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Administrative data

Endpoint:
health surveillance data
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labelling and/or risk assessment.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1987

Materials and methods

Study type:
human medical data
Endpoint addressed:
basic toxicokinetics
Principles of method if other than guideline:
The test substance kinetics were studied after oral and intravenous administration to 10 patients with impaired renal function, three of whom were being evaluated for intestinal malabsorption.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Purity: no data

Method

Type of population:
general
Ethical approval:
not specified
Details on study design:
Ten Patients with renal insufficiency, three of whom also had gastro intestinal disease, for which evaluation of malabsorption was warranted, were examined. Patients with less severe renal failure were tested to define the level of impairment of renal function that is associated with decreases in the rate and extent of the test substance absorption and to examine the relationship between renal clearance (CLr) of the test substance and estimated glomerular filtration rate. The results of the kinetic analysis were also compared with standard clinical indexes of the test substance absorption to evaluate their utility in patients with moderately impaired renal function.

Results and discussion

Results:
D-xylose kinetics was studied after oral administration to 10 patients with impaired renal function, three of whom were being evaluated for intestinal malabsorption. The 0.32 ± 0.06 L/kg (mean ± SD) distribution volume of D-xylose in patients with uncomplicated renal impairment was larger than the value of 0.23 ± 0.04 L/kg that the authors reported previously for normal subjects (P < 0.01). Renal clearance was also reduced, averaging 87% of glomerular filtration rate estimated from creatinine clearance, so that the elimination-phase half-life was prolonged to 138 ± 39 minutes from 75 ± 11 minutes in normal individuals (P < 0.01). The 25 g oral D-xylose dose was 77.4% ± 14.8% absorbed in the patients with uncomplicated renal impairment, similar to the 69.4% ± 13.6% absorption reported in normal individuals. However, the absorption half-life was prolonged from 31 ± 12 minutes in normal subjects to a value of 62 ± 23 minutes (P < 0.02). Of the usual clinical indexes of D-xylose absorption, the serum concentration measured 1 hour after the oral dose was best correlated with the extent of D-xylose absorption (r = 0.76; P < 0.01), and the standard lower normal limit of 0.2 mg/mL was satisfactory.

Any other information on results incl. tables

Parameter values characterizing the test substance distribution and elimination are summarized in Table 2 below, along with the results obtained in normal subjects and patients on dialysis.  

Table 2. Parameters describing distribution and elimination kinetics of D-xylose

 

VC(L)

Vss(L)

Vss(L/kg)

*CLI(mL/min)

CLR (mL/min)

CLNR(mL/min)

CLNR(mL/min kg)

T½(min)

Renal insufficiency

1

16.1

26.7

0.40

320

11.1

91.4

1.36

190

2

5.3

22.3

0.25

1032

30.9

172.3

1.91

83

3

12.7

20.3

0.26

854

34.6

101.8

1.32

108

4

6.0

15.4

0.35

449

29.2

74.3

1.69

114

5

9.9

20.6

0.29

211

22.8

73.3

1.03

175

6

12.8

21.4

0.32

376

21.4

77.3

1.17

154

7

13.4

20.6

0.38

297

26.3

71.3

1.32

152

Mean

10.9

21.0

0.32

506

25.2

94.5

1.40

139

SD

4.0

3.3

0.06

313

7.7

36.1

0.30

39

Malabsorption

1

18.7

22.1

0.61

222

30.7

76.7

2.11

143

2

14.8

19.6

0.31

403

39.8

73.3

1.16

122

3

13.0

23.5

0.59

91

43.2

47.7

1.19

174

Previous Results

Normal Patients

Mean (n=12)

8.5

17.2

0.23

578

88.8

90.9

1.23

75

SD

4.9

3.7

0.04

508

20.4

28.9

0.35

11

Dialysis Patients

Mean (n=9)

8.7

22.7

0.33

790

----

43.3

0.65

388

SD

5.9

7.9

0.09

737

----

9.4

0.17

137

Note: *CLI= intercompartmental clearance

The 0.32±0.06 L/kg (mean±SD) Vcin patients with moderate renal insufficiency was similar to the value of 0.33±0.09 L/kg for patients on dialysis and was larger than the value of 0.23±0.04 L/kg in normal subjects (P < 0.01). Nonetheless, only a weak correlation could be demonstrated between D-xylose Vc and glomerular filtration rate in the seven patients with uncomplicated renal insufficiency (r = 0.62; P > 0.05). CLRof D-xylose was less than in normal subjects (P < 0.001) and was approximately 87% of the estimated glomerular filtration rate. Although the patients in this study did not exhibit reductions in non-renal D-xylose clearance (CLNR), increased VCand reduced CLRprolonged the elimination t½from 75±11 minutes in normal individuals to 138±39 minutes in patients with renal insufficiency (P < 0.01).

Parameters describing the kinetics of D-xylose absorption are summarized in Table 3 below.

Table 3. Parameters describing absorption kinetics of D-xylose

 

Peak (D-xylose(mg/mL)

Time to peak(min)

Lag(min)

*Ka(hr-1)

*Ko(hr-1)

t½a(min)

f(%)

Renal insufficiency

1

0.56

60

4

0.994

0.246

34

80.2

2

0.35

90

6

0.424

0.143

73

74.8

3

0.62

120

4

0.813

0.008

51

99.0

4

0.41

60

8

0.411

0.402

5

50.6

5

0.66

120

6

0.423

0.131

75

76.4

6

0.56

180

18

0.428

0.062

31

87.4

7

0.62

110

16

0.990

0.364

62

73.1

Mean

0.54

106

9

0.640

0.194

23

77.4

SD

0.12

42

6

0.280

0.149

 

14.8

Malabsorption

1

0.18

240

30

0.114

0.263

110

30.1

2

0.39

90

14

0.487

0.482

72

50.3

3

0.38

180

14

0.118

0.132

166

47.2

Previous Results

Normal Patients

Mean (n=12)

0.54

71

22

1.031

0.492

31

69.4

SD

0.10

15

16

0.332

0.345

12

13.6

Dialysis Patients

Mean (n=9)

0.48

166

45

0.555

0.668

65

48.6

SD

0.20

82

24

0.416

0.613

65

13.3

Note: *Ka  Koare parameters of the kinetic model.

In patients with uncomplicated renal insufficiency, the t½of D–xylose was prolonged from 31±12 minutes in normal individuals to a value of 62±23 minutes (P < 0.02) that was similar to the average for functionally anephric patients. However, the time to reach peak D-xylose levels was not significantly prolonged in patients with uncomplicated renal insufficiency and they had a D-xylose bioavailability of 77.4%±14.8% that was similar to the value of 69.4%±13.6% that we found previously in normal subjects. Of the three patients with clinical evidence of malabsorption, only the first had an absolute bioavailability of D-xylose (f) that was outside the range of 42.2% to 96.6% that is the 95% confidence interval of our results in normal subjects. When the results from all patients are included, Kais only moderately well correlated with f (r = 0.66; P < 0.05).

Other indexes of D-xylose absorption are summarized in Table 4 below.

Table 4. Other indexes of D-xylose absorption

 

1-hr serum (D-xylose) *(mg/mL)

5-Hr urine D-xylose excretion*(g)

Fur(%)

Renal insufficiency

1

0.56

0.75

----

2

0.26

1.65

49.4

3

0.53

4.35

91.6

4

0.41

1.93

38.7

5

0.46

1.98

54.0

6

0.36

2.30

83.0

7

0.53

2.13

47.5

Mean

0.44

2.16

60.7

SD

0.11

1.09

21.4

Malabsorption

1

0.05

1.21

39.7

2

0.27

2.95

44.0

3

0.07

0.40

31.7

Correlation with f

r

0.76

0.50

0.86

P

<0.01

>0.05

<0.002

Note: After 25 gram oral D-xylose

 

Serum concentrations measured 1 hour after oral D-xylose administration are well correlated with f (r = 0.76; P < 0.01), but there is only a weak correlation between 5-hour D-xylose recovery in urine and f (r = 0.50; P > 0.05). A better correlation is obtained when 24-hour urine recoveries are used to estimate fURfrom equation 1 (r = 0.86; P < 0.002).

Applicant's summary and conclusion

Conclusions:
D-xylose kinetics was studied after oral administration to 10 patients with impaired renal function, three of whom were being evaluated for intestinal malabsorption. The 0.32 ± 0.06 L/kg (mean ± SD) distribution volume of D-xylose in patients with uncomplicated renal impairment was larger than the value of 0.23 ± 0.04 L/kg that the authors reported previously for normal subjects (P < 0.01). Renal clearance was also reduced, averaging 87% of glomerular filtration rate estimated from creatinine clearance, so that the elimination-phase half-life was prolonged to 138 ± 39 minutes from 75 ± 11 minutes in normal individuals (P < 0.01). The 25 g oral D-xylose dose was 77.4% ± 14.8% absorbed in the patients with uncomplicated renal impairment, similar to the 69.4% ± 13.6% absorption reported in normal individuals. However, the absorption half-life was prolonged from 31 ± 12 minutes in normal subjects to a value of 62 ± 23 minutes (P < 0.02). Of the usual clinical indexes of D-xylose absorption, the serum concentration measured 1 hour after the oral dose was best correlated with the extent of D-xylose absorption (r = 0.76; P < 0.01), and the standard lower normal limit of 0.2 mg/mL was satisfactory. The study and the conclusions which are drawn from it fulfil the quality criteria (validity, reliability, repeatability).
Executive summary:

The authors previously compared the absolute bioavailability of D-xylose in normal subjects and patients requiring hemodialysis and demonstrated that these patients absorbed D-xylose less completely (48.6% vs. 69.4%) and at a slower rate than did normal subjects. In addition, they found that the D-xylose Vwas increased and that CLNR was decreased in these functionally anephric patients. Both of these changes prolonged the elimination t½of this compound. The authors now extended observations to patients with less severely impaired renal function and conclude that the absolute bioavailability and the CLNR of D-xylose appear to be maintained at normal levels in patients whose CLCR ranges from 30 to 50 mL/min. However, the t½ of D-xylose absorption is prolonged and the Vis increased to the same extent as that for patients on dialysis. The prolongation of elimination t½ in patients with moderately impaired renal function results from this increased Vand the reduced CLof D-xylose.

Although Huguenin et al. reported that the correlation coefficient between D-xylose CLand CLCR was 0.85, the results summarized extend these observations and indicate that the CLof D-xylose averages 87% of estimated glomerular filtration rate. Accordingly, it appears that there is approximately 13% net tubular reabsorption of glomerularly filtered D-xylose. Some tubular reabsorption of D-xylose is expected in humans since it has been demonstrated that there is 25% tubular reabsorption of filtered D-xylose in dogs.

Xu is determined by the relationship:

XU=f . D_____CLr______             

CLNR+CLNR

where D is the test dose. Since CLNR is not affected in patients with only moderately impaired renal function, these individuals will excrete less of a D-xylose test dose in their urine than will subjects with normal renal function. Both this and the delayed rate of D-xylose absorption contribute to the poor correlation that we found in these patients between the 5-hour recovery of D-xylose in urine and the absolute bioavailability of this compound. In addition, there are practical difficulties inherent in obtaining accurate urine collections that account for the fact that estimates of the extent of D-xylose absorption that are based on 24-hour recovery in urine do not correlate perfectly with results calculated from kinetic analysis of serum concentration data.

The relationship between impaired renal function and reduced D-xylose CLis of particular interest because the standard D-xylose test has been based on the recovery of this compound in urine for 5 hours after administration of a 25 g oral dose. If the usual lower limit of 4 g for the 5-hour urine recovery of D-xylose were applied to our results, D-xylose malabsorption would have been suspected in all but one of the patients with uncomplicated renal insufficiency, despite the fact that the patient absorbed the oral D-xylose dose to a normal extent. In these patients the 2.16±1.09 g 5-hour recovery of D-xylose in urine was similar to the value of 1.8±1.1 g reported by Finlay and colleagues et al. for seven patients with chronic renal disease.

Other investigators have attempted to circumvent the confounding effect of impaired renal function on the D-xylose test by relying on estimated peak D-xylose concentrations measured in plasma or serum obtained 1 hour after an oral test dose. If 0.2 mg/mL is taken as the lower limit of normal, all patients with uncomplicated renal failure and patient 2 with suspected malabsorption would be considered to have normal D-xylose absorption. Although this latter patient underwent multiple resections of the ileum for Crohn's disease, this normal result is consistent with clinical experience that Crohn's disease affects primarily the distal small intestine and that proximal intestinal absorption of carbohydrate is usually well preserved. On the other hand, abnormal results were obtained in patient 1, whose scleroderma bowel disease was severe enough to require parenteral nutrition, and in patient 3, who had severe Crohn's ileitis with partial bowel obstruction. Bacterial overgrowth probably accounted for D-xylose malabsorption in these two patients. Thus even though the results are limited to a small number of patients, they are consistent with the empirically established use of 1-hour, postdose D-xylose plasma or serum levels as a diagnostic test for carbohydrate malabsorption.

Formal determination of the extent of D-xylose absorption also guards against the inappropriate diagnosis of D-xylose malabsorption in patients with uncomplicated renal insufficiency. However, only patient 1 with the most severe malabsorption had a clearly abnormal result. Theoretically, reductions in D-xylose kmight be expected to parallel impaired intestinal mucosal transport more closely than the extent of D-xylose absorption or the 1-hour serum D-xylose level. For example, these latter indexes are affected by the rate at which intestinal bacteria metabolize D-xylose and would not distinguish between a primary mucosal defect and bacterial overgrowth, which is a recognized cause of D-xylose malabsorption. If a value of 0.367 hr-1 is taken as the lower limit of normal (mean - 2 SD), it was seen that kwas normal in the patients with uncomplicated renal insufficiency and was abnormal in the two patients with the most severely compromised gastrointestinal function. This parallels the pattern of the 1-hour serum D-xylose level. However, further studies are needed to fully assess the discriminatory utility of estimating kas a test of carbohydrate absorption.