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AGONIST, AFTER A SINGLE ORAL AND INTRAVENOUS DOSE IN HUMANS
Department of Experimental Medicine, Drug Metabolism and Pharmacokinetics, & Bioanalytical Chemistry and Clinical Science, AstraZeneca R&D, Mölndal, Sweden
(Received January 12, 2004; accepted June 1, 2004)
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Abstract |
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and 
agonist, were studied in eight healthy male subjects. The subjects initially received either a single oral or intravenous (i.v.) dose of 1 mg of [14C]tesaglitazar. After a washout period, they received 1 mg of nonlabeled tesaglitazar via the alternative administration route. Serial blood samples and complete urine and feces were collected until 336 h postdose. Tesaglitazar absorption was rapid, with maximum plasma concentration (Cmax) at 
1 h postdose, and the absolute bioavailability was approximately 100%, suggesting no, or negligible, first-pass metabolism. Mean plasma clearance was 0.16 l/h and the volume of distribution at steady state was 9.1 liters. After either route of administration, the plasma concentration-time profiles of radioactivity and tesaglitazar were virtually identical, indicating low systemic metabolite concentrations and formation rate limitation of metabolite elimination. The elimination half-life of radioactivity and tesaglitazar was 45 h. Radioactivity recovery was complete in all subjects, with mean values of 99.9% (i.v.) and 99.6% (oral). Tesaglitazar was mainly metabolized before excretion, and most radioactivity (91%) was recovered in urine. Approximately 20% of the dose was recovered unchanged after either administration route, resulting in a renal clearance of 0.030 l/h. Most of the radioactivity in urine was identified as acyl glucuronide of tesaglitazar. Plasma protein binding of tesaglitazar was high (99.9%), and the mean blood-plasma partitioning ratio was 0.66, suggesting low affinity for red blood cells. There was no indication of partial inversion of the (S)-enantiomer to the corresponding (R)-form. Tesaglitazar was well tolerated.
and agonist (Cronet et al., 2001
; Ljung et al., 2002). The chemical structure and metabolic pathway of tesaglitazar are shown in Fig. 1. The biologically active form of tesaglitazar is the (S)-enantiomer. In vivo studies in the ob/ob mouse and in vitro studies with the (R)-enantiomer have shown that the R-form is approximately 100 times less potent than its antipode (B. Ljung, unpublished data).
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Tesaglitazar has been shown to lower circulating triglyceride, glucose, and insulin levels in ob/ob mice, which are models of type 2 diabetes, and to lower circulating triglyceride and insulin levels in obese, fa/fa Zucker rats, which are models of insulin resistance (Ljung et al., 2002). Also, clinical evaluation has shown that tesaglitazar improves lipid and glucose metabolism, increases insulin sensitivity, and improves the atherogenic lipoprotein profile in patients with dyslipidemia associated with insulin resistance (Fagerberg et al., 2003).
In a dose-escalation study in healthy males who were given single oral tesaglitazar doses, tesaglitazar demonstrated a Cmax within 1 h. The area under the plasma concentration time curve (AUC) and the Cmax increased proportionally with increasing doses, indicating linear pharmacokinetics in the dose range studied (H. Ericsson, unpublished data). In addition, administration of tesaglitazar together with food had no effect on the extent of absorption (AUC), although the rate of absorption was reduced in the fed state (Samuelsson et al., 2003).
The aim of the present study was to evaluate the pharmacokinetics of tesaglitazar, including absorption, distribution, metabolism, and excretion, in healthy male subjects after oral or intravenous (i.v.) administration of single doses of 14C-labeled and unlabeled tesaglitazar. Parts of the study have been presented previously (Ericsson et al., 2003).
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Materials and Methods |
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Subjects and Study Design. Healthy males were enrolled in this two-period, open-label, randomized crossover study (SH-SBC-0002). The following inclusion criteria were used: male, age 30 to 55 years, body mass index 19 to 30 kg/m2, no significant abnormal physical findings (including 12-lead ECG, blood pressure, and heart rate), no laboratory values outside the normal range at the pretreatment physical examination, and signed informed consent to participate in the study. Subjects who required concurrent medication or prescribed medication within 2 weeks of the study start, had donated blood within 12 weeks, were smokers or used other nicotine products, or had a history of any surgical or medical condition known to interfere with absorption, distribution, metabolism, and excretion characteristics of drugs were not allowed to participate in the study. The subjects remained at the laboratory for at least 10 days in period 1 and were discharged from the clinic 7 days after dosing in period 2. The study was conducted in accordance with the Good Clinical Practice guidelines and the Declaration of Helsinki. The Independent Inveresk Research Ethics Committee, Inveresk Research, Tranent, Scotland, approved the protocol before the start of the study.
Dose Administration. Tesaglitazar was given as a single oral or i.v. dose in the morning after fasting overnight. On the first day in study period 1, a 1-mg dose of [14C]tesaglitazar (1.85 MBq) was given as a 50-ml oral solution or as a 50-ml 10-min intravenous infusion. The vehicle used for both oral and i.v. dosing was a 5 mM sodium bicarbonate buffer (pH 8.5). On the first day in study period 2, 1 mg of nonlabeled tesaglitazar was given orally or i.v. (the same dose volume and vehicle as described above) via the alternative administration route in study period 1. The two drug administrations were given 14 days apart.
Collection of Blood Samples and Excreta. On the first day in each study period, blood samples (10 ml) were drawn from an indwelling plastic cannula in the forearm vein (when i.v., contralateral to the infusion arm) and subsequently by venipuncture. After oral dosing, blood samples were collected at the following times: predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96, 120, 144, 192, 240, and 336 h postdose. The same collection schedule was used after i.v. infusion except in the first half-hour when samples were collected 0.17 and 0.33 h after the start of infusion.
Urine was collected predose, at 0 to 6, 6 to 12, and 12 to 24 h on the first day, and then over 24-h periods for at least 10 days after dosing. During a collection interval, collected urine was stored in a refrigerator. At the end of the interval the urine bottles were shaken and weighed and aliquots of the samples were stored frozen (<-15°C) until analysis. Feces were collected over 24-h periods for 10 days after dosing in period 1.
Radioactivity Measurements. The concentration of total radioactivity in plasma, urine, and feces was measured by liquid scintillation counting after mixing the samples with liquid scintillation fluid. Feces samples were homogenized in tap water and combusted using a Packard Tri-Carb Automatic Sample Oxidizer (Canberra Industries, Pangbourne, UK). Radioactivity less than 30 dpm above background was considered to be below the limit of quantification. The total radioactivity in urine and feces was expressed as a percentage of the total administered radioactive dose, and the total radioactivity in plasma was expressed as micromoles of tesaglitazar equivalents per liter.
Plasma and Urine Analysis of Tesaglitazar and Its Corresponding (R)-Enantiomer. Tesaglitazar was analyzed in plasma and urine according to a recently published analytical method (Svennberg et al., 2003). Tesaglitazar and the deuterated (D5) internal standard were extracted from the acidified biological sample by a mixture of dichloromethane and isohexane. After centrifugation, the aqueous phase was frozen and the organic phase transferred to a new tube and evaporated to dryness under nitrogen. After redissolution, an aliquot of the extract was injected onto a Zorbax SB-CN column (50 x 4.6 mm, 3.5-µm particle size; Agilent Technologies, Palo Alto, CA) with acetonitrile in aqueous formic acid-ammonium acetate-sodium acetate as the mobile phase. The retention time for the analytes was approximately 1.5 min. Tesaglitazar and the internal standard were monitored as disodium adduct ions at m/z 267 and m/z 272, and product ions of m/z 453 and m/z 458, respectively, on an API 365 mass spectrometer (Applied Biosystems, Foster City, CA). For [14C]tesaglitazar, the corresponding mass numbers were increased by two units. The limit of quantification (LOQ) for the analytical method was 3 nM [coefficient of variation (CV) <20%] and the CV was less than 5% for concentrations above 10 nM. The enantioselective method for tesaglitazar and for the R-enantiomer in plasma and urine used the same sample work-up procedure, internal standard, and mass spectrometric parameters as the achiral method presented above. The enantioseparation was performed on a Chiralpak AD stationary phase column (50 x 4.6 mm, 10-µm particle size; Daicel Chemical Industries, Tokyo, Japan) using a nonpolar mobile phase of formic acid in a mixture of isopropanol and isohexane. The retention times were 6.4 min for tesaglitazar and 5.1 min for the R-enantiomer. To promote ion formation, a make-up flow of ammonium acetate-sodium acetate in ethanol was added to the mobile phase postcolumn before entering the mass spectrometer. The LOQ was 20 nM for both enantiomers in plasma and 50 nM in urine (CV <20%). Repeatability expressed as CVs was less than 3% at concentrations above 2 to 3 times LOQ.
Metabolic Patterns in Urine and Feces. Metabolic patterns were determined in urine samples collected up to 48 h after dose and in feces samples, where most of the radioactivity was excreted. Urine was centrifuged at 10,000g for 10 min, and the resultant supernatant was injected directly onto the LC column. Feces homogenates were mixed with ammonium acetate buffer (0.1 M, pH 7) and extracted with isohexane. After freezing, the isohexane phase was discarded and the remainder was thawed, mixed with acetonitrile, and centrifuged. The supernatant was passed through a solid-phase column (ChromaBond C18ec, 200 mg) preconditioned with acetonitrile and ammonium acetate buffer (pH 7), centrifuged, and passed through the same solid-phase column. The sample was dried under nitrogen, dissolved in (10%) acetonitrile and centrifuged at 10 000 g for 10 min. The resultant supernatant was injected directly onto the LC column. Less than 0.3% of the radioactivity was found in the preextraction isohexane phase.
A reversed-phase gradient LC system with radiochemical detection was used to record the urinary and fecal metabolic patterns. The LC system consisted of a gradient pump and an autosampler from Hewlett Packard (Palo Alto, CA). The software used for instrument control and for collection and evaluation of data was Hewlett Packard Chemstation and FLO-ONE (PerkinElmer Life and Analytical Sciences, Boston, MA) for LC and radioactivity detection, respectively. The analytical column used was a Supelcosil ABZ+Plus (150 x 4.6 mm i.d.; 5-µm particle size) protected by a Supelguard ABZ+Plus precolumn (20 x 4.0 mm i.d; Supelco, Bellefonte, PA). A gradient of two mobile phases was pumped at a flow of 1 ml/min. Mobile phases A and B consisted of 5% and 70% acetonitrile and a final concentration of 5 mM aqueous ammonium acetate (pH 4), respectively. After sample injection (100 µl), mobile phase B was increased from 0 to 20% in 7 min, from 20 to 25% in 8 min, from 25 to 100% in 10 min, and eventually ran for 15 min at 100%. An equilibration time of 6 min with 100% mobile phase A was allowed before injection of the next sample. The radioactivity in the eluate was continuously measured using a Radiomatic on-line radioactivity detector, model C525TRX (PerkinElmer Life and Analytical Sciences) with a 500-µl flow-cell and scintillation fluid at 3 ml/min (Ultima-FLO AP; PerkinElmer Life and Analytical Sciences). The sample recovery from the column was calculated by comparing the amount of radioactivity eluted from the column with the known amount of radioactivity injected. The overall recovery of applied radioactivity was found to be almost complete (>95%) for urine and feces.
Structural Determination of Metabolites. The chemical structure of metabolites in urine was determined by liquid chromatography (LC)/mass spectrometry using an ion trap mass spectrometer (Thermo Finnigan, San Jose, CA) with an electrospray ionization source. Mass spectra were acquired in the positive ionization mode, and the mass analyzer was scanned over the range m/z 150 to 800. The capillary temperature was set at 200°C. The mass spectrum of a peak in the total ion chromatogram corresponding to a peak in the radio chromatogram was obtained after background subtraction (Xcalibur version 1.0; Thermo Finnigan). The urine was concentrated 8 times with a vacuum evaporator (SpeedVac System AES1010; Savant Instruments, Holbrook, NY) and centrifuged at 10,000g for 10 min before 100 µl of the supernatant was injected into the LC/mass spectrometry system. The gradient LC system was the same as the one described above. Identification of metabolites in urine was based on comparison with synthetic reference compounds in terms of identical LC retention times and mass spectra of metabolites. Due to the low concentration of tesaglitazar and its metabolites in the samples of feces, identification was based on comparison with synthetic reference compounds in terms of identical LC retention times.
Determination of Plasma Protein Binding and Blood-Plasma Partitioning. The plasma protein binding of tesaglitazar was determined in duplicate in vitro by ultrafiltration on five individual human (male) plasma samples at a concentration of 100 µM. Adsorption to the membrane or the ultrafiltration device was negligible. The linearity of the plasma protein binding for tesaglitazar was established in the concentration range 1.25 to 141 µM. Assay of the plasma and ultrafiltrate was performed by LC-tandem mass spectrometry (see above). The free fraction was given as the ratio of concentrations in ultrafiltrate and plasma. Blood-plasma partitioning of [14C]tesaglitazar was determined in freshly collected blood from two male volunteers. Blood was incubated with [14C]tesaglitazar in the concentration range 1.2 to 170 µM. Blood and plasma samples were assayed in duplicate for radioactivity and the blood-plasma partitioning was calculated as the concentration of radioactivity in whole blood divided by the radioactivity in the corresponding plasma samples. The stability of [14C]tesaglitazar was verified for these incubation conditions.
Pharmacokinetic Analysis. Actual sampling times were used in the pharmacokinetic calculations. When [14C]tesaglitazar was administered, the plasma and urine concentrations of tesaglitazar were calculated as the sum of the radiolabeled and nonlabeled tesaglitazar concentrations. The pharmacokinetic parameters were estimated by noncompartmental methods using WinNonlin Pro (version 3.1; Pharsight, Mountain View, CA). The maximum plasma concentrations (Cmax), the time to reach this concentration (tmax), elimination half-life (t1/2), and total AUC were estimated. The AUC was calculated by log-linear trapezoidal rule from time 0 to the time for the last measurable concentration (tlast) plus the extrapolated residual area to infinity. The residual area after tlast was calculated as Clast, pred/
Z, where Clast, pred was the predicted concentration at tlast and Z was the terminal rate constant determined by linear regression analysis of ln plasma concentration versus time, using the last plasma concentrations (between 6 and 9 points) from each subject. The t1/2 was calculated as ln2/Z.
The plasma clearance (CL) and volume of distribution at steady state (Vss) of tesaglitazar were estimated from the intravenous data using standard equations (Wagner, 1976):
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where AUMC is the area under the first moment of the plasma concentration-time curve from time 0 to infinity and TINF is the infusion time. Absolute bioavailability (F) of the oral tesaglitazar solution was determined by the following equation:
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The renal clearance (CLR) of tesaglitazar was calculated as
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where Ae is the total amount excreted unchanged in urine. Descriptive statistics (mean, S.D., minimum and maximum) were used to summarize the data for each pharmacokinetic parameter.
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Results |
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Pharmacokinetics. The mean plasma concentrations of total radioactivity and tesaglitazar versus time following oral and i.v. administration of [14C]tesaglitazar are presented in Fig. 2. The derived pharmacokinetic parameters are presented in Table 1. The plasma concentrations of tesaglitazar were almost identical to the plasma concentrations of total radioactivity after either dosing route, and tesaglitazar accounted for almost the entire radioactivity in plasma at all time points. The AUC0-192h of total radioactivity and tesaglitazar showed that tesaglitazar accounted for more than 90% of the radioactivity in plasma. The oral [14C]tesaglitazar solution (1 mg) was rapidly absorbed, and the mean Cmax was 0.66 µM for radioactivity and 0.61 µM for tesaglitazar. The median time to reach these concentrations, tmax, was 0.5 h for both total radioactivity and tesaglitazar. After a 10-min i.v. infusion of [14C]tesaglitazar (1 mg), the highest concentration of radioactivity was 0.73 µM and the median time to reach this concentration, tmax, was 0.25 h (5 min postinfusion). The highest concentration of tesaglitazar was 0.74 µM. After oral dosing, the absolute bioavailability of tesaglitazar was 100%. The mean CL was 0.16 l/h and the volume of distribution at steady state (Vss) was 9.1 liters. After administration by either route, the initial rapid decline in plasma concentrations of total radioactivity and tesaglitazar was followed by a somewhat slower phase. Eventually, plasma concentrations declined slowly and monoexponentially, and the elimination half-lives of radioactivity and tesaglitazar were virtually identical (45 h; Fig. 2; Table 1).
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Plasma Protein Binding and Blood-Plasma Partitioning of Tesaglitazar. The degree of protein binding was high and concentration-independent. The mean value of the free fraction of tesaglitazar was 0.11% and ranged from 0.10 to 0.13%. The mean blood-to-plasma concentration ratio was 0.66 (range 0.52-0.84).
Metabolite Profile of Tesaglitazar. Metabolic patterns were determined in urine and feces samples. Representative examples of metabolic patterns in urine and feces after oral and i.v. administration are presented in Fig. 3. In the urine samples collected 0 to 48 h after dose administration, a large fraction of the radioactivity had the same retention time as tesaglitazar. This radioactivity fraction accounted for about 14% (oral) and 23% (i.v.) of the given dose. The main metabolite eluted earlier than the unchanged compound and accounted for about 35% (oral) and 32% (i.v.) of the dose given that was excreted within the first 48 h.
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The predominant peak in the samples of feces had the same retention time as tesaglitazar (retention time 25.5 min). Based on LC retention times, there were no qualitative differences in the metabolic patterns in urine between the two routes of administration. The same observation was made for the feces samples.
Identification of Metabolites of Tesaglitazar. The predominant mass peaks in the spectra of tesaglitazar and its metabolites were those of the ammonium adducts ([M + NH4]+), as shown in Fig. 4. The protonated molecular ion ([M + H]+) at m/z 409 was always minor under the conditions used. Figure 4C shows the mass spectrum of [14C]tesaglitazar and tesaglitazar, and a ratio of labeled to unlabeled tesaglitazar of about 1:2 of the administered dose. The metabolites with retention times of about 23.2 and 24.6 min (Fig. 3) are acyl glucuronides of tesaglitazar. These conjugates showed identical mass spectra and are isomers of the 1-(O)-ß-glucuronide of tesaglitazar formed by acyl migration, i.e., 2-, 3-, and 4-O-acyl glucuronides. The mass spectrum of one of these conjugates is shown in Fig. 4D. The predominant peak in the samples of feces corresponded to unchanged tesaglitazar. The enantioselective analysis of urine samples showed that concentrations for the (R)-enantiomer were all below the LOQ (50 nM) and, therefore, no samples were analyzed for the R-form in plasma.
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Mass Balance and Excretion. The mean recovery of radioactivity following oral and i.v. administration is shown in Fig. 5. After i.v. administration, the mean ± S.D. recovery was 91.7 ± 1.7% in urine and 8.2 ± 3.2% in feces. The corresponding values after oral administration were 90.6 ± 3.3% and 9.0 ± 3.4%, respectively. The recovery of total radioactivity was quantitative in all subjects with a mean recovery of 99.9% (i.v.) and 99.6% (oral), respectively. Tesaglitazar was mainly metabolized before excretion, and most of the radioactivity was recovered in urine. Approximately 20% of the dose was recovered unchanged in the urine after either dosing route, and the renal clearance was approximately 0.03 l/h (Table 1). The rest of the radioactivity excreted in urine was identified as the acyl glucuronides of tesaglitazar.
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Tolerability. There were two adverse events during the study (cough with associated chest pain), both of which were reported by the same subject. Neither event was serious or caused withdrawal from the study. There were no clinically significant changes in ECG, blood pressure, heart rate, or clinical laboratory variables.
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Discussion |
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and agonist being developed to treat the glucose and lipid abnormalities associated with type 2 diabetes and metabolic syndrome. This study evaluated the pharmacokinetics of tesaglitazar, including absorption, distribution, metabolism, and excretion of tesaglitazar, following i.v. and oral administration in healthy male subjects. The 1-mg dose of tesaglitazar administered in the present study was anticipated to be in the therapeutic dose range. After oral administration of tesaglitazar, the compound was rapidly absorbed and the absolute bioavailability was close to 100%, suggesting complete absorption with no or negligible first-pass metabolism. Tesaglitazar accounted for more than 90% of the total radioactivity in plasma but was mainly metabolized before excretion. Declines in radioactivity and tesaglitazar were virtually identical, suggesting that metabolite elimination was faster than tesaglitazar elimination and was formation rate-limited; i.e., the amount of metabolite in the body was determined by the rate of formation and subsequent elimination. The relatively long half-life of tesaglitazar will lead to a higher plasma concentration after repeated daily dosing. Assuming time- and dose-independent pharmacokinetics, the present results suggest that plasma levels of tesaglitazar would be approximately 3 times higher at steady state than after administration of a single dose. The pharmacokinetic results also suggest that once-daily dosing seems to be an optimal dosing regimen for tesaglitazar.
The only metabolite identified in the present study was the acyl glucuronide of tesaglitazar, and the metabolism in humans was essentially similar to that seen in monkeys (M. Elebring, unpublished data). Acyl glucuronides appear as isomers of ß-1-(O)-glucuronide formed by acyl migration (Spahn-Langguth and Benet, 1992). Several acyl glucuronides are also known to form the aglycone and undergo enterohepatic recycling (Roberts et al., 2002). Tesaglitazar also seems to undergo enterohepatic recycling since plasma-concentration time profiles of radioactivity and tesaglitazar indicated a somewhat slower phase immediately after the rapid distribution phase. However, this enterohepatic cycling does not contribute to a large extent to the total elimination of tesaglitazar and/or its metabolite, since only about 10% of the administered radioactivity was recovered in feces after administration by either route. Thus, biliary elimination and/or intestinal secretion is not a significant route of elimination for tesaglitazar and/or the acyl glucuronides of tesaglitazar. However, enterohepatic recycling is likely to contribute to the relatively long half-life of tesaglitazar.
Inhibition of P450 enzymes is the basis of most metabolism-based drug-drug interactions (DDIs). UDP-glucuronosyltransferase (UGT)-mediated DDIs are less frequent, and relatively few reports are found in the literature (Lin and Wong, 2002; Prueksaritanont et al., 2002). Plausible explanations for this outcome could be the low substrate affinity, overlapping substrate specificity, or lack of inhibitors to use as tools for evaluation of UGTs in the past, which has made these enzymes less studied from a predictive and clinically relevant drug-drug interaction point of view. The introduction of cloned and expressed isoforms of human UGT has contributed to increased investigation of these enzymes (Ethell et al., 2001). Different in vitro systems have been used successfully to predict the in vivo pharmacokinetics of drugs that are mainly or partly metabolized by UGTs (Izumi et al., 1997; Andersson et al., 2001; Soars et al., 2002). In addition, in vitro approaches similar to those used to predict drug-drug interactions by P450s are increasingly being reported for compounds mainly metabolized by UGTs (Gilissen et al., 2000; Lautala et al., 2000). However, the reported enzyme kinetic parameters are generally much higher than for compounds metabolized by P450s, and also well above therapeutic concentrations. Thus, the low substrate affinity and/or overlapping substrate specificity of different UGTs indicate that drug-drug interactions based on competitive inhibition of UGTs are less likely than competitive inhibition of P450s. Furthermore, the magnitude of reported DDIs via inhibition of glucuronidation is relatively modest (Lin and Wong, 2002). This study identified acyl glucuronides as the only metabolites of tesaglitazar. In vitro studies with a panel of different recombinant human UGTs suggest that formation of the acyl glucuronide is mediated via UGT1A3 and UGT2B7 (unpublished data). In addition, a previous study reported that tesaglitazar is not an inhibitor of the major drug-metabolizing P450s in vitro (Rubin et al., 2003). Taken together, these results suggest that tesaglitazar has a low potential to cause any P450 inhibition-based drug-drug interactions in humans. In addition, since tesaglitazar is not metabolized by P450s, inducers and/or inhibitors of these enzymes are not likely to affect the disposition of tesaglitazar either.
After administration by either route, approximately 90% of the dose was excreted in the urine. Most of the radioactivity in urine was identified as acyl glucuronide of the parent drug and the remainder, approximately 20% of the dose, as tesaglitazar. Although the elimination of tesaglitazar via the kidney was slow, tubular secretion of tesaglitazar is likely to contribute to renal clearance since the value exceeded the maximum elimination by filtration alone (glomerular filtration rate x unbound fraction). However, since the main metabolite was the acyl glucuronide of tesaglitazar and collected urine was not acidified, parts of the parent drug recovered in urine may be due to hydrolysis of the conjugate resulting in an overestimation of the renal clearance of tesaglitazar.
Potential inversion was examined by an enantioselective analysis of urine samples. Due to the relatively slow elimination of tesaglitazar, urine concentrations were moderately high and the LOQ of the analytical method was 50 nM. Given the diluted urine in combination with the LOQ of the analytical method, we could conclude only that the potential inversion was less than 10%. However, a previous study that evaluated inversion in human plasma samples detected no R-enantiomer despite tesaglitazar plasma levels of 10 µM. This result suggested that the racemization of tesaglitazar is less than 0.5% (unpublished data).
In conclusion, after either oral or intravenous administration of [14C]tesaglitazar, the recovery of total radioactivity was complete in all subjects. After oral dosing, tesaglitazar was rapidly absorbed and the bioavailability was complete. The only metabolite identified was the acyl glucuronide of tesaglitazar. Tesaglitazar was the predominant compound in plasma, and the plasma concentrations of metabolite were low in comparison with parent compound. The major route of excretion was via the kidney, and a small portion of the dose was recovered unchanged. Tesaglitazar was a typical low-clearance drug with a small volume of distribution. The elimination half-life was long, and it is likely that enterohepatic recycling contributed to the long half-life of tesaglitazar. Based on pharmacokinetic results, once-daily dosing seems to be an optimal dosing regimen for tesaglitazar. The metabolic profile of tesaglitazar suggests a low potential for drug-drug interaction by P450 inhibition. There was no indication of partial inversion of the S-enantiomer to the corresponding (R)-form. The plasma protein binding of tesaglitazar was high, and the low blood-plasma concentration ratio suggests a low affinity for red blood cells. In healthy subjects, oral and i.v. doses of tesaglitazar were considered safe and well tolerated.
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Acknowledgments |
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Footnotes |
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Address correspondence to: Hans Ericsson, Experimental Medicine, Astra-Zeneca R&D, Mölndal, Sweden. E-mail: Hans.ericsson{at}astrazeneca.com
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