J Endocrinol Metab

Journal of Endocrinology and Metabolism, ISSN 1923-2861 print, 1923-287X online, Open Access

Article copyright, the authors; Journal compilation copyright, J Endocrinol Metab and Elmer Press Inc

Journal website http://www.jofem.org

Original Article

Volume 1, Number 3, August 2011, pages 113-124

Influence of Efavirenz and Nevirapine on the Pharmacodynamics and Pharmacokinetics of Gliclazide in Rabbits

Figure 1. Study design for conducting pharmacodynamic and pharmacokinetic interaction studies of selected non-nucleoside reverse transcriptase inhibitors (NNRTIs) with gliclazide in rabbits.

Figure 4. Mean insulin levels (µU/mL) of gliclazide before and after treatment with efavirenz in normal rabbits (n = 6) (Data are expressed as mean ± SD; *Significant difference at P < 0.05 compared to gliclazide control).

Figure 5. Mean serum gliclazide concentration (ng/mL) before and after treatment with efavirenz in rabbits (n = 6; inset = semi log scale) (Data are expressed as mean ± SD).

Figure 6. Mean insulin levels (µU/mL) of gliclazide before and after treatment with nevirapine in normal rabbits (n = 6) (Data are expressed as mean ± SD; No significant difference at P < 0.05 compared to gliclazide control).

Figure 7. Mean serum gliclazide concentration (ng/mL) before and after treatment with nevirapine in rabbits (n = 6; inset = semi log scale) (Data are expressed as mean ± SD).

**Table 1.** Mean Percent Blood Glucose Reduction of Gliclazide in Presence and Absence of Efavirenz in Rabbits (n = 6)
Time (hr)	Gliclazide	Efavirenz	Efavirenz + Gliclazide (Single dose treatment)	Efavirenz + Gliclazide (Multiple dose treatment)
Data are expressed as mean ± SD; ^*Significant at P < 0.05 compared to gliclazide control.
1	16.68 ± 5.13	-2.65 ± 1.86	5.44 ± 5.47^*	10.56 ± 3.59^*
2	22.84 ± 6.61	-4.40 ± 2.35	11.43 ± 3.77^*	15.69 ± 3.42^*
3	32.82 ± 5.34	-1.98 ± 2.93	21.86 ± 3.11^*	26.33 ± 2.55^*
4	24.41 ± 4.65	0.14 ± 3.04	11.07 ± 3.97^*	16.05 ± 3.74^*
6	22.85 ± 6.14	1.56 ± 2.29	8.89 ± 2.25^*	13.15 ± 2.60^*
8	17.56 ± 3.84	3.67 ± 4.28	6.99 ± 3.09^*	11.30 ± 3.00^*
12	8.51 ± 6.13	5.79 ± 4.77	5.14 ± 3.17	9.89 ± 1.84
16	3.74 ± 6.04	7.55 ± 3.86	0.69 ± 2.24	5.43 ± 4.01
20	2.28 ± 6.01	6.85 ± 4.97	-0.80 ± 2.70	2.90 ± 3.60
24	0.03 ± 6.63	6.18 ± 2.20	-2.71 ± 4.44	1.79 ± 2.56

Table 1. Mean Percent Blood Glucose Reduction of Gliclazide in Presence and Absence of Efavirenz in Rabbits (n = 6)

Time (hr)

Gliclazide

Efavirenz

Efavirenz + Gliclazide (Single dose treatment)

Efavirenz + Gliclazide (Multiple dose treatment)

Data are expressed as mean ± SD; ^*Significant at P < 0.05 compared to gliclazide control.

16.68 ± 5.13

-2.65 ± 1.86

5.44 ± 5.47^*

10.56 ± 3.59^*

22.84 ± 6.61

-4.40 ± 2.35

11.43 ± 3.77^*

15.69 ± 3.42^*

32.82 ± 5.34

-1.98 ± 2.93

21.86 ± 3.11^*

26.33 ± 2.55^*

24.41 ± 4.65

0.14 ± 3.04

11.07 ± 3.97^*

16.05 ± 3.74^*

22.85 ± 6.14

1.56 ± 2.29

8.89 ± 2.25^*

13.15 ± 2.60^*

17.56 ± 3.84

3.67 ± 4.28

6.99 ± 3.09^*

11.30 ± 3.00^*

8.51 ± 6.13

5.79 ± 4.77

5.14 ± 3.17

9.89 ± 1.84

3.74 ± 6.04

7.55 ± 3.86

0.69 ± 2.24

5.43 ± 4.01

2.28 ± 6.01

6.85 ± 4.97

-0.80 ± 2.70

2.90 ± 3.60

0.03 ± 6.63

6.18 ± 2.20

-2.71 ± 4.44

1.79 ± 2.56

**Table 2.** Mean Pharmacokinetic Parameters of Gliclazide Before and After Efavirenz Administration in Rabbits (n = 6)
Pharmacokinetic parameter	Gliclazide	Efavirenz + Gliclazide (Single dose treatment)	Efavirenz + Gliclazide (Multiple dose treatment)
Data are expressed as mean ± SD; ^*Significant at P < 0.05 compared to gliclazide control.
C_max (ng/mL)	391.21 ± 5.50	342.58 ± 13.45^*	363.37 ± 14.47^*
T_max (h)	3.00 ± 0.00	3.00 ± 0.00	3.00 ± 0.00
AUC_0-24 (ng/mL/h)	4465.66 ± 168.89	3441.40 ± 278.44^*	3841.04 ± 293.26^*
AUC_0-inf (ng/mL/h)	5520.68 ± 277.21	3907.52 ± 292.87^*	4441.83 ± 370.97^*
AUMC_0-24 (ng/mL/h*h)	43954.52 ± 2041.06	31748.24 ± 3094.48^*	36293.66 ± 3715.04^*
AUMC_0-inf (ng/mL/h*h)	83977.99 ± 6954.70	47878.08 ± 5839.39^*	57613.10 ± 7573.52^*
MRT_0-24 (h)	9.84 ± 0.09	9.21 ± 0.15^*	9.43 ± 0.25^*
MRT_0-inf (h)	15.19 ± 0.60	12.24 ± 1.05^*	12.94 ± 0.84^*
Vd (L)	14.71 ± 0.66	15.15 ± 2.97	14.93 ± 1.60
CL (L/h)	0.06 ± 0.03	1.51 ± 0.11^*	1.33 ± 0.11^*
K_el (h^-1)	0.07 ± 0.00	0.10 ± 0.02^*	0.09 ± 0.01^*
T_½ (h)	9.62 ± 0.67	7.01 ± 1.45^*	7.84 ± 0.93^*

Table 2. Mean Pharmacokinetic Parameters of Gliclazide Before and After Efavirenz Administration in Rabbits (n = 6)

Pharmacokinetic parameter

Gliclazide

Efavirenz + Gliclazide (Single dose treatment)

Efavirenz + Gliclazide (Multiple dose treatment)

Data are expressed as mean ± SD; ^*Significant at P < 0.05 compared to gliclazide control.

C_max (ng/mL)

391.21 ± 5.50

342.58 ± 13.45^*

363.37 ± 14.47^*

T_max (h)

3.00 ± 0.00

AUC_0-24 (ng/mL/h)

4465.66 ± 168.89

3441.40 ± 278.44^*

3841.04 ± 293.26^*

AUC_0-inf (ng/mL/h)

5520.68 ± 277.21

3907.52 ± 292.87^*

4441.83 ± 370.97^*

AUMC_0-24 (ng/mL/h*h)

43954.52 ± 2041.06

31748.24 ± 3094.48^*

36293.66 ± 3715.04^*

AUMC_0-inf (ng/mL/h*h)

83977.99 ± 6954.70

47878.08 ± 5839.39^*

57613.10 ± 7573.52^*

MRT_0-24 (h)

9.84 ± 0.09

9.21 ± 0.15^*

9.43 ± 0.25^*

MRT_0-inf (h)

15.19 ± 0.60

12.24 ± 1.05^*

12.94 ± 0.84^*

Vd (L)

14.71 ± 0.66

15.15 ± 2.97

14.93 ± 1.60

CL (L/h)

0.06 ± 0.03

1.51 ± 0.11^*

1.33 ± 0.11^*

K_el (h^-1)

0.07 ± 0.00

0.10 ± 0.02^*

0.09 ± 0.01^*

T_½ (h)

9.62 ± 0.67

7.01 ± 1.45^*

7.84 ± 0.93^*

**Table 3.** Mean Percent Blood Glucose Reduction of Gliclazide in Presence and Absence of Nevirapine in Rabbits (n = 6)
Time (hr)	Gliclazide	Nevirapine	Nevirapine + Gliclazide^* (Single dose treatment)	Nevirapine + Gliclazide^* (Multiple dose treatment)
Data are expressed as mean ± SD; ^*No significant difference at P < 0.05 compared to gliclazide control.
1	18.98 ± 3.65	-0.26 ± 7.67	18.53 ± 5.83	20.33 ± 5.49
2	25.19 ± 2.65	1.13 ± 9.86	25.89 ± 6.86	24.69 ± 3.34
3	34.03 ± 2.11	3.48 ± 6.91	35.46 ± 2.97	33.65 ± 2.13
4	26.34 ± 2.83	2.48 ± 5.10	28.09 ± 8.32	25.70 ± 2.87
6	24.09 ± 3.43	0.02 ± 9.80	23.82 ± 4.34	22.50 ± 3.71
8	18.20 ± 6.07	0.11 ± 7.43	18.14 ± 7.46	17.55 ± 3.06
12	10.90 ± 4.08	0.42 ± 9.04	13.43 ± 5.94	11.91 ± 2.35
16	5.39 ± 3.91	-1.39 ± 8.01	7.20 ± 4.87	5.37 ± 5.07
20	3.54 ± 4.10	-1.37 ± 7.14	3.92 ± 4.12	2.78 ± 5.92
24	2.13 ± 3.62	-1.67 ± 5.39	1.04 ± 3.05	0.29 ± 3.68

Table 3. Mean Percent Blood Glucose Reduction of Gliclazide in Presence and Absence of Nevirapine in Rabbits (n = 6)

Time (hr)

Gliclazide

Nevirapine

Nevirapine + Gliclazide^* (Single dose treatment)

Nevirapine + Gliclazide^* (Multiple dose treatment)

Data are expressed as mean ± SD; ^*No significant difference at P < 0.05 compared to gliclazide control.

18.98 ± 3.65

-0.26 ± 7.67

18.53 ± 5.83

20.33 ± 5.49

25.19 ± 2.65

1.13 ± 9.86

25.89 ± 6.86

24.69 ± 3.34

34.03 ± 2.11

3.48 ± 6.91

35.46 ± 2.97

33.65 ± 2.13

26.34 ± 2.83

2.48 ± 5.10

28.09 ± 8.32

25.70 ± 2.87

24.09 ± 3.43

0.02 ± 9.80

23.82 ± 4.34

22.50 ± 3.71

18.20 ± 6.07

0.11 ± 7.43

18.14 ± 7.46

17.55 ± 3.06

10.90 ± 4.08

0.42 ± 9.04

13.43 ± 5.94

11.91 ± 2.35

5.39 ± 3.91

-1.39 ± 8.01

7.20 ± 4.87

5.37 ± 5.07

3.54 ± 4.10

-1.37 ± 7.14

3.92 ± 4.12

2.78 ± 5.92

2.13 ± 3.62

-1.67 ± 5.39

1.04 ± 3.05

0.29 ± 3.68

**Table 4.** Mean Pharmacokinetic Parameters of Gliclazide Before and After Nevirapine Administration in Rabbits (n = 6)
Pharmacokinetic parameter	Gliclazide	Nevirapine + Gliclazide (Single dose treatment)	Nevirapine + Gliclazide (Multiple dose treatment)
Data are expressed as mean ± SD; ^*Significant at P < 0.05 compared to gliclazide control.
C_max (ng/mL)	387.56 ± 7.66	381.39 ± 9.99	382.89 ± 8.12
T_max (h)	3.00 ± 0.00	3.00 ± 0.00	3.00 ± 0.00
AUC_0-24 (ng/mL/h)	4078.99 ± 33.82	3950.86 ± 41.72^*	4008.58 ± 31.63^*
AUC_0-inf (ng/mL/h)	4848.35 ± 106.93	4768.58 ± 168.22	4814.29 ± 83.18
AUMC_0-24 (ng/mL/h*h)	39348.41 ± 518.98	38091.96 ± 634.91^*	38748.57 ± 394.60^*
AUMC_0-inf (ng/mL/h*h)	66857.42 ± 4918.08	68074.90 ± 7688.14	67925.90 ± 4060.08
MRT_0-24 (h)	9.65 ± 0.05	9.64 ± 0.08	9.67 ± 0.06
MRT_0-inf (h)	13.78 ± 0.72	14.24 ± 1.10	14.10 ± 0.61
Vd (L)	14.17 ± 1.03	15.32 ± 1.91	14.92 ± 1.39
CL (L/h)	1.23 ± 0.07	1.25 ± 0.08	1.24 ± 0.05
K_el (h^-1)	0.09 ± 0.01	0.08 ± 0.01	0.08 ± 0.01
T_½ (h)	8.05 ± 0.86	8.56 ± 1.32	8.40 ± 0.77

Table 4. Mean Pharmacokinetic Parameters of Gliclazide Before and After Nevirapine Administration in Rabbits (n = 6)

Pharmacokinetic parameter

Gliclazide

Nevirapine + Gliclazide (Single dose treatment)

Nevirapine + Gliclazide (Multiple dose treatment)

Data are expressed as mean ± SD; ^*Significant at P < 0.05 compared to gliclazide control.

C_max (ng/mL)

387.56 ± 7.66

381.39 ± 9.99

382.89 ± 8.12

T_max (h)

3.00 ± 0.00

AUC_0-24 (ng/mL/h)

4078.99 ± 33.82

3950.86 ± 41.72^*

4008.58 ± 31.63^*

AUC_0-inf (ng/mL/h)

4848.35 ± 106.93

4768.58 ± 168.22

4814.29 ± 83.18

AUMC_0-24 (ng/mL/h*h)

39348.41 ± 518.98

38091.96 ± 634.91^*

38748.57 ± 394.60^*

AUMC_0-inf (ng/mL/h*h)

66857.42 ± 4918.08

68074.90 ± 7688.14

67925.90 ± 4060.08

MRT_0-24 (h)

9.65 ± 0.05

9.64 ± 0.08

9.67 ± 0.06

MRT_0-inf (h)

13.78 ± 0.72

14.24 ± 1.10

14.10 ± 0.61

Vd (L)

14.17 ± 1.03

15.32 ± 1.91

14.92 ± 1.39

CL (L/h)

1.23 ± 0.07

1.25 ± 0.08

1.24 ± 0.05

K_el (h^-1)

0.09 ± 0.01

0.08 ± 0.01

T_½ (h)

8.05 ± 0.86

8.56 ± 1.32

8.40 ± 0.77