Orthosulfamuron

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2002

Report date:

2002

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: Council Directive 91/414/EEC, Part A, Annex II, Section 5 amended by Commission Directive 94/79/EC, Annex I, Section 5

GLP compliance:

yes

Test material

Test material information

Constituent 1

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

Test material:
[14C-U-phenyl]IR5878 Lot 182
Specific radioactivity: 342008 dpm/µg
154.058 µCi/mg
5.700 MBq/mg
Radiochemical purity: > 97% (by TLC and HPLC)

Unlabelled IR5878
Batch number: 20525/03/9
Purity: > 98% (by HPLC)

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

Species and Strain: Male and Female Sprague Dawley rats

Sex:

male/female

Details on test animals or test system and environmental conditions:

Test animals:
Species and Strain: Male and Female Sprague Dawley rats
Age: 6 to 11 weeks
Body weight: 177 ÷ 268 g
Housing: during pre-trial periods the animals were housed in pairs, where possible, in polypropylene and stainless steel cages with raised wire mesh floors. Following dose administration, the rats used for excretion studies were housed singly in all-glass metabolism cages specially designed for the separate, quantitative collection of urine and faeces. In all other phases of the study, the rats were housed singly in polypropylene and stainless steel cages with wire mesh floors.
Feed: a complete diet of known formulation (SDS Rat and Mouse Maintenance Diet No. 1, Special Diet Services, 1 Stepfield, Witham, Essex) and domestic mains quality water were available ad libitum.

Environmental conditions:
Temperature and humidity measured during the study ranged from 18 ÷ 28°C and 40 ÷ 75%, respectively.
Light hours were 07:00 – 19:00 h.

Administration / exposure

Route of administration:

oral: unspecified

Details on exposure:

The study was conducted in 10 phases: excretion kinetics following single (5 mg/kg bw and 1000 mg/kg bw) and repeated (5 mg/kg bw for 15 consecutive days) oral administration of the test item (Phase 1-3); blood kinetics (Phase 4-6) and tissue distribution (Phase 7-9), following the same 3 administration regimens indiucated above, and biliary elimination (Phase 10) following a single low dose oral administration (5 mg/kg bw).

Duration and frequency of treatment / exposure:

The study was conducted in 10 phases: excretion kinetics following single (5 mg/kg bw and 1000 mg/kg bw) and repeated (5 mg/kg bw for 15 consecutive days) oral administration of the test item (Phase 1-3); blood kinetics (Phase 4-6) and tissue distribution (Phase 7-9), following the same 3 administration regimens indiucated above, and biliary elimination (Phase 10) following a single low dose oral administration (5 mg/kg bw).

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

5 mg/kg bw (total dose)

Doses / concentrations 2

Dose / conc.:

1 000 mg/kg bw (total dose)

Doses / concentrations 3

Dose / conc.:

5 mg/kg bw/day

Remarks:

For 15 days

No. of animals per sex per dose / concentration:

The test material was administered to 24 Sprague Dawley rats. A first group of 4 male and 4 female rats received a single oral dose of 5 mg/kg bw of [14C-U-phenyl]IR5878. A second group of 4 male and 4 female rats received a single oral dose of 1000 mg/kg bw of [14C-U-phenyl]IR5878. Finally a third group of 4 male and 4 female rats received a multiple oral dose of IR5878: once daily for 14 consecutive days with cold IR5878 followed by one dose of [14C-U-phenyl]IR5878 on day 15 (target dose 5 mg/kg bw).

Details on dosing and sampling:

Following dose administration of [14C-U-phenyl]IR5878 urine and faeces were collected at various timepoints until sacrifice. At post mortem the gastrointestinal tract and carcass were retained. All samples from each group of animal were analysed for total radioactive residues (TRR). Urine were analysed directly by liquid scintillation counting (LSC). All other sample matrices were analysed for TRR by combustion followed by LSC.
Following dose administration of [14C-U-phenyl]IR5878 whole blood samples were collected at various timepoints, by venesection of a tail vein. Samples from each group of animal were analysed for total radioactive residues (TRR) by combustion followed by LSC.
At Tmax, 1-2 hours following dose administration of [14C-U-phenyl]IR5878, the animals were killed. At necroscopy were removed bone, brain, brown fat, gastrointestinal tract, heart, liver, lung, muscle, residual carcass, spleen, subcutaneous fat and the whole blood. All samples from each group of animal were analysed for total radioactive residues (TRR) by combustion followed by LSC.
Following dose administration of [14C-U-phenyl]IR5878 bile, urine and faeces were collected at various timepoints until sacrifice. At post mortem the gastrointestinal tract and carcass were retained. All samples from each group of animal were analysed for total radioactive residues (TRR). Bile and urine were analysed directly by liquid scintillation counting (LSC).

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Based on the overall results obtained from the 10 phases experiments, it can be concluded that [14C-U-phenyl]-IR5878 orally administered at 5 mg/kg bw is absorbed very rapidly (peak blood concentration 1 h) and quite extensively (70-80%). Indeed, over 90% of the administered radioactivity was recovered in the excreta within 48 hours post-treatment. At 72 hours after IR5878 administration, faeces accounted for the highest proportion of the dose (66.38% and 52.93% in male and female, respectively). However, in bile-cannulated rats, about 36-38% of the dose was detected in bile over 48 hours, indicating that the biliary escretion was an important route of elimination In the same animals faeces samples contained about 17% of the administered dose by 72 hours post dose, and this presumably represented unabsorbed dose. The urine of bile duct cannulated animals contained mean values of 36-40% of dose at 72 hours post dose, consistently with results obtained in similarly dosed non-cannulated animals (30-38% of the administered dose). IR5878 was widely distributed to the different organs: however, the tissue containing the highest concentration at Tmax was the gastrointestinal tract; the only other tissues to contain a concentration greater than the one associated with whole blood were the liver and the kidney. There was no marked difference between sexes. By 72 hours post dose concentrations were low in the blood (approaching the limit of quantification), as well as in the carcass (< 0.5%), indicating a rapid clearance of IR5878.

Details on distribution in tissues:

IR5878 was widely distributed to the different organs: however, the tissue containing the highest concentration at Tmax was the gastrointestinal tract; the only other tissues to contain a concentration greater than the one associated with whole blood were the liver and the kidney. There was no marked difference between sexes. By 72 hours post dose concentrations were low in the blood (approaching the limit of quantification), as well as in the carcass (< 0.5%), indicating a rapid clearance of IR5878.

Details on excretion:

Excretion kinetics (Phases 1, 2, 3)
During all three excretion phases, the main route of elimination of total radioactivity was via the faeces for both male and female animals. The excretion of total radioactivity in urine and faeces was very rapid, with the majority of the radioactivity being excreted within ca 12-24 hours of dose administration. There were little differences in the excretion pattern of radioactivity between the male and female animals.

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

Findings

Excretion kinetics (Phases 1, 2, 3)

During all three excretion phases, the main route of elimination of total radioactivity wasviathe faeces for both male and female animals. The excretion of total radioactivity in urine and faeces was very rapid, with the majority of the radioactivity being excreted within ca 12-24 hours of dose administration. There were little differences in the excretion pattern of radioactivity between the male and female animals.

 

Single dose administrationmg/kg bw (Phase 1)

The overall mean recovery of radioactivity at 72 hours after administration of 5 mg/kg bw of [¹⁴C-U-phenyl]IR5878 was 99.59% and 94.45% respectively in the male and female animals. A mean of 66.38% and 52.93% of the dose was recovered, respectively in the male and female animals, in the faeces. Excretion in the urine accounted for 30.34% and 37.93% of the dose, respectively in the male and female animals. Small amounts of radioactivity (<0.5%) were detected in the gastrointestinal tract and carcass. The excretion of total radioactivity in urine and faeces was very rapid, with the majority of the radioactivity being excreted withinca12 hours (urine) andca24 hours (faeces) after dose administration. The excretion pattern of radioactivity was similar in male and female animals.

The results (as mean of the results for each animal of the group) are summarised in Table 5.1-1.

 

Table 5.1-1:          Cumulative excretion of total radioactivity after a single dose administration of 5 mg/kg bw of [¹⁴C-U-phenyl]IR5878 (expressed as % of the administered dose)

	Urine	Faeces	Cagewash	Gastrointestinal tract	Carcass^1	Recovery
Male
6 hours	23.27					23.27
12 hours	28.83	37.79	2.22			68.83
24 hours	29.84	60.36	2.46			92.66
48 hours	30.27	65.69	2.56			98.52
72 hours	30.34	66.38	2.65	0.04	0.14	99.59
Female
6 hours	28.41					28.41
12 hours	35.45	20.76	2.38			58.59
24 hours	37.06	41.62	2.76			81.44
48 hours	37.77	52.20	2.95			92.92
72 hours	37.93	52.93	3.19	0.06	0.33	94.45

¹Carcass includes all the bone, muscle, fat and other tissues not completely sampled at necropsy

 

Single dose administration at 1000 mg/kg bw (Phase 2)

The overall mean recovery of radioactivity at 72 hours after administration of 1000 mg/kg bw of [¹⁴C-U-phenyl]IR5878 was 91.85% and 91.84% respectively in the male and female animals. A mean of 72.89% and 66.27% of the dose was recovered, respectively in the male and female animals, in the faeces. Excretion in the urine accounted for 17.65% and 23.28% of the dose, respectively in the male and female animals. Only small amounts of radioactivity were detected in the gastrointestinal tract and carcass (<0.3%). The excretion of total radioactivity in urine and faeces was very rapid, with the majority of the radioactivity (about 85%) being excreted withinca24 hours after dose administration. The excretion pattern of radioactivity was similar in male and female animals.

The results (as mean of the results for each animal of the group) are summarised in Table 5.1-2.

 

Table 5.1-2:          Cumulative excretion of total radioactivity after a single dose administration of 1000 mg/kg bw of [¹⁴C-U-phenyl]IR5878 (expressed as % of the administered dose)

	Urine	Faeces	Cagewash	Gastrointestinal tract	Carcass^1	Recovery
Male
6 hours	7.44					7.44
12 hours	14.36	53.76	0.66			68.78
24 hours	16.68	67.67	0.89			85.23
48 hours	17.56	72.53	1.07			91.16
72 hours	17.65	72.89	1.15	0.03	0.12	91.85
Female
6 hours	9.63					9.63
12 hours	18.81	40.48	1.44			60.73
24 hours	21.94	60.97	1.97			84.88
48 hours	23.16	65.89	2.08			91.13
72 hours	23.28	66.27	2.18	0.04	0.06	91.84

¹Carcass includes all the bone, muscle, fat and other tissues not completely sampled at necropsy

 

Multiple dose administrationmg/kg bw (Phase 3)

The recovery of total radioactivity following multiple oral administrations were similar to those obtained following a single dose administration of 5 mg/kg bw of [¹⁴C-U-phenyl]IR5878. By the end of 72 hours collection period, the overall mean recovery in male and female animals was 96.19% and 96.91% respectively. About 50-62% of the dose was recovered in the faeces. Excretion in the urine accounted for 31-40% of the dose. Only small amounts of radioactivity were detected in gastrointestinal tract and carcass (<0.3%). The excretion of total radioactivity in urine and faeces was very rapid, with the majority of the radioactivity being excreted withinca12 hours (urine) andca24 hours (faeces) after dose administration. The excretion pattern of radioactivity was similar in male and female animals.

The results (as mean of the results for each animal of the group) are summarised in Table 5.1-3.

 

Table 5.1-3:          Cumulative excretion of total radioactivity after a multiple dose administration of 5 mg/kg bw of [¹⁴C-U-phenyl]IR5878 (expressed as % of the administered dose)

	Urine	Faeces	Cagewash	Gastrointestinal tract	Carcass^1	Recovery
Male
6 hours	25.32					25.32
12 hours	28.79	31.42	1.29			61.50
24 hours	30.77	54.79	1.60			87.17
48 hours	31.40	61.83	1.75			94.98
72 hours	31.52	62.76	1.84	0.07	0.00	96.19
Female
6 hours	31.58					31.58
12 hours	37.86	13.46	3.82			55.14
24 hours	39.68	34.82	4.18			78.68
48 hours	40.55	49.42	4.34			94.31
72 hours	40.69	50.73	4.60	0.08	0.70	96.91

¹Carcass includes all the bone, muscle, fat and other tissues not completely sampled at necropsy

 

Blood kinetics (Phases 4, 5, 6)

The excretion pattern of radioactivity between the male and female animals for all three blood kinetics phases was similar. The sacrifice times selected for Phases 7, 8 and 9 were 1 hour, 2 hours and 1 hour post dose, respectively

 

Single dose administrationmg/kg bw (Phase 4)

Following a single oral administration of [¹⁴C-U-phenyl]IR5878mg/kg bw,minutes post dose mean concentrations of total radioactivity in whole blood for male and female animals were 1.717 and 2.303 µg equiv.g^-1, respectively. These values increased slightly up to 1 hour post dose (T_max) when the highest concentration was reached (C_max), with mean values of 2.328 and 2.411 µg equiv.g^-1for the male and femaleanimals, respectively. Mean concentrations then declined in a biphasic manner with concentrations decreasing rapidly to 0.361 µg equiv.g^-1(males) and 0.332 µg equiv.g^-1(females)hours post dose. Thereafter, the rate of decline slowed, with low mean concentrations of radioactivity in the whole blood observed at 72 hours post dose (0.01 µg equiv.g^-1for both males and females).

The half-life (T_1/2) was 10.89 hours (males) andhours (females) and AUC (area under the blood concentration vs. time curve) wash µg.g^-1(males) and 12.89 h µg.g^-1(females).

The results are summarised in Tables 5.1-4 and 5.1-5.

 

Table 5.1-4:          Concentration of total radioactivity in whole blood after a single dose administration of 5 mg/kg bw of [¹⁴C-U-phenyl]IR5878 (expressed as µg equiv.g^-1)

Timepoint	Male	Female
6 min	1.717	2.303
12 min	2.185	2.271
24 min	2.090	2.356
1 h	2.328	2.411
2 h	1.243	1.284
4 h	0.734	0.669
6 h	0.554	0.469
8 h	0.361	0.332
24 h	0.089	0.084
48 h	0.027	0.026
72 h	0.010	0.006

 

Table 5.1-5:          Main pharmacokinetic parameters after a single dose administration of 5 mg/kg bw of  [¹⁴C-U-phenyl]IR5878

	Cmax	Tmax	T1/2	r^2	AUC
Male	2.328 µg equiv.g^-1	1 hour	10.89 hours	0.974	13.35h µg.g^-1
Female	2.411 µg equiv.g^-1	1 hour	11.09hours	0.974	12.89 h µg.g^-1

 

Single dose administration at 1000 mg/kg bw (Phase 5)

Following a single oral administration of [¹⁴C-U-phenyl]IR5878 at 1000 mg/kg bw,minutes post dose mean concentrations of total radioactivity measured in whole blood wereand 25.31 µg equiv.g^-1for male and female animals, respectively. Concentrations increased rapidly until a peak (T_max) was reachedhours post dose for the female animals and 4 hours post dose for the male animals, with mean values (C_max) of 285.09 and 305.02 µg equiv.g^-1, respectively. Following each peak, concentrations decreased rapidly until 24 hours post dose and then continued to decrease at a slower rate. At the end of the collection period (72 hours post dose) low levels of radioactivity remained in the whole blood (equiv.g^-1andµg equiv.g^-1for males and females, respectively).

The half-life (T_1/2) was 10.88 hours (males) and 11.87 hours (females) and AUC (area under the blood concentration vs. time curve) was 5595.59 h µg.g^-1(males) and 4299.67 h µg.g^-1(females). The slower rate of clearance of radioactivity from the whole blood paralled the slightly longer T_max; in addition the AUC values (about 300-400 fold higher compared to the low level dosed animals) indicate a saturation of the clearance pathways in the whole blood.

The results are summarised in Tables 5.1-6 and 5.1-7.

 

Table 5.1-6:          Concentration of total radioactivity in whole blood after a single dose administration of 1000 mg/kg bw of [¹⁴C-U-phenyl]IR5878 (expressed as µg equiv.g^-1)

Timepoint	Male	Female
6 min	13.45	25.31
12 min	30.14	55.23
24 min	76.71	126.66
1 h	208.65	243.70
2 h	294.63	285.09
4 h	305.02	239.65
6 h	280.46	199.09
8 h	227.61	198.90
24 h	58.04	22.84
48 h	17.04	16.52
72 h	13.47	8.00

 

Table 5.1-7:          Main pharmacokinetic parameters after a single dose administration of 1000 mg/kg bw of [¹⁴C-U-phenyl]IR5878

	Cmax	Tmax	T1/2	r^2	AUC
Male	305.02 µg equiv.g^-1	4 hour	10.88 hours	0.889	5595.59 h µg.g^-1
Female	285.09 µg equiv.g^-1	2 hour	11.87 hours	0.954	4299.67 h µg.g^-1

 

Multiple dose administrationmg/kg bw (Phase 6)

Following multiple oral administrations of non-radiolabelled IR5878 (14 consecutive days) and a single oral dose administration on day 15 of 5 mg/kg bw of [¹⁴C-U-phenyl]IR5878,minutes post dose mean concentrations of total radioactivity in whole blood for male and female animals were 2.700 and 4.788 µg equiv.g^-1, respectively. In both male and female animals the mean peak concentration was reachedmin post final dose (T_max); the levels remained almost constant up to 1 hour in male and 24 minutes in female. Mean levels of radioactivity then decreased rapidly to 0.583 and 0.487 µg equiv.g^-1, until 4 hours post final dose, in male and female, respectively. The decline continued thereafter at a slower rate. The mean concentration of total radioactivity was below the limit of detection for all animals at 72 hours post final dose.

The half-life (T_1/2) washours (males) and 10.85 hours (females) and AUC (area under the blood concentration vs. time curve) wash µg.g^-1(males) and 13.78 h µg.g^-1(females). These results perfectly overlap with those obtained after a single dose oral administration, indicating that at this low dose, no saturation of any process, neither induction of the specific pathways in the test item biotrasformation occurred.

The results are summarised in Tables 5.1-8 and 5.1-9.

 

Table 5.1-8:          Concentration of total radioactivity in whole blood after a multiple dose administration        of 5 mg/kg bw of [¹⁴C-U-phenyl]IR5878 (expressed as µg equiv.g^-1)

Timepoint	Male	Female
6 min	2.703	4.788
12 min	3.203	6.322
24 min	2.716	5.973
1 h	2.997	2.480
2 h	1.406	0.981
4 h	0.583	0.487
6 h	0.418	0.392
8 h	0.329	0.289
24 h	0.076	0.088
48 h	0.016	0.022
72 h	0.005	0.008

 

Table 5.1-9:          Main pharmacokinetic parameters after a multiple dose administration of 5 mg/kg bw of  [¹⁴C-U-phenyl]IR5878

	Cmax	Tmax	T1/2	r^2	AUC
Male	3.203 µg equiv.g^-1	12 min	9.27hours	0.999	13.14h µg.g^-1
Female	6.322 µg equiv.g^-1	12 min	10.85 hours	0.995	13.78 h µg.g^-1

 

Tissue distribution (Phases 7, 8, 9)

For all three phases the distribution of total radioactivity was similar for male and female animals, with the highest mean concentration at T_maxfound in the gastrointestinal tract. However, at 72 hours post dose, the carcass, including all the organs and the tissues, contained amounts of radioactivity < 0.70% of dose, showing an almost complete clearance.

 

Single dose administrationmg/kg bw (Phase 7)

Following dose administrationmg/kg bw, the mean concentration of total radioactivity in the gastrointestinal tract at T_maxwas 27.41 (61.81% dose) and 29.48 µg equiv.g^-1(53.82% dose) for male and female animals, respectively. Lower concentrations were found in the liver (meanandµg equiv.g^-1, respectively) which accounted for 11.28% and 8.77% of the dose, respectively, and kidneys (meanandµg equiv.g^-1, respectively, corresponding to 1.72% and 0.65%). All other tissues contained mean concentrations < 3 µg equiv.g^-1and accounted for < 0.2% of the dose for both male and female animals, with the exception of carcass, containing 0.68 µg equiv.g^-1(males) andµg equiv.g^-1(females) of total radioactivity, corresponding to 10.89% (males) and 8.00% (females) of the administered dose. The total recovery of radioactivity was about 86% and 70% of the administered dose, in male and female, respectively.

The results are summarised in Tables 5.1-10 and 5.1-11.

 

Table 5.1-10:        Amount of radioactivity in tissues at T_maxafter a single dose administration of 5 mg/kg bw of           [¹⁴C-U-phenyl]IR5878 expressed in µg equiv.g^-1

Sample	Male	Female
	µg equiv.g^-1	µg equiv.g^-1
Bone	0.341	0.346
Brain	0.165	0.206
Fat-brown	0.713	0.576
Fat subcutaneous	0.639	0.667
Heart	0.989	0.844
Kidneys	8.456	3.511
Liver	11.183	9.302
Lungs	1.739	1.750
Muscle	0.479	0.415
Spleen	0.525	0.577
Gastrointestinal tract	27.409	29.476
Carcass^1	0.678	0.497
Whole blood	2.856	2.410

¹Carcass includes all the bone, muscle, fat and other tissues not completely sampled at necropsy

 

Table 5.1-11:        Amount of radioactivity in tissues at T_maxafter a single dose administration of 5 mg/kg bw of           [¹⁴C-U-phenyl]IR5878 expressed in % administered dose

Sample	Male	Female
	% administered dose	% administered dose
Brain	0.02	0.03
Heart	0.09	0.08
Kidneys	1.72	0.65
Liver	11.28	8.77
Lungs	0.20	0.24
Spleen	0.03	0.03
Gastrointestinal tract	61.81	53.82
Carcass^1	10.89	8.00
Total	86.05	71.62

¹Carcass includes all the bone, muscle, fat and other tissues not completely sampled at necropsy

 

Single dose administration at 1000 mg/kg bw (Phase 8)

Following dose administration at 1000 mg/kg bw, the mean concentration of total radioactivity in the gastrointestinal tract was 5861.40 (70.17% dose) and 5707.40 µg equiv.g^-1(62.18% dose) for male and female animals, respectively. Mean concentrations were about 300 µg equiv.g^-1(females) for whole blood, 260-400 µg equiv.g^-1for the kidneys, and 260-280 µg equiv.g^-1for the liver. The mean recoveries of radioactivity from liver and kidneys were 1.3% and <0.4% of the administered dose, respectively. Residues in the remaining tissues were lower, with mean values ranging between 27.80 to 161.37 µg equiv.g^-1(≤0.15% dose). Carcass was an exception, containing 128.37 and 97.84 µg equiv.g^-1for male and female animals, respectively, accounting for 9.97% and 7.74% of the administered dose, respectively. The total recovery of radioactivity was about 83% and 72% of the administered dose, in male and female, respectively.

The results are summarised in Tables 5.1-12 and 5.1-13.

Table 5.1-12:        Amount of radioactivity in tissues at T_maxafter a single dose administration of 1000 mg/kg bw of  [¹⁴C-U-phenyl]IR5878 expressed in µg equiv.g^-1

Sample	Male	Female
	µg equiv.g^-1	µg equiv.g^-1
Bone	27.80	32.72
Brain	31.29	45.79
Fat-brown	91.20	138.78
Fat subcutaneous	48.92	108.01
Heart	122.95	161.52
Kidneys	406.75	259.78
Liver	266.90	282.88
Lungs	161.37	223.31
Muscle	72.01	95.43
Spleen	71.28	111.54
Gastrointestinal tract	5861.40	5707.40
Carcass^1	128.37	97.84
Whole blood	305.06	311.81

¹Carcass includes all the bone, muscle, fat and other tissues not completely sampled at necropsy

 

Table 5.1-13:        Amount of radioactivity in tissues at T_maxafter a single dose administration of 1000 mg/kg bw of  [¹⁴C-U-phenyl]IR5878 expressed in % administered dose

Sample	Male	Female
	% administered dose	% administered dose
Brain	0.02	0.03
Heart	0.05	0.08
Kidneys	0.37	0.25
Liver	1.27	1.32
Lungs	0.10	0.15
Spleen	0.03	0.03
Gastrointestinal tract	70.17	62.18
Carcass^1	9.97	7.74
Total	82.87	71.78

¹Carcass includes all the bone, muscle, fat and other tissues not completely sampled at necropsy

 

Multiple dose administrationmg/kg bw (Phase 9)

Following an oral administration of [¹⁴C-U-phenyl]IR5878 after multiple oral administrations of non-radiolabelled IR5878 for 14 consecutive days, the mean concentration of total radioactivity in the gastrointestinal tract was 27.695 µg equiv.g^-1(males) and 23.114 µg equiv.g^-1(females) which accounted for 51.76% (males) and 41.27% (females) of dose, respectively. Liver and kidneys from male contained 12.049 µg equiv.g^-1(10.32% dose) and 12.218 µg equiv.g^-1(2.03% dose), respectively; in female 11.997 µg equiv.g^-1(9.93% dose) and 3.714 µg equiv.g^-1(0.67% dose) were detected in liver and kidney, respectively. Residues in the remaining tissues were lower, accounting fortoµg equiv.g^-1for both sexes (£0.18% to£0.29% dose). Carcass was an exception, with mean concentration values of 0.756 and 0.641 µg equiv.g^-1for male and female animals, respectively, corresponding to 12.00% and 9.79% of the administered dose. The total recovery of radioactivity was about 76% and 62% of the administered dose in male and female, respectively.

The results are summarised in Tables 5.1-14 and 5.1-15.

 

Table 5.1-14:        Amount of radioactivity in tissues at T_maxafter a multiple dose administration of 5 mg/kg bw of  [¹⁴C-U-phenyl]IR5878 expressed in µg equiv.g^-1

Sample	Male	Female
	µg equiv.g^-1	µg equiv.g^-1
Bone	0.255	0.200
Brain	0.233	0.337
Fat-brown	0.830	0.883
Fat subcutaneous	0.677	1.171
Heart	1.049	1.179
Kidneys	12.218	3.714
Liver	12.049	11.997
Lungs	1.953	2.448
Muscle	0.489	0.560
Spleen	0.596	0.749
Gastrointestinal tract	27.695	23.114
Carcass^1	0.756	0.641
Whole blood	2.990	3.118

¹Carcass includes all the bone, muscle, fat and other tissues not completely sampled at necropsy

 

Table 5.1-15:        Amount of radioactivity in tissues at T_maxafter a multiple dose administration of 5 mg/kg bw of  [¹⁴C-U-phenyl]IR5878 expressed in % administered dose

Sample	Male	Female
	% administered dose	% administered dose
Brain	0.02	0.05
Heart	0.07	0.09
Kidneys	2.03	0.67
Liver	10.32	9.93
Lungs	0.18	0.29
Spleen	0.02	0.03
Gastrointestinal tract	51.76	41.27
Carcass^1	12.00	9.79
Total	76.40	62.13

¹Carcass includes all the bone, muscle, fat and other tissues not completely sampled at necropsy

 

Biliary elimination (Phase 10)

72 hours after a single administration of 5 mg/kg bw [¹⁴C-U-phenyl]IR5878, the overall mean recovery of radioactivity was 99.40% and 93.79% in male and female, respectively. Elimination of radioactivity was mainlyviaurine (39.64% and 36.58% of the administered dose in male and female, respectively) and bile (38.37% and 36.36% of the administered dose in male and female), for a mean recovery of 78.01% and 72.94% in male and female, respectively. These values indicate that most of the radioactivity recovered in faeces came from entero-hepatic circulation. Excretion in faeces accounted for about 17% of the dose in both sexes, wich summed up with the bile radioactivity content gave rise to a recovery representing about 53-55% of the administered dose. The excretion of total radioactivity in urine, bile and faeces was very rapid, with the majority of the radioactivity being excreted withinca12 hours of dose administration. These values were consistent with the recovery of radioactivity in faeces and urine observed during excretion kinetic study phases. At 72 hours levels of radioactivity in the gastrointestinal tract and carcass were <0.2% of the dose. No differences between sexes were identified.

The results are summarised in Table 5.1-16.

 

Table 5.1-16:        Cumulative biliary elimination of total radioactivity after a single dose administration of 5 mg/kg bw of [¹⁴C-U-phenyl]IR5878 (expressed as % of the administered dose)

	Urine	Faeces	Bile	Cagewash	Gastrointestinal tract	Carcass^1	Recovery
Male
6 hours	30.64		36.50				67.14
12 hours	37.14	4.11	38.01	3.71			82.96
24 hours	38.75	13.21	38.21	3.87			94.03
48 hours	39.53	16.59	38.35	3.94			98.41
72 hours	39.64	17.05	38.37	4.11	0.16	0.07	99.40
Female
6 hours	29.98		33.57				63.55
12 hours	34.64	5.40	35.71	2.85			78.61
24 hours	35.85	13.24	36.18	3.13			88.41
48 hours	36.50	17.28	36.33	3.21			93.31
72 hours	36.58	17.47	36.36	3.28	0.06	0.08	93.79

¹Carcass includes all the bone, muscle, fat and other tissues not completely sampled at necropsy

Applicant's summary and conclusion

Conclusions:

Based on the overall results obtained from the 10 phases experiments, it can be concluded that [14C-U-phenyl]-IR5878 orally administered at 5 mg/kg bw is absorbed very rapidly (peak blood concentration 1 h) and quite extensively (70-80%). Indeed, over 90% of the administered radioactivity was recovered in the excreta within 48 hours post-treatment. At 72 hours after IR5878 administration, faeces accounted for the highest proportion of the dose (66.38% and 52.93% in male and female, respectively). However, in bile-cannulated rats, about 36-38% of the dose was detected in bile over 48 hours, indicating that the biliary escretion was an important route of elimination In the same animals faeces samples contained about 17% of the administered dose by 72 hours post dose, and this presumably represented unabsorbed dose. The urine of bile duct cannulated animals contained mean values of 36-40% of dose at 72 hours post dose, consistently with results obtained in similarly dosed non-cannulated animals (30-38% of the administered dose). IR5878 was widely distributed to the different organs: however, the tissue containing the highest concentration at Tmax was the gastrointestinal tract; the only other tissues to contain a concentration greater than the one associated with whole blood were the liver and the kidney. There was no marked difference between sexes. By 72 hours post dose concentrations were low in the blood (approaching the limit of quantification), as well as in the carcass (< 0.5%), indicating a rapid clearance of IR5878.

At the higher dose level (1000 mg/kg bw) the excretion pattern following single oral administration was consistent with the single low dose level data and again there was no marked sex difference. Over 90% of the administered dose was recovered by 48 hours post dose with the majority of the administered radioactivity being recovered in faeces with mean recoveries of 72.89% (males) and 66.27% (females) of dose at 72 hours post dose. Urine contained mean values of 17.65% and 23.28% of the dose at 72 hours post dose in male and female, respectively. The slower rate of clearance of radioactivity from the whole blood paralled the slightly longer Tmax when compared to the low dose results; in addition the AUC values, about 300-400 fold higher compared to the low level oral dosed animals, indicate a saturation of the clearance pathways in the whole blood but no saturation for the absorption processes (Cmax about 200-fold higher than the one attained after a single low dose administration). However, at 72 hours post dose, the carcass, including all the organs and the tissues, contained amounts of radioactivity < 0.70% of dose, showing an almost complete clearance.

The excretion of radioactivity after the repeated treatment with low doses (5 mg/kg bw) of IR5878 for 15 days was not different from the pattern shown after a single oral dose administration. Again the greater proportion of the administered dose was excreted in faeces (62.76% and 50.73% in male and female) at 72 hours post dose. Urine contained mean values of 31.52% and 40.69% of dose at 72 hours post dose in male and female, respectively. The pharmacokinetics parameters (Cmax, Tmax, AUC, T1/2) obtained in the single and the repeated dose experiments also overlap, as well as the pattern of distribution and recovery of radioactivity in the carcass, 72 h after the last treatment. These results indicated that IR5878 has no potential for bioaccumulation neither the ability to induce specific pathways of its own biotransformation.

Executive summary:

IR5878 was administered to Sprague Dawley rats. Four groups rats received a single oral dose of 5 mg/kg bw of [¹⁴C-U-phenyl]IR5878 (excretion kinetic, blood kinetic, tissue distribution and biliary elimination evaluation). Further three groups of rats received a single oral dose of 1000 mg/kg bw of [¹⁴C-U-phenyl]IR5878 (excretion kinetic, blood kinetic and tissue distribution evaluation). Finally three groups of rats received a multiple oral dose of IR5878: once daily for 14 consecutive days with cold IR5878 followed by one dose of [¹⁴C-U-phenyl]IR5878 on day 15 (target dose 5 mg/kg bw) (excretion kinetic, blood kinetic and tissue distribution evaluation).

Based on the overall results obtained from the 10 phases experiments, it can be concluded that [¹⁴C-U-phenyl]-IR5878 orally administeredmg/kg bw is absorbed very rapidly (peak blood concentration 1 h) and quite extensively (70-80%). Indeed, over 90% of the administered radioactivity was recovered in the excreta within 48 hours post-treatment. At 72 hours after IR5878 administration, faeces accounted for the highest proportion of the dose (66.38% and 52.93% in male and female, respectively). However, in bile-cannulated rats, about 36-38% of the dose was detected in bile over 48 hours, indicating that the biliary escretion was an important route of elimination In the same animals faeces samples contained about 17% of the administered dose by 72 hours post dose, and this presumably represented unabsorbed dose. The urine of bile duct cannulated animals contained mean values of 36-40% of dose at 72 hours post dose, consistently with results obtained in similarly dosed non-cannulated animals (30-38% of the administered dose). IR5878 was widely distributed to the different organs: however, the tissue containing the highest concentration at T_maxwas the gastrointestinal tract; the only other tissues to contain a concentration greater than the one associated with whole blood were the liver and the kidney. There was no marked differences between sexes. By 72 hours post dose concentrations were low in the blood (approaching the limit of quantification), as well as in the carcass (< 0.5%), indicating a rapid clearance of IR5878.

At the higher dose level (1000 mg/kg bw) the excretion pattern following single oral administration was consistent with the single low dose level data and again there was no marked sex difference. Over 90% of the administered dose was recovered by 48 hours post dose with the majority of the administered radioactivity being recovered in faeces with mean recoveries of 72.89% (males) and 66.27% (females) of dose at 72 hours post dose. Urine contained mean values of 17.65% and 23.28% of the dose at 72 hours post dose in male and female, respectively. The slower rate of clearance of radioactivity from the whole blood paralled the slightly longer T_maxwhen compared to the low dose results; in addition the AUC values, about 300-400 fold higher compared to the low level oral dosed animals, indicate a saturation of the clearance pathways in the whole blood but no saturation for the absorption processes (C_maxabout 200-fold higher than the one attained after a single low dose administration). However, at 72 hours post dose, the carcass, including all the organs and the tissues, contained amounts of radioactivity < 0.70% of dose, showing an almost complete clearance.

The excretion of radioactivity after the repeated treatment with low doses (5 mg/kg bw) of IR5878 for 15 days was not different from the pattern shown after a single oral dose administration. Again the greater proportion of the administered dose was excreted in faeces (62.76% and 50.73% in male and female) at 72 hours post dose. Urine contained mean values of 31.52% and 40.69% of dose at 72 hours post dose in male and female, respectively. The pharmacokinetics parameters (C_max, T_max, AUC, T_1/2) obtained in the single and the repeated dose experiments also overlap, as well as the pattern of distribution and recovery of radioactivity in the carcass, 72 h after the last treatment. These results indicated that IR5878 has no potential for bioaccumulation neither the ability to induce specific pathways of its own biotransformation.