Interaction of Carbamazepine with Herbs, Dietary Supplements, and Food: A Systematic Review

Table 3

Summary of the included in vitro, animal and clinical studies on interactions between carbamazepine and dietary supplement/food.

Dietary supplement (DS)/food	Dietary products	Study type	Subject/model (number)	Study design	Outcome measures	Effect	Mechanism	References
Food	Alcohol	Animal	Male CD-1 mice (10 in each group)	Randomized parallel design	PD parameters	Additive neurotoxicity (ethanol-induced motor incoordination and loss of righting reflex potentiated )	Nonadenosinergic action	Dar et al. 1989 [54]
Food	Alcohol	Human	Healthy volunteers (8)	Open label crossover study	PK parameters	No effect on pharmacokinetics of CBZ	Low ethanol level in subjects	Sternebring et al. 1992 [55]
Food	Alcohol	Human	Alcoholics (7)	Open label crossover study	PK parameters	Increased AUC0--12h of CBZ and decreased AUC0--12h of CBZ 10,11-epoxide	Acute inhibition of CBZ metabolism and/or accelerated CBZ metabolism in abstinence phase due to enzyme induction by previous ethanol abuse	Sternebring et al. 1992 [55]
Food	Butter	Animal	New Zealand white rabbit; (8 in each group)	Crossover study	PK parameters	Increased bioavailability of CBZ	Improved solubility and dissolution of poorly soluble CBZ	Sidhu et al. 2004 [56]
Food	Caffeine	Human	Healthy male volunteers (6)	Open label crossover study	PK parameters	Decreased bioavailability and increased 𝑉𝑑 of CBZ	Involving metabolism by mixed function oxidase	Vaz et al. 1998 [57]
Food	Caffeine	Animal	Albino Swiss male mice with maximal electroshock seizure model; (7 in each group)	Randomized controlled parallel study	PK and PD parameters	Acute caffeine decreased antiepileptic efficacy of CBZ but had no effect on plasma level of CBZ	N.D.	Czuczwar et al. 1990 [58]
Food	Caffeine	Animal	Swiss male mice with maximal electroshock seizure model; (8 in each group)	Randomized controlled study	PK and PD parameters	Chronic caffeine dose-dependently decreased anti-epileptic efficacy of CBZ but had no effect on plasma level of CBZ	May induce changes in neurotransmitter system causing sensitization effect	Gasior et al. 1996 [59]
Food	Coca-Cola	Human	Healthy male volunteers (10)	Randomized two-way crossover design	PK parameters	Increased bioavailability of CBZ; no change in elimination 𝑡1/2	Enhanced dissolution of CBZ by its acidity	Malhotra et al. 2002 [60]
DS	Folinic acid	Animal	Male Sprague-Dawley rats; (4 in each group)	Randomized parallel controlled design	PK parameters	No effect on plasma or brain level of CBZ	N.D.	Simth and Carl 1982 [61]
Food	Grapefruit juice	Human	Patients with epilepsy (10)	Randomized crossover study	PK parameters	Increased bioavailability of CBZ	Inhibited CYP3A4-mediated intestinal and hepatic metabolism of CBZ	Garg et al. 1998 [62]
Food	Honey	Animal	Angora grey rabbit; (6 in each group)	Nonrandomized design	PK parameters	Decreased bioavailability of CBZ	Decreased metabolism of CBZ by inducing CYP enzymes	Koumaravelou et al. 2002 [63]
Food	Honey	Human	Healthy volunteers; (10)	Randomized crossover study	PK parameters	Single dose of honey has no effect on pharmacokinetics of CBZ	N.D.	Malhotra et al. 2003 [64]
Food	Honey	Human	Healthy male volunteers (12)	Open label crossover study	PK parameters	Multiple doses of honey have no effect on pharmacokinetics of CBZ	Flavanoids in honey may not affect human CYP3A4 activity	Thomas et al. 2007 [65]
Food	Kinnow Juice	Human	Healthy male volunteers (9)	Randomized crossover study	PK parameters	Increased bioavailability of CBZ	Inhibited CYP3A activity	Garg et al. 1998 [66]
DS	Melatonin	Animal	Female Swiss mice; (12 in each group)	Randomized parallel design	PK and PD parameters	Potentiated the anticonvulsant activity of CBZ but impair long-term memory but no effect on plasma and brain levels of CBZ	Enhanced GABAergic transmission in CNS	Borowicz et al. 1999 [67]
DS	Melatonin	Human	Children with epilepsy (28)	Double-blind randomized control study	PK and PD parameters	Increased glutathione reductase (antioxidant) activity but no effect on plasma level of CBZ and its metabolite	Antagonized CBZ-triggered reactive oxygen species accumulation	Gupta et al. 2004 [68]
DS	Melatonin	Animal	Male Swiss albino mice with maximal electroshock seizure model; (7 in each group)	Randomized parallel design	PK and PD parameters	Synergistic anti-epileptic effect but no effect on plasma level of CBZ	N.D.	Gupta et al. 2004 [69]
DS	Nicotinamide	Human	Children with epilepsy (2)	Case report	PK parameters	Increased plasma level of CBZ and decreased clearance of CBZ	N.D.	Said et al. 1989 [70]
Food	Pomegranate juice	Animal	Male Wistar rats (5-6 in each group)	Randomized parallel design	PK parameters	Increased 𝐶max and AUC of CBZ; no change in elimination 𝑡1/2 and AUC ratio of CBZ 10,11-epoxide to CBZ	Inhibited enteric but not hepatic CYP3A activity	Hidaka et al. 2005 [71]
Food	Pomegranate juice	Ex vivo	Male Wistar rats (3 in each group)	In vitro everted and noneverted sac method	PK parameters	Decreased intestinal transport of CBZ	Induced enteric CYP3A4	Adukondalu et al. 2010 [72]
Food	Soybean	Animal	Albino Wistar rats; (6 in each group)	Randomized parallel design	PK parameters	Decreased bioavailability of CBZ, increased plasma clearance and 𝑉𝑑 of CBZ	Decreased gastric emptying and enhanced elimination of CBZ	Singh and Asad 2010 [73]
Food	Star Fruit Juice	Animal	Male Wistar rats (6 in each group)	Randomized parallel design	PK parameters	Increased 𝐶max and AUC of CBZ; no change in elimination 𝑡1/2 and AUC ratio of CBZ 10,11-epoxide to CBZ	Inhibited enteric but not hepatic CYP3A activity	Hidaka et al. 2006 [74]

N.D.: not determined by authors.