)-O-desmethyltramadol were determined. CYP2D6 genotyping was performed with regard to *3, *4, *6, and *9 alleles. Results There were 28 poor metabolizers of sparteine (10.1% [confidence interval, 6.8%-14.2%]). Very low recoveries of (+)-M1 were found in poor metabolizers (0.53% [range, 0.1%-1.1%]) compared with extensive metabolizers (8.7% [range, 1.7%-23.2%]). A bimodal distribution of the metabolic ratio of (−)-M1/(+)-M1 was found. The visual antimode was 2.0. This new phenotype test had only 1 misclassified subject compared with sparteine phenotyping (sensitivity and negative predictive value, 100% specificity, 99.6% positive predictive value, 96.6%). Of the 28 sparteine poor metabolizers, 26 were found to be genotypically poor metabolizers with regard to the inactivating mutations *3, *4, and *6. Conclusion Fifty milligrams of tramadol is an alternative CYP2D6 phenotype probe by use of the 8-hour urinary ratio of (−)-M1/(+)-M1. The poor metabolizers have a metabolic ratio of 2.0 or higher. Clinical Pharmacology & Therapeutics (2005) 77, 458–467; doi: 10.1016/j.clpt.2005.01.014

Objective Tramadol hydrochloride (INN, tramadol) exerts its antinociceptive action through a monoaminergic effect mediated by the parent compound and an opioid effect mediated mainly by the O-demethylated metabolite (+)-M1. O-demethylation is catalyzed by cytochrome P450 (CYP) 2D6. Paroxetine is a very potent inhibitor of CYP2D6. The objective of this study was to investigate the influence of paroxetine pretreatment on the biotransformation and the hypoalgesic effect of tramadol. Methods With and without paroxetine pretreatment (20 mg daily for 3 consecutive days), the formation of M1 and the analgesic effect of 150 mg of tramadol were studied in 16 healthy extensive metabolizers of sparteine in a randomized, double-blind, placebo-controlled, 4-way crossover study by use of experimental pain models. Results With paroxetine pretreatment, the area under the plasma concentration-time curve (AUC) of (+)- and (−)-tramadol was increased (37% [P = .001] and 32% [P = .002], respectively), and the corresponding AUCs of (+)- and (−)-M1 were decreased (67% [P = .0004] and 40% [P = .0008], respectively). (+)-M1 and (−)-M1 could be determined in all subjects throughout the study period regardless of paroxetine pretreatment. The sums of differences between postmedication and premedication values of pain measures differed between the placebo/tramadol and the placebo/placebo combination, with median values as follows: pressure pain tolerance threshold, 390 kPa (95% confidence interval [CI], 211 to 637 kPa) versus −84 kPa (95% CI, − 492 to −32 kPa) (P = .001); single sural nerve stimulation pain tolerance threshold, 25.8 mA (95% CI, 15.3 to 29.8 mA) versus 9.0 mA (95% CI, 1.5 to 14.8 mA) (P = .005); pain summation threshold, 10.7 mA (95% CI, 5.2 to 17.6 mA) versus 5.0 mA (95% CI, 2.8 to 11.2 mA) (P = .066); cold pressor pain, −4.2 cm · s (95% CI, −6.8 to −1.9 cm · s) versus −0.4 cm · s (− 1.4 to 1.4 cm · s) (P = .002); and discomfort, −4.7 cm (95% CI, −10.6 to −2.8 cm) versus 0.5 cm (−0.1 to 1.4 cm) (P = .002). The sums of differences of the paroxetine/tramadol combination also differed from placebo/tramadol for some of the measures, with median values as follows: cold pressor pain, −2.2 cm · s (95% CI, −3.7 to −0.4 cm · s) (P = .036, compared with placebo/tramadol); and discomfort, −2.0 cm (95% CI, −5.6 to −1.2 cm) (P = .056). For the other measures, the hypoalgesic effect was retained on the paroxetine/tramadol combination, with median values as follows: pressure pain tolerance threshold, 389 kPa (95% CI, 141 to 715 kPa) (P = .278, compared with placebo/tramadol); single sural nerve stimulation pain tolerance threshold, 12.5 mA (95% CI, 6.2 to 28.3 mA) (P = .278); and pain summation threshold, 8.2 mA (95% CI, 4.4 to 14.6 mA) (P = .179). Paroxetine in combination with placebo showed no analgesic effect. Conclusions It is concluded that paroxetine at a dosage of 20 mg once daily for 3 consecutive days significantly inhibits the metabolism of tramadol to its active metabolite M1 and reduces but does not abolish the hypoalgesic effect of tramadol in human experimental pain models, particularly in opioid-sensitive tests. Clinical Pharmacology & Therapeutics (2005) 77, 312–323; doi: 10.1016/j.clpt.2004.11.002

Background: A four-drug cytochrome P450 (CYP) phenotyping cocktail was developed to rapidly and safely determine CYP2D6, CYP2C19, CYP2C9 and CYP1A2 enzyme activity and phenotype. Methods: The cocktail consisted of the single CYP phenotyping probes of 50 mg tramadol (CYP2D6), 20 mg omeprazole (CYP2C19), 25 mg losartan (CYP2C9) and 200 mg caffeine (CYP1A2) and was administered as a single oral dose. For enzyme activity measurements, urine was collected as 8 h post-administration and blood was sampled at 4 h. The enzyme activity was determined by metabolic ratios of molar concentrations of the drugs and their enzyme catalyzed metabolites and was correlated to the relevant genotypes. Results: In a pilot study in 12 healthy male volunteers the CYP genotype-phenotype correlation and robustness of the cocktail was successfully determined without detection of any adverse drug reactions. In the subsequent population study, four female volunteers experienced unexpected and unacceptable moderate and severe adverse reactions (ARs) of headache, dizziness, nausea, vomiting, blue fingers, nails and lips and difficulties in urinating, which led to the study being prematurely terminated after inclusion of only 25 subjects (17 males, 7 females). Conclusion: Attention must be paid to adverse reactions when designing new combinations of phenotype cocktails regardless of the doses and drugs involved. We specifically warn against the combination of tramadol, omeprazole, losartan and caffeine.

The aim of the present study was to determine the impact of CYP2C19*17 on the pharmacokinetics and pharmacodynamics of the active metabolite of clopidogrel and the pharmacokinetics of proguanil. Thus, we conducted an open-label two-phase cross-over study in 31 healthy male volunteers (11 CYP2C19*1/*1, 11 CYP2C19*1/*17 and nine CYP2C19*17/*17). In Phase A, the pharmacokinetics of the derivatized active metabolite of clopidogrel (CAMD) and platelet function were determined after administration of a single oral dose of 600 mg clopidogrel (Plavix; Sanofi-Avensis, Horsholm, Denmark). In Phase B, the pharmacokinetics of proguanil and its metabolites cycloguanil and 4-chlorphenylbiguanide (4-CPB) were determined in 29 of 31 subjects after a single oral dose of 200 mg proguanil given as the combination drug Malarone (GlaxoSmithKline Pharma, Brondby, Denmark). Significant correlations were found between the area under the time-concentration curve (AUC0-∞ ) of CAMD and both the absolute ADP-induced P2Y12 receptor-activated platelet aggregation (r = -0.60, P = 0.0007) and the percentage inhibition of aggregation (r = 0.59, P = 0.0009). In addition, the CYP2C19*17/*17 and CYP2C19*1/*17 genotype groups had significantly higher percentage inhibition of platelet aggregation compared with the CYP2C19*1/*1 subjects (geometric mean percentage inhibition of 84%, 73% and 63%, respectively; P = 0.014). Neither the absolute ADP-induced P2Y12 receptor-activated platelet aggregation, exposure to CAMD nor the pharmacokinetic parameters of proguanil, cycloguanil and 4-CPB exhibited any significant differences among the genotype groups. In conclusion, carriers of CYP2C19*17 exhibit higher percentage inhibition of platelet aggregation, but do not have significantly lower absolute P2Y12 receptor-activated platelet aggregation or higher exposure to the active metabolite after a single oral administration of 600 mg clopidogrel.

OBJECTIVE: The aim of this study was to determine the association between the renal clearance (CLrenal) of metformin in healthy Caucasian volunteers and the single-nucleotide polymorphism (SNP) c.808G>T (rs316019) in OCT2 as well as the relevance of the gene-gene interactions between this SNP and (a) the promoter SNP g.-66T>C (rs2252281) in MATE1 and (b) the OCT1 reduced-function diplotypes. METHODS: Fifty healthy volunteers genotyped for the c.808G>T were enrolled in the study. The distribution was 25 GG, 20 GT, and 5 TT volunteers. The pharmacokinetics of a 500 mg single oral dose of metformin was studied. RESULTS: When analyzed alone, the c.808 (G>T) affected neither the CLrenal nor the secretory clearance (CLsec) of metformin. However, both CLrenal and CLsec were increased for the volunteers with minor alleles in c.808 (G>T) who were also homozygous for the reference variant g.-66T>C: CLrenal: GG, GT, and TT: 28.1, 34.5, and 44.8 l/h (P=0.004), respectively and CLsec: GG, GT, and TT: 21.4, 27.8, and 37.6 l/h (P=0.005), respectively. In the volunteers with minor alleles in c.808 (G>T) who were also heterozygous for g.-66T>C, both CLrenal and CLsec were found to be reduced (PT) carrying the g.-66T>C reference genotype. CONCLUSION: We report counteracting effects of the c.808 (G>T) and g.-66T>C on the renal elimination of metformin. When adjusted for the genetic variation g.-66T>C, our results suggest that c.808 (G>T) could have a dominant genotype to phenotype correlation.

PURPOSE: To investigate paroxetine's putative dose-dependent impact on pupil reaction and inhibition of the O-demethylation of tramadol.METHODS: Twelve healthy CYP2D6 extensive metabolizers participated in this double-blinded randomized five-way placebo controlled cross-over study; they received placebo, 10, 20, 30, and 50 mg paroxetine as single oral doses at bedtime. Next morning the pupil was measured followed by oral intake of 50 mg of tramadol, and urine was collected for 8 h. Three hours after ingestion of tramadol a second measurement of the pupil was performed. Enantioselective urine concentrations of (+/-)-tramadol and (+/-)-O-desmethyltramadol (M1) were determined.RESULTS: With placebo, the median maximum pupil diameter was 6.43 mm (range 5.45-7.75 mm) before tramadol and 6.22 mm (4.35-7.65 mm) after 50 mg of tramadol (P = 0.4935). Paroxetine resulted in a statistically significant, dose-dependent dilatation of the pupil with a geometric mean difference of 1.17 (95% CI 1.10-1.24) after ingestion of 50 mg paroxetine (P < 0.001). Likewise, a reduction in the relative constriction amplitude with a geometric mean difference of 0.81 (95% CI 0.71-0.92) (P < 0.001) was seen. A dose-dependent inhibition of the metabolism of tramadol by an increase in the two urinary metabolic ratios (+)-tramadol / (+)-M1 [geometric mean difference 9.09, 95% CI 5.60-14.73 (P < 0.001)] and (-)-M1 / (+)-M1 [geometric mean difference 2.84, 95% CI 2.15-3.77 (P < 0.001)] was also observed.CONCLUSIONS: Paroxetine is a dose-dependent dilator of the pupil and as expected a dose-dependent inhibitor of (+)-tramadol's O-demethylation.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The only existing study of CYP2C19*17-associated alterations in drug pharmacokinetics was retrospective and compared probe drug metabolic ratios. • The CYP2C19*17 allele had been associated with a two- and fourfold decrease in omeprazole and S/R-mephenytoin metabolic ratios. WHAT THIS STUDY ADDS • This study characterized the single-dose pharmacokinetics of omeprazole, along with the 5-hydroxy and sulphone metabolites, in CYP2C19*17/*17 and CYP2C19*1/*1 subjects. • The observed differences in omeprazole AUC∞ suggest that the CYP2C19*17 allele is an important explanatory factor behind individual cases of therapeutic failure. AIMS To investigate the influence of the CYP2C19*17 allele on the pharmacokinetics of omeprazole, a commonly used CYP2C19 probe drug, in healthy volunteers. METHODS In a single-dose pharmacokinetic study, 17 healthy White volunteers genotyped as either CYP2C19*17/*17 or CYP2C19*1/*1 received an oral dose of 40 mg of omeprazole. Plasma was sampled for up to 10 h postdose, followed by quantification of omeprazole, 5-hydroxy omeprazole and omeprazole sulphone by high-performance liquid chromatography. RESULTS The mean omeprazole AUC∞ of 1973 h nmol l−1 in CYP2C19*17/*17 subjects was 2.1-fold lower [95% confidence interval (CI) 1.1, 3.3] than in CYP2C19*1/*1 subjects (4151 h nmol l−1, P = 0.04). A similar trend was observed for the sulphone metabolite with the CYP2C19*17/*17 group having a mean AUC∞ of 1083 h nmol l−1, 3.1-fold lower (95% CI 1.2, 5.5) than the CYP2C19*1/*1 group (3343 h nmol l−1, P = 0.03). A pronounced correlation (r2 = 0.95, P

Ultrarapid drug metabolism of antidepressants has been associated with therapeutic failures. The CYP2C19*17 allele has been associated with higher levels of CYP2C19 gene transcription and increased rates of omeprazole and mephenytoin metabolism. The aim of this study was to compare the impact of the CYP2C19*17 allele on omeprazole single-dose kinetics with escitalopram exposure at steady state in volunteers genotyped as either CYP2C19*17/*17 or CYP2C19*1/*1. Sixteen healthy volunteers participated in both study parts, five homozygous for CYP2C19*17 and 11 homozygous for CYP2C19*1. Individual pharmacokinetic parameters were determined after single-dose omeprazole of 40 mg and after 1 week on escitalopram 5 mg b.i.d. Escitalopram area under the concentration time curve from zero to 12 h (AUC0–12h) was 21% lower in homozygous carriers of CYP2C19*17 compared with CYP2C19*1 (p = 0.08). There was a significant correlation between escitalopram exposure at steady state and the single-dose kinetics of omeprazole (Spearman correlation coefficient of 0.67; p = 0.006). Based on our investigation using two different CYP2C19 substrates, we concluded that a clinically significant difference in escitalopram or omeprazole kinetics between the genotypes appears unlikely.

AIMS: To determine the effect of CYP2C8 genotype and of fluvoxamine on the pharmacokinetics of rosiglitazone.METHODS: Twenty-three healthy subjects with the following genotypes were included in a two-phase, open-label, cross-over trial: CYP2C8*3/ *3 (n = 3), CYP2C8*1/ *3 (n = 10) and CYP2C8*1/ *1 (n = 10). In Phase A, the subjects were given 4 mg rosiglitazone as a single oral dose. In Phase B, the subjects were treated with multiple oral doses of 50 mg fluvoxamine maleate for 3 days prior to the single oral administration of 4 mg rosiglitazone. Plasma concentrations of rosiglitazone and relative amounts of N-desmethylrosiglitazone were measured in both phases for 24 h after drug administration.RESULTS: The pharmacokinetics of rosiglitazone and N-desmethylrosiglitazone were not significantly different between the CYP2C8 genotypic groups. Fluvoxamine caused a statistically significant (P = 0.0066) increase in the AUC(0-infinity) of rosiglitazone, with a geometric mean ratio of 1.21 [95% confidence interval (CI) 1.06-1.39]. The elimination half-life (t(1/2)) was also significantly higher (P = 0.0203) with a geometric mean ratio of 1.38 [95% CI 1.06-1.79]. The coadministration of fluvoxamine had no influence on the pharmacokinetics of N-desmethylrosiglitazone.CONCLUSION: The importance of the CYP2C8*3 mutation in the in vivo metabolism of rosiglitazone could not be confirmed. Fluvoxamine increased the AUC(0-infinity) and t(1/2) of rosiglitazone moderately and hence may be a weak inhibitor of CYP2C8.

The human CYP2C is a subfamily of P450 enzymes that metabolize approximately 20% of clinically used drugs (Goldstein 2001). The four members of the subfamily are: CYP2C8, CYP2C9, CYP2C18 and CYP2C19. CYP2C9 is an enzyme of major importance in human drug metabolism. Substrates for CYP2C9 include phenytoin (Banpai et al. 1996), S-warfarin (Rettie et al. 1992), acenocoumarol (Verstuyft et al. 2003a), losartan (Stearns et al. 1995), tolbutamide (Miners & Birkett 1996), glipizide (Kidd et al. 1999), fluvastatin (Kirchheiner et al. 2003) and some NSAIDs (Miners & Birkett 1998). Six different human CYP2C9 cDNA sequences have been reported to make the enzyme polymorphic (Stubbins et al. 1996). Since the wildtype CYP2C9*1 and the single nucleotide polymorphisms CYP2C9*2 and CYP2C9*3 were discovered first, they have undergone more thorough investigation showing that the allelic variants CYP2C9*2 and CYP2C9*3 encode enzymes with decreased substrate turnover (Craig et al. 2002; Kirchheiner et al. 2002; Shon et al. 2002). The CYP2C9*2 allele, which is derived from a C430»T single nucleotide polymorphism in exon 3, encodes the Arg144»Cys substitution, whereas a A1075»C single nucleotide polymorphism in exon 7 results in the substitution Ile359»Leu for CYP2C9*3 (Stubbins et al. 1996). The allele frequencies of CYP2C9*1, CYP2C9*2 and CYP2C9*3 and the genotype frequencies of CYP2C9*1/*1, CYP2C9*1/*2, CYP2C9*1/*3, CYP2C9*2/*2, CYP2C9*2/ *3 and CYP2C9*3/*3 for a Nordic population in Denmark were determined. Two hundred seventy-six healthy Nordic (mainly Danish) volunteers of Caucasian origin were enrolled in the study. The 154 males and 122 females aged 19–42 were primarily students at the University of Southern Denmark. The pro

The aim of this study was to investigate the pharmacokinetics of loratadine and its active metabolite desloratadine after single-dose administration of loratadine as a conventional tablet, orally disintegrating tablet (smelt tablet) and a chewing gum formulation with and without the collection of saliva.Twelve healthy male volunteers participated in a four-period cross-over trial evaluating the effect of dosage forms on the pharmacokinetics of a single dose of loratadine. Loratadine was administered as two 10-mg conventional tablet, two 10-mg smelt tablet, a 30-mg portion of medicated chewing gum without collection of saliva and a 30-mg portion of medicated chewing gum with collection of saliva. Blood samples were taken at predefined sampling points 0-24 h after medication, and the plasma concentrations of loratadine and desloratadine were determined by high-performance liquid chromatography. Each study period was separated by a wash-out period of at least 7 days.The mean dose-corrected area under the plasma concentration-time curve extrapolated to infinity AUC(0-infinity) for the chewing gum formulation was statistically significantly increased compared to the tablet formulation (geometric mean ratio: 2.68; 95%CI: 1.75-4.09). Desloratadine pharmacokinetic parameters from the chewing gum formulation were not statistically significantly different from the conventional tablet. Neither loratadine nor desloratadine pharmacokinetics of the smelt tablet formulation were statistically significantly different from the conventional tablet formulation. Plasma concentrations of desloratadine following the administration of loratadine as chewing gum with saliva collection were very low.Our study showed that formulation of loratadine as a medicated chewing gum results in an almost threefold increase in relative bioavailability. This is most likely due to a bypass of first-pass metabolism as this study suggests that approximately 40% of the absorbed loratadine was absorbed via the oral mucosa.