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EC number: 469-070-1 | CAS number: 17861-60-8
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
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- Nanomaterial pour density
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- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
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Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 21 March 2019 - 27 April 2020
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 020
- Report date:
- 2020
Materials and methods
- Objective of study:
- absorption
- distribution
- excretion
- metabolism
- toxicokinetics
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 417 (Toxicokinetics)
- Deviations:
- yes
- Remarks:
- The target radioactive dose level in the Study Plan was approximately 2.0 MBq/kg, but the achieved radioactive dose level for Groups 3 and 6, however, was approximately 1.3 MBq/kg; this deviation had no impact on the integrity of the study.
- GLP compliance:
- yes (incl. QA statement)
Test material
- Reference substance name:
- -
- EC Number:
- 469-070-1
- EC Name:
- -
- Cas Number:
- 17861-60-8
- Molecular formula:
- C9H26O2Si3
- IUPAC Name:
- 4-ethyl-2,2,4,6,6-pentamethyl-3,5-dioxa-2,4,6-trisilaheptane
- Test material form:
- liquid
- Remarks:
- Clear colourless liquid
Constituent 1
- Radiolabelling:
- yes
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on species / strain selection:
- Wistar Han (albino) {RccHan:WIST]; Species typically used for toxicokinetic studies
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source:
- Age at study initiation: 13 - 17 weeks
- Weight at study initiation: 199 - 249 grams
- Housing: Solid-bottom polycarbonate cages with stainless steel lids including
wood flakes and environmental enrichment (plastic tunnel/shelter, wooden chewblock)
- Diet (e.g. ad libitum): VRF1 diet ad libitum
- Water (e.g. ad libitum):tap water ad libitum
- Acclimation period:At least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24 degrees C
- Humidity (%): 40 - 70%
- Air changes (per hr): Not available
- Photoperiod (hrs dark / hrs light): Alternating 12-hour light/dark
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: Dried corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The corn oil was divided into aliquots of approximately 250mL in 500mL glass containers or 500mL in 1000mL glass containers. 10g of molecular sieves per 100 mL of corn oil was added to each container. Each container was then flushed with nitrogen and sealed in glass container. Corn oil was considered dried after a storage period of 48 hours.
Non-radiolabelled formulations were prepared as follows:
An aliquot of non-radiolabelled Y-14877 was added to a volume of dried corn oil. Additional dried corn oil was then added sufficient to achieve the target formulation concentration.
Radiolabelled formulations were prepared as follows:
Appropriate aliquots of [14C]Y-14877 and non-radiolabelled Y-14877 were added to a volume of dried corn oil. Additional dried corn oil was then added sufficient to achieve the target formulation concentration. - Duration and frequency of treatment / exposure:
- 13-daily oral doses of non-radiolabelled Y-14877 followed by a single oral dose of [14C]Y-14877 on Day 14
Doses / concentrationsopen allclose all
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Remarks:
- Group 1, 4 and 7
- Dose / conc.:
- 200 mg/kg bw/day (nominal)
- Remarks:
- Group 2, 5, and 8
- Dose / conc.:
- 600 mg/kg bw/day (nominal)
- Remarks:
- Group 3, 6, and 9
- No. of animals per sex per dose / concentration:
- Group 1, 2, 3: 16 females
Group 4, 5, 6: 4 females
Group 7, 8, 9: 2 females - Control animals:
- no
- Positive control reference chemical:
- Not applicable
- Details on study design:
- Blood Kinetics (Groups 1-3)
Groups of 16 female rats received repeated consecutive daily oral doses of non-radiolabelled Y-14877 (Days 1 - 13) and [14C]Y-14877 (Day 14) at dose levels of 50 mg/kg/day (Group 1), 200 mg/kg/day (Group 2) or 600 mg/kg/day (Group 3). Two serial blood samples (ca 1 mL) and one terminal blood sample (ca 6 – 8 mL) was taken from each subgroup, after administration of the radiolabelled (14th) dose as follows:
Subgroup 1: Predose, 0.5 and 1 hours
Subgroup 2: 2, 4 and 6 hours
Subgroup 3: 3, 12 and 24 hours
Subgroup 4: 48, 96 and 168 hours
Serial blood samples were collected by venipuncture of a caudal vein and terminal samples taken by cardiac puncture under isoflurane/oxygen anesthesia without recovery. All blood samples were delivered into tubes containing K2EDTA anticoagulant.
Whole blood was sampled for determination of radioactivity content. The remaining whole blood was used to obtain plasma by centrifugation (ca 2000 × g at 4°C for 10 min); blood cells were discarded. An aliquot of plasma (0.1 mL) was immediately subsampled for unchanged Y-14877 measurement and then promptly transferred to deep frozen storage (-70°C ± 10°C). Remaining plasma was retained for radioactivity measurement.
Excretion Balance (Groups 4-9)
Groups of 4 female rats (Groups 4 – 6) and 2 female rats (Groups 7 – 9) received repeated consecutive daily oral doses of non-radiolabelled Y-14877 (Days 1 - 13) and [14C]Y-14877 (Day 14) at dose levels of 50 mg/kg/day (Group 4 and 7), 200 mg/kg/day (Group 5 and 8) or 600 mg/kg/day (Group 6 and 9). Total excreta, as detailed below, were collected from each animal after administration of the radiolabelled (14th) dose.
Urine: Predose (overnight prior to Day 14 dosing), 0 – 6, 6 – 24, 24 – 48, 48 – 72, 72 – 96, 96 – 120, 120 – 144 and 144 - 168 h post dose
Faeces: Predose (overnight prior to Day 14 dosing), 0 – 24, 24 – 48, 48 – 72, 72 – 96, 96 – 120, 120 - 144 and 144 – 168 h post dose
Expired air: – 24, 24 – 48, 48 – 72, 72 – 96, 96 – 120, 120 – 144, and 144 - 168 h post dose
Cage wash (water; 100 mL): 24, 48, 72, 96, 120, 144 and 168 h post dose
Cage wash (methanol; 100 mL): 168 h post dose
Urine was collected into containers cooled in solid CO2, and faeces were collected separately at ambient temperature. Expired air was initially trapped in 1M potassium hydroxide solution only (Groups 4 – 6) and
the radioactivity in the traps was monitored. Following review of total excreta, it was apparent that this trap design was not suitable for collection of expired radioactivity. Following
investigatory work with several alternative trap designs, expired air from Groups 7 – 9 was trapped in 1M potassium hydroxide solution and charcoal traps. Radioactivity in the traps was monitored and total excreta approached 90%.
- Dose selection rationale:
Previous studies with the test item have demonstrated it to be well tolerated by adult rats at dosages up to 600 mg/kg/day. In order to determine if there is a change in linearity at the LOEL, the following dose levels have been selected based on an OECD 421 study previously conducted:
Low dose (NOEL) = 50 mg/kg/day
Mid dose (LOEL) = 200 mg/kg/day
High dose = 600 mg/kg/day
- Rationale for animal assignment (if not random): Random - Details on dosing and sampling:
- The dose solutions were administered orally using a graduated syringe with rubber gavage tube at a nominal rate of 4 mL formulation/kg body weight. The actual amount of formulation administered was determined from the weight (radiolabelled dose of excretion studies only) or volume of dosing formulation given.
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, blood, plasma, cage washes, expired air
- Time and frequency of sampling: See study design
Urine: Predose (overnight prior to Day 14 dosing), 0 – 6, 6 – 24, 24 – 48, 48 – 72, 72 – 96, 96 – 120, 120 – 144 and 144 - 168 h post dose
Faeces: Predose (overnight prior to Day 14 dosing), 0 – 24, 24 – 48, 48 – 72, 72 – 96, 96 – 120, 120 - 144 and 144 – 168 h post dose
Expired air: 0 – 24, 24 – 48, 48 – 72, 72 – 96, 96 – 120, 120 – 144, and 144 - 168 h post dose
Cage wash (water; 100 mL): 24, 48, 72, 96, 120, 144 and 168 h post dose
Cage wash (methanol; 100 mL): 168 h post dose
All samples generated during the course of this study were stored at -20 ± 10°C except during analysis, apart from whole blood which was stored at +5 ± 3°C until measurement of
radioactivity was complete and then subsequently at -20 ± 10°C. Plasma subsamples for bioanalytical assay were stored at -70 ± 10°C.
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces, plasma
- Time and frequency of sampling: See study design
Plasma was pooled (equal volume from each sample) to provide representative samples for the following times: Group 1, 2 and 3: 1 hour, 6 hours and 24 hours post dose.
Urine was pooled (equal proportions of the total urine weight voided) to provide representative samples at the following times: Group 4, 5 and 6: 0 – 24 hours, 24 – 48 hours and 48 – 72 hours post dose.
Faeces homogenates were pooled (equal proportions of the total faeces homogenate weight) to provide representative samples at the following times: Group 4, 5 and 6: 0 – 24 hours and 24 – 48 hours post dose.
- Method type(s) for identification: HPLC Prodigy ODS(2) 5µm + C18 guard column; Flow-through system using a liquid scintillant cell
- Limits of detection and quantification: Radioactivity in gross amounts of less than twice the background level was considered to be below the limit of accurate determination (limit of detection). - Statistics:
- For the determination of total radioactivity and concentrations of radioactivity in samples, total weights, replicate weights and liquid scintillation counting data were recorded and processed using the DEBRA automated laboratory data capture and processing system (V5.5.4.49, LabLogic Systems Ltd, Sheffield, UK).
The limit of quantification (gross dpm) was taken as 2 x background. Concentration data below the limit of quantification were denoted as BLQ and considered equal to zero when calculating the mean and standard deviation of the mean (sd). Mean and sd values were not calculated if the results for at least half of the animals in a group were BLQ, and were denoted as BLQ and -, respectively. An exception is excretion data, where BLQ and no samples (NS) were taken as zero, and the mean and sd calculated even if only one value was quantifiable. If no values were quantifiable the mean and standard deviation values were denoted as BLQ and -, respectively.
Pharmacokinetic parameters were calculated using the computer program Phoenix WinNonlin version 8.1 (Certara USA, Inc.).
Results and discussion
- Preliminary studies:
- None
Main ADME resultsopen allclose all
- Type:
- absorption
- Results:
- There appeared to be no correlation on the rate of absorption of radioactivity with dose level, indicating that absorption for plasma and whole blood is non-linear.
- Type:
- distribution
- Results:
- Increases in the Cmax and AUCt of Y-14877 between low and mid dose level in plasma were greater than proportional.
- Type:
- excretion
- Results:
- The primary routes of excretion of radioactivity, at the low and mid dose levels, were urine and expired air.
- Type:
- metabolism
- Results:
- Plasma radioactivity was initially attributable to a single component corresponding chromatographically with Y-14877.Faecal elimination of radioactivity increased with increasing dose and with the primary radioactivity component corresponding to Y-14877.
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- Following repeated consecutive daily oral doses of non-radiolabelled Y-14877 (Days 1 - 13) and [14C]Y-14877 (Day 14) to four female rats at 50 mg/kg/day (low), 200 mg/kg/day (mid) and 600 mg/kg/day (high), absorption of radioactivity (attributable to [14C]Y-14877 and its metabolites) was slow with Tmax in plasma ranging from 3 hours (mid dose level) to 6 hours (low and high dose level) and the Tmax in whole blood, for all dose levels, occurring at 12 hours. There appeared to be no correlation on the rate of absorption of radioactivity with dose level, indicating that absorption for plasma and whole blood is non-linear. See table below
- Details on distribution in tissues:
- The Cmax and AUCt of Y-14877 in plasma increased with increasing dose of [14C]Y-14877. For the Cmax these increases (1.44-fold from mid to high dose level and 6.69-fold from low to high dose level) were less than proportional over the nominal dose range (3-fold from mid to high dose level and 12-fold from low to high dose level). For AUCt, however, the increase from mid to high dose level (2.69-fold) was approaching consistency with increasing dose whereas the increase from low to high dose level (20.1-fold) was greater than proportional over the nominal dose range. Proportionality was not observed for the AUCt between the low and high dose level or the mid and high dose level. Linearity was not observed for the Cmax and AUCt with increasing dose.
The whole blood to plasma ratio of total radioactivity, calculated using AUCt was between 0.5 and 0.67, indicating little distribution of radioactivity into red blood cells. A significant proportion of radioactivity was retained in the carcass. No other tissues were evaluated.
- Details on excretion:
- The primary routes of excretion of radioactivity, at the low and mid dose levels, were urine and expired air. At the high dose level radioactivity was excreted mainly in the faeces.
Excretion was slow and incomplete at the end of the sample collection period (168 hours post dose) with a significant proportion of radioactivity retained in the carcass. The proportion of dose excreted in urine generally decreased with increasing dose as did the proportion recovered in the carcass, possibly indicating a saturation of absorption at the mid and high dose levels. The increase in the proportion of dose recovered in expired air, however, possibly indicated that the biotransformation of absorbed radioactivity to volatile metabolites was the primary route of elimination. See table below.
Toxicokinetic parametersopen allclose all
- Key result
- Toxicokinetic parameters:
- Tmax: 2.0 h
- Remarks:
- Y-14877 50 mg/kg/day
- Key result
- Toxicokinetic parameters:
- Tmax: 3.0 h
- Remarks:
- Y-14877 200 mg/kg/day
- Key result
- Toxicokinetic parameters:
- Tmax: 6 h
- Remarks:
- Y-14877 600 mg/kg/day
- Key result
- Toxicokinetic parameters:
- Cmax: 10.2 ug/mL
- Remarks:
- Y-14877 50 mg/kg/day
- Key result
- Toxicokinetic parameters:
- Cmax: 47.2 ug/mL
- Remarks:
- Y-14877 200 mg/kg/day
- Key result
- Toxicokinetic parameters:
- Cmax: 68.2 ug/mL
- Remarks:
- Y-14877 600 mg/kg/day
- Key result
- Toxicokinetic parameters:
- AUC: 78.8 h*ug/mL
- Remarks:
- Y-14877 50 mg/kg/day
- Key result
- Toxicokinetic parameters:
- AUC: 529 h*ug/mL
- Remarks:
- Y-14877 200 mg/kg/day
- Key result
- Toxicokinetic parameters:
- AUC: 1430 h*ug/mL
- Remarks:
- Y-14877 600 mg/kg/day
Metabolite characterisation studies
- Metabolites identified:
- yes
- Remarks:
- Plasma: P1, P2, P3 Urine: U1, U2, U3, U4, U5 Faeces: F1, F2, F3, F4, F5, F6, F7, F8, F9, F10, F11, F12, F13
- Details on metabolites:
- PLASMA
Plasma radioactivity was initially attributable to a single component (P3) corresponding chromatographically with Y-14877. Transformation of Y-14877 to P1 occurred at all three dose levels. The percentages associated with this component (P3), however, decreased over time in favor of an earlier eluting component P1. These data, therefore, suggest that the primary biotransformation of systemically available Y-14877 was conversion of the test item to a significantly more polar metabolite.
50 mg/kg/day: The radioactive concentration in plasma at 1-hour post dose was too low for accurate detection and quantification of metabolites.At 6 hours post dose, P3 (corresponds chromatographically with Y-14877) was the most abundant component accounting for 60.5% TRR (6.73 µg equivs/g). P1, which accounted for 14.7% TRR (1.64 µg equivs/g), and P2 which accounted for 6.3% TRR (0.696 µg equivs/g) were also notable components. At 24 hours post dose, P1 which accounted for 77.3% of TRR (2.88 µg equivs/g) was the only discrete component detected.
200 mg/kg/day: At 1-hour post dose, P3 (corresponds chromatographically with Y-14877), which accounted for 93.3% of TRR (2.95 µg equivs/g) was the only discrete component detected. At 6 hours post dose, P3 was the most abundant component accounting for 71.2% TRR (24.5 µg equivs/g). P1 which accounted for 13.5% TRR (4.63 µg equivs/g) and P2 which accounted for 5.9% TRR (2.02 µg equivs/g) were also notable components. At 24 hours post dose, P1 was the most abundant component accounting for 76.0% of TRR (11.2 µg equivs/g). P3 which accounted for 4.2% TRR (0.614 µg equivs/g) was also a notable component.
600 mg/kg/day: At 1-hour post dose, P3, (corresponds chromatographically with Y-14877) which accounted for 91.4% of TRR (14.6 µg equivs/g) was the only discrete component detected. At 6 hours post dose, P3 was the most abundant component accounting for 75.3% TRR (67.8 µg equivs/g). P1 which accounted for 13.2% TRR (11.8 µg equivs/g) was also a notable component. At 24 hours post dose, P1 was the most abundant component accounting for 72.1% of TRR (21.1 µg equivs/g). P3 which accounted for 14.3% TRR (4.19 µg equivs/g) was also a notable component.
URINE
Metabolite profiles in urine were generally similar (four metabolites) at all dose levels indicating that the biotransformation pathway of absorbed radioactivity was unaffected by dose level, though the % dose associated with these four metabolites generally decreased with increasing dose level, which was consisent with decrease in overall urinary recovery.
50 mg/kg/day: During 0 – 72 hours post dose, the most abundant component was U2 which accounted for 14.7% of dose. U1 (5.0% of dose), U3 (9.6% of dose) and U4 (3.2 % of dose) were also notable components.
200 mg/kg/day: During 0 – 72 hours post dose, the most abundant component was U2 which accounted for 9.7% of dose. U1 (3.6% of dose), U3 (6.2% of dose) and U4 (3.6 % of dose) were also notable components.
600 mg/kg/day: During 0 – 72 hours post dose, the most abundant component was U3 which accounted for 6.5% of dose. U1 (2.8% of dose), U2 (5.6% of dose) and U4 (3.1 % of dose) were also notable components. U5 (0.7% of dose) was also detected.
FAECES
Faecal elimination of radioactivity increased with increasing dose, though the increase was not linear with increasing dose, and with the primary radioactivity component corresponding to Y-14877, it is likely that the radioactivity recovered was unabsorbed oral dose. The presence of a number of polar metabolites in faeces, however, could be indicative of biliary excretion based on the report authors conclusions.
At 50 mg/kg/day: During 0 – 48 hours post dose, the most abundant component was F8 (corresponds chromatographically with Y-14877) which accounted for 5.7% of dose. F5, which accounted for 2.4% of dose, was also a notable component. Other notable components included F3, F4, F11 and F12 which accounted for 1.1 – 1.5% of dose. All other metabolites accounted for <=0.8% dose.
At 200 mg/kg/day: During 0 – 48 hours post dose, the most abundant component was F8 (corresponds chromatographically with Y-14877) which accounted for 10.3% of dose. F5, which accounted for 3.2% of dose, was also a notable component. All other metabolites accounted for <=0.8% dose.
At 600 mg/kg/day: During 0 – 48 hours post dose, the most abundant component was F8 (corresponds chromatographically with Y-14877) which accounted for 20.1% of dose. F5, which accounted for 3.0% of dose, was also a notable component. Another notable component was F13 which accounted for 1.9% of dose. All other metabolites accounted for <=0.7% dose.
Bioaccessibility (or Bioavailability)
- Bioaccessibility (or Bioavailability) testing results:
- Not available
Any other information on results incl. tables
Plasma and Whole Blood Pharmacokinetic Data
|
(a) Value must be treated with caution as the data did not meet the acceptance criteria – ie. AUC % Extrapolation >20%
Excretion of Radioactivity During 0 -168 hours Post Final Dose (% administered dose)
Sample | 50 mg/kg/day (Group 4 and 7) |
200 mg/kg/day (Group 5 and 8) |
600 mg/kg/day (Group 6 and 9) |
Urine | 36.91 | 26.76 | 21.88 |
Faeces | 17.71 | 21.27 | 34.50 |
Cage wash | 2.21 | 2.23 | 2.22 |
Expired Air | 21.34 | 26.69 | 18.43 |
Carcass | 11.48 | 10.50 | 7.35 |
Total Recovery | 93.69 | 89.24 | 92.71 |
Applicant's summary and conclusion
- Conclusions:
- Following repeated 14 consecutive daily oral doses of Y-14877, the rate of absorption of radioactivity was not linear with increasing dose level. Circulating Y-14877 was metabolized to significantly more polar components at all dose levels, though metabolic profiles indicated that the biotransformation pathway of Y-14877 was not affected by dose level. The rate of biotransformation based on half-lives of radioactivity was not linear in whole blood or plasma with increasing dose. Excretion in urine decreased and in faeces increased with increasing dose level in a nonlinear fashion. Excretion in expired air did not show a clear (linear) pattern with increasing dose.
In summary, the toxicokinetics of Y-14877 following repeated oral dosing provide adequate information on its absorption, distribution, biotransformation (i.e. metabolism) and excretion and suggests these processes are not linear with increasing dose. The kinetically derived maximum dose appears to be below 200 mg/kg bw/day. - Executive summary:
The kinetics (absorption, distribution, metabolism and excretion) of [14C]Y-14877 was determined following 13-daily oral doses of non-radiolabelled Y-14877 followed by a single oral dose of [14C]Y-14877 on Day 14.
Pharmacokinetic
Following repeated consecutive daily oral doses of non-radiolabelled Y-14877 (Days 1 - 13) and [14C]Y-14877 (Day 14) to four female rats at 50 mg/kg/day (low), 200 mg/kg/day (mid) and 600 mg/kg/day (high), absorption of radioactivity (attributable to [14C]Y-14877 and its metabolites) was slow with Tmax in plasma ranging from 3 hours (mid dose level) to 6 hours (low and high dose level) and the Tmax in whole blood, for all dose levels, occurring at 12 hours. There appeared to be no correlation on the rate of absorption of radioactivity with dose level, indicating that absorption for plasma and whole blood is non-linear.
The Tmax of Y-14877 in plasma appeared to increase with increasing dose level (2, 3 and 6 hours at low, mid and high dose levels, respectively) but did not increase in a linear fashion. Tmax of Y-14877 in plasma were earlier than radioactivity for the low dose, but at the mid and high dose, the Tmax was the same as that observed in radioactivity.
The Cmax and AUCt of radioactivity in female rat plasma and whole blood, increased with increasing dose of Y-14877. Increases in the Cmax (plasma) and AUCt (whole blood and plasma) were generally proportional between the low and mid dose levels. Proportionality was not observed for increases in Cmax between low and mid dose levels (whole blood), between low and high dose levels (plasma or whole blood) or between mid and high dose levels (plasma or whole blood). Proportionality was not observed for the AUCt between the low and high dose level or the mid and high dose level. Linearity was not observed for the Cmax and AUCt with increasing dose.
Increases in the Cmax and AUCt of Y-14877 between low and mid dose level in plasma were greater than proportional. The increases in Cmax from mid to high and from low to high were less than proportional in plasma, whereas the increases in the AUCt, from mid to high dose was approaching proportionality and from low to high dose was significantly higher in plasma. The higher than proportional increases observed in the AUCt, particularly at the high dose level, but also at the mid dose, were due to accumulation of systemically available Y-14877 following the previous 13 daily non-radiolabelled dose administrations. Linearity was not observed for the Cmax and AUCt with increasing dose.
The half-life of plasma radioactivity was similar at the low and high dose level (59.4 and 59.1 hours, respectively) and slightly quicker (53.3 hours) at the mid dose level. The half-life of whole blood radioactivity was 23.2 hours at the low dose level, 68 hours at the mid dose level and 19.5 hours at the high dose level. These data suggest that there is no correlation on rate of clearance of absorbed radioactivity with dose level, indicating that clearance is nonlinear.
The half-life of Y-14877, where calculable, increased with dose level (3.2 hours at the low dose level and 79.2 hours at the high dose level) though this increase was not linear with increasing dose. The determination of the half-life of Y-14877 at the mid dose level did not met acceptance criteria (specifically greater than 20% of the AUC0-t was determined by extrapolation thus the estimation of the elimination rate constant was considered unreliable) but was estimated at 148.3 hours; this value however should be treated with caution.
Excretion
The primary routes of excretion of radioactivity, at the low and mid dose levels, were urine and expired air. At the high dose level radioactivity was excreted mainly in the faeces. Excretion was slow and incomplete at the end of the sample collection period (168 hours post dose) with a significant proportion of radioactivity retained in the carcass. The proportion of dose excreted in urine generally decreased with increasing dose as did the proportion recovered in the carcass, possibly indicating a saturation of absorption at the mid and high dose levels. The increase in the proportion of dose recovered in expired air, however, possibly indicated that the biotransformation of absorbed radioactivity to volatile metabolites was the primary route of elimination.
Metabolism
Plasma radioactivity was initially attributable to a single component (P3) corresponding chromatographically with Y-14877. Transformation of Y-14877 to P1 occurred at all three dose levels. The percentages associated with this component (P3), however, decreased over time in favor of an earlier eluting component P1. These data, therefore, suggest that the primary biotransformation of systemically available Y-14877 was conversion of the test item to a significantly more polar metabolite. Metabolite profiles in urine were generally similar (four metabolites) at all dose levels indicating that the biotransformation pathway of absorbed radioactivity was unaffected by dose level, though the % dose associated with these four metabolites generally decreased with increasing dose level, which was consistent with decrease in overall urinary recovery. Faecal elimination of radioactivity increased with increasing dose, though the increase was not linear with increasing dose, and with the primary radioactivity component corresponding to Y-14877, it is likely that the radioactivity recovered was unabsorbed oral dose. The presence of a number of polar metabolites in faeces, however, could be indicative of biliary excretion as indicated by report authors.
In conclusion, following repeated 14 consecutive daily oral doses of Y-14877, the rate of absorption of radioactivity was not linear with increasing dose level. Circulating Y-14877 was metabolized to significantly more polar components at all dose levels, though metabolic profiles indicated that the biotransformation pathway of Y-14877 was not affected by dose level. The rate of biotransformation based on half-lives of radioactivity was not linear in whole blood or plasma with increasing dose. Excretion in urine decreased and in faeces increased with increasing dose level in a nonlinear fashion. Excretion in expired air did not show a clear (linear) pattern with increasing dose. The kinetically derived maximum dose appears to be below 200 mg/kg bw/day.
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