a short class seminar

1. +
Effects of grapefruit
juice on simvastatin
drug
prepared by Mohammad Alyami
Student ID : 109068062
Pharmacology module
PHM 016
MSc in Pharmaceutical
sciences

2. +
Outline
Introduction
Methods
Results
Discussion
Conclusion

3. +
Introduction
 Simvastatin (Zocor) is used to treat
hypercholesterolemia.(Statin)
 Half life 2 hrs.
 HMG-CoA reductase inhibitor.
 Metabolized by : CYP3A4 and carboxyl esterases.
 Bioavailability of simvastatin is 5 %.

4. +
Cont. Introduction
 Side effects of statins :
 Musculoskeletal adverse effects ,myopathies .
 Rhabdomyolysis with CYP3A4 inhibitors with
acute renal failure (cyclosporin , midazolam.)
 Focus on the study which conducted in Finland
which is
 “Effects of regular consumption of grapefruit
juice on the pharmacokinetics of simvastatin”

5. +
Mechanism of action
www.nature.com
Simvastatin
www.rxlist.com

6. +
The study…
Method
 a-Volunteers:
- A randomized study with two group 10/10 .
- 20- 24 years / 63-80 kg
- Non-smoker
- They were not allowed to eat any grapefruit
products two weeks before the first study day.

7. +
Cont. Method
b- Study
design
First and
second day
Third day
Controlled
group
200ml of water +
breakfast at 8
a.m.
simvastatin 40
mg + water at 9
a.m
Examined
Group
200ml of
grapefruit juice +
breakfast at 8 a.m.
simvastatin 40 mg
+ water at 9 a.m.

8. +
Cont. Method
 c- Restrictions ...
Fasted overnight.
Two served heavy and light meal were
served 3hrs and 7 hrs. after giving the drug.
Coffee, tea, or cola were not allowed during
the study days.

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Cont. Method
 The blood sample were taken before giving
Simvastatin (at zero drug conc) and then at the first
half hour continued 1-2-3-4-5-…. 24 hrs.
 Concentration of Simvastatin and Simvastatin acid
were Measured by :
 a- liquid chromatography.
 b- Ion spray tandem mass spectrometry.

10. +

11. +
Pharmacokinetics parameters
 Cmax = Maximum drug concentration
 Tmax = The time of the maximum
concentration.
 AUC= Area under the curve.
 Ke = Elimination rate .
 t1/2 = The drug half life.
t1/2 = ln2/ke

12. +
Mean of changes
Simvastatin
With Grapefruit
Simvastatin acid
With Grapefruit
Cmax increased 3.9-
fold. (range 2.3–
9.3-fold)
Increased 4.3-fold
(2.7–7.7-fold)
AUC
(0-24hr)
Increased 3.6-
fold (range 1.8–
6.0-fold)
increased 3.3-fold
(2.1–5.6-fold)
Tmax unchanged unchanged
t ½ unchanged 2.4 h
Figure 3. Mean of Simvastatin and Simvastatin acid with
grapefruit juice. Adopted from Lilja,J., Neuvonen, M.,
Neuvonen, P.(2044) pp. 50-60 .

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-5
0
5
10
15
20
25
30
-5 0 5 10 15 20 25 30
Simvastatinconc.ng/ml
Time (hr)
simvastatin…
Simvastati…
Figure 1. Simvastatin concentration against time . Simvastatin with
grapefruit juice (yellow), Simvastatin with water (white). Adopted
from Lilja, J., Neuvonen, M., Neuvonen, P.(2044) pp. 50-60 .
Simvastatin / Grapefruit juice

14. +
-2
0
2
4
6
8
10
12
14
-5 0 5 10 15 20 25 30
Simvastatinacidconc.ng/ml
Time (hr)
Simvastatin acid
(mg/ml)/ greapefruit
Simvastatin/water
Figure 2. Simvastatin acid concentration against time. Simvastatin
acid with grapefruit juice (yellow), Simvastatin with water (white).
Adopted from Lilja,J., Neuvonen, M., Neuvonen, P.(2044) pp. 50-
60 .
Simvastatin acid / Grapefruit juice

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Discussion
 One glass of Grapefruit juice increased Simvastatin
and simvastatin acid concentration considerably .
 A glass of Grapefruit juice increased AUC of
simvastatin as much as calcium channel bookers
verapamil and diltiazem.
 Due to inhibition of CYP3A4.

16. +
Cont. Discussion
 However , some variations could be
considerably important :
 - Variety of CYP3A4 from one to one.
 -Drug –drug interaction
 - Juice batches
 For example , CYP3A4 does not inhibit
Pravastatin, fluvastatin and rosuvastatin (
Statins), Hence it dose not increase the Cmax .

17. +
Cont. Discussion
 A previous study has showed that 250 ml grapefruit
juice for 3 days increased lovastatin and lovastatin
acid AUC by 94% and 57%.(Lovastatin was given
12 hrs. after grapefruit had been taken.)
 The author suggested that the effect of drinking a
daily grapefruit juice has a minor effect lovastatin
kinetics.

18. +
conclusion
 One grapefruit juice significantly increased effect on
Simvastatin concentration in plasma.
 Grapefruit inhibited simvastatin metabolism
pathways via inhibition CYP3A4
 Finally. A void drinking grapefruit juice with
Simvastatin even 12 hrs. later.

19. +
References
 Lilja, J., Neuvonen, M., Neuvonen, P. (2044). Effects of
regular consumption of grapefruit juice on the
pharmacokinetics of simvastatin. British Journal of Clinical
Pharmacology, Vol 58,iss 1, pp.40-50. Available online at:
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-
2125.2004.02095.x/full. accessed on 13-10-2013.
 rxList the internet drug index . Zocor.
http://www.rxlist.com/zocor-drug.htm. Accessed on
13/10/2013.
 www.google image.com
 www.nature.com

20. +
Bibliography
 Rang,H.P.,Dale,J.M.,Flower.R.J.,& Henderson, G.(2012).Range
and Dale’s Pharmacology. UK. British library cataloguing in
publication data.