In recent years, advancements in medical science have led to significant improvements in diagnostic tools and pharmaceutical therapy. These developments have played a major role in reducing mortality rates in developed countries, enabling the management and treatment of various acute and infectious diseases. However, chronic diseases, such as cardiovascular disorders, remain a growing concern, with treatment strategies primarily focused on symptom management rather than eradication. Although advanced medication can arrest the development of these conditions, its failure to cure them has led to a chronic need for their use, which may result in harmful side effects and a reduction in patients' quality of life. Consequently, most patients resorted to complementary alternative medicine, including herbal medicine, to accompany normal therapy. According to World Health Organization (WHO) estimates, almost 80% of the world's population uses alternative medicines and natural health products for their health care. 1

In chronic diseases, conventional pharmacological therapies tend to depend on synthetic drugs that act on specific disease mechanisms. Herbs, as part of alternative medicine, can provide distinct therapeutic advantages because they are multi-component in nature. These traditional herbal remedies, although used over a long period across the world, vary from mainstream drugs in the sense that they are composed of multiple bioactive compounds that can interact with each other and with contemporary pharmacological agents. The complexity of such interactions poses potential concerns since these interactions may augment or cancel out the action of mainstream drugs. Thus, it is essential to understand herb-drug interactions to avoid side effects and enhance therapeutic benefits. 2, 3

Herbal remedies, such as garlic, which are commonly used, usually operate by pharmacological principles similar to those of orthodox drugs, such as drug-drug interaction mechanisms.4 Nutritional aspects, particularly those of fruits, vegetables, and herbs, have also been found to affect human health and play a critical role in the prevention and management of different diseases, such as cardiovascular disease (CVD). Findings from epidemiological research indicate that high consumption of these foods is linked to decreased mortality due to chronic diseases, such as CVD and cancer. 5, 6 This has generated more interest in the ability of phytochemicals, bioactive plant constituents, to prevent or control these disease states. Garlic (Allium sativum) has been recognized for its cardiovascular effects, with an increasing amount of evidence for its use in the prevention and treatment of CVD. 7

Garlic is a member of the Liliaceae family and has been used as both a food and medicine for centuries. Its medicinally beneficial attributes are largely due to organosulfur compounds, but other bioactive molecules such as peptides, steroids, terpenoids, flavonoids, and phenols also play a role in its medicinal activity. 8 These molecules synergize to exert beneficial effects on cardiovascular health, inflammation, and oxidative stress. Garlic also has essential amino acids, glycosides, minerals such as selenium, and an enzyme such as alliinase, which contribute to its medicinal value. 9, 10 Studies have shown that garlic not only plays a role in the overall health of the heart but also interacts with standard heart-protecting medications, possibly contributing to its efficiency. For example, research has indicated that taking garlic along with medications, such as captopril 11 and propranolol 12, enhances heart function and survival rates in animal models of heart disease. In addition, garlic has been demonstrated to synergistically interact with calcium channel blockers and diuretics, such as hydrochlorothiazide 13, 14, indicating that its enzymatic activity might significantly contribute to increasing the therapeutic effects of these drugs.

This study aimed to investigate the pharmacokinetic interactions between garlic and some of the most widely used cardioprotective agents, namely, amlodipine, losartan, enalapril maleate, and carvedilol. By understanding the impact of pretreated garlic on the ADME of these drugs in animal models, this study will offer valuable insights into how garlic can influence the efficacy and safety of cardiovascular medication. This study has the potential to inform clinical practice regarding the use of herbal remedies in conjunction with pharmacologic therapy so that patients may gain from the complementary action of both forms of treatment without increasing the risk of adverse drug interactions.

For Amlodipine, garlic lowered Cmax (P<0.01) and plasma half-life (P<0.05) but increased the elimination rate constant and volume of distribution (P<0.001). The clearance increased but was not significant. In the Losartan group, garlic increased the Cmax and reduced the plasma half-life, elimination rate constant, and clearance (P<0.05). The volume of distribution also increased. In the Enalapril + Garlic group, Cmax, AUC₀-₂₄, and AUC∞ were considerably higher (P<0.001), reflective of increased exposure to the drug. The Tmax in the GH-treated group decreased relative to that of enalapril alone, reflecting quick absorption. The Cmax of a 250 mg/kg dose of GH was notably high and showed increased bioavailability. In the presence of GH, the AUC₀-₂₄ was notably higher, while elimination half-life (T½) was also extended to 5.2 hours. Moreover, the volume of distribution and clearance decreased drastically, and the elimination rate constant decreased slightly. Cmax, AUC₀-₂₄, and AUC∞ were significantly increased (P<0.001) for Carvedilol + Garlic. Tmax was decreased slightly, but T½ was increased in the case of a 250 mg/kg GH dose. Clearance and Vd also decreased significantly, indicating the retention of drugs in the body for a longer time (Table 2).

The plasma concentration profiles of Drug A alone and in the amlodipine-garlic treated group were compared at various time points. A decrease in AUC was observed when garlic was co-administered, indicating that garlic could induce CYP enzymes, thereby increasing drug metabolism. For Losartan (Drug B), the plasma concentration profile reflected a notable increase in AUC in the losartan-garlic-treated group, indicating inhibition of CYP enzymes, which most probably delayed the metabolism of the drug and extended its systemic residence. In the same manner, the plasma concentration profile of enalapril (Drug C) reflected an increase in AUC with garlic administration, indicating that CYP enzyme inhibition is involved in its metabolism, hence increasing drug exposure. In the case of carvedilol (Drug D), a mild increase in AUC was noted in the carvedilol-garlic treated group, which is probably due to the inhibition of CYP enzymes responsible for its metabolism, leading to decreased clearance and increased drug retention.

The research aimed to investigate the pharmacokinetic interactions of garlic (Allium sativum) with the cardioprotective medicines amlodipine, losartan, enalapril, and carvedilol with the help of experimental models on rats. Herb-drug interactions have become more prominent in the spotlight because they can increase or decrease the efficacy of medicines and produce beneficial or toxic effects. Although herbal remedies are popular, there have been few reports of major interactions, usually because of underreporting or the generally innocuous nature of most herbs. However, there is new evidence that some herbal remedies, such as garlic, can interact with cardiovascular drugs; therefore, more stringent scientific scrutiny is required.

Amlodipine, a calcium channel blocker (CCB), is commonly used to treat cardiovascular disorders. It inhibits transmembrane influx of calcium ions through calcium channels, mainly in the heart and vascular smooth muscles because of the heterogeneity of calcium channels and the 'use-dependence' nature of CCBs to block preferentially the most active channels. Amlodipine is orally well absorbed with peak blood levels after 6–12 hours and is 60–65% bioavailable. It is subjected to intensive hepatic metabolism through CYP3A4, and the majority of its metabolites are excreted through the urine. The terminal half-life of elimination is 35–50 hours, and steady-state plasma levels are achieved after 7–8 days of uninterrupted administration. The pharmacokinetic profile noted in this study is consistent with earlier reports, validating the slow clearance and long half-life of amlodipine, which justifies its once-daily dosing. 15, 16

Notably, although this work indicates that CYP3A4 is the major metabolizing enzyme, amlodipine has been reported to undergo extensive hepatic metabolism with low first-pass metabolism. 16 This apparent discrepancy calls for future research into the possibility of inter-individual variability in metabolism or the effect of co-administered agents, such as garlic.

Losartan, an angiotensin II receptor blocker, is quickly metabolized to its active metabolite E3174, mainly through CYP2C9. E3174 is 10–40 times more potent at the AT1 receptor than losartan and shows noncompetitive antagonism with slow dissociation from the receptor, resulting in an elimination half-life of 6–9 hours. 17 Although this study did not directly examine the pharmacokinetic interaction of garlic with losartan, other pertinent interactions have been reported. For example, grapefruit juice, an inhibitor of CYP3A4, has been shown to decrease the metabolism of losartan to E3174, which may influence its therapeutic effect. 18 Likewise, phenytoin, another CYP2C9 substrate, is a conversion inhibitor of losartan, indicating that drug-garlic interactions may also occur through such mechanisms. 19

Garlic (Allium sativum L.), commonly prized for its medicinal properties, is rich in bioactive constituents such as S-allylcysteine (SAC) and S-allylmercaptocysteine (SAMC), which are formed through enzymatic conversion of alliin to allicin. Fresh garlic homogenate (GH) was used in this study to represent the most frequently consumed form with high concentrations of bioactive constituents. GH was administered orally for 30 days to ensure maximum SAC and SAMC levels, which have been reported to have antioxidant and cardioprotective effects. 20, 21 These results indicated that GH significantly increased the bioavailability of enalapril and carvedilol. The pharmacokinetic profiles of these drugs varied considerably in GH-pretreated animals, possibly because of the modulation of CYP enzymes by garlic. Higher garlic doses resulted in increased allicin levels, which are typically converted into the antioxidants SAC and SAMC. However, at excessively high concentrations, the incomplete metabolism of allicin may lead to disturbances in biochemical and histological parameters. Enalapril, an angiotensin-converting enzyme (ACE) inhibitor, has been shown to have antihypertensive effects similar to those of garlic-derived allicin. Research has confirmed that garlic lowers blood pressure, triglyceride levels, and insulin levels in a model of hypertension, which supports the potential benefits of enalapril with garlic for better management of cardiovascular effects. 21

Carvedilol, a non-selective beta-blocker with antioxidant activity, also showed a changed pharmacokinetic profile when co-administered with GH. The elevated bioavailability of carvedilol in GH-treated animals indicated that the bioactive components of garlic regulate CYP enzymes, resulting in increased drug absorption and prolonged action. Similar observations have been made with propranolol, another beta-blocker in which GH substantially increased its bioavailability and half-life. 21 Notably, whereas garlic enzyme inhibition can be proposed to account for the enhanced bioavailability of carvedilol, other processes, including stereoselective metabolism and genetic differences in CYP2D6, might also play a role in the inter-individual variability of carvedilol metabolism. 22 These results indicate that the garlic-carvedilol interaction is more complex than enzyme inhibition.

The findings of this study underscore the significance of incorporating herb–drug interactions in clinical settings. The enhanced bioavailability of enalapril and carvedilol implies the possibility of dose reduction through co-administration with GH, which may reduce adverse effects such as hypotension, cough, syncope, hyperkalaemia, and renal impairment without affecting therapeutic effectiveness. However, careful observation of electrolyte balance is required in such patients, especially those taking diuretics, to avoid conditions such as hypokalaemia, hypochloremic alkalosis, and hyponatremia. Dry mouth, thirst, lethargy, confusion, muscle weakness, oliguria, tachycardia, nausea, and vomiting all require immediate electrolyte determination and corrective management. Although these results suggest some positive interactions with GH co-administration, additional research is needed to establish these interactions in human populations. Future studies should investigate the specific mechanisms underlying the effect of garlic on drug metabolism and its clinical significance in patients undergoing long-term cardiovascular treatment.

This study postulates that garlic has the potential to modulate CYP enzymes, modifying the metabolism of amlodipine and losartan but enhancing the bioavailability of enalapril and carvedilol. Such interactions can affect drug efficacy and safety, warranting careful monitoring, particularly in cardiovascular therapy, for extended periods. The decreased clearance and extended half-life of enalapril and carvedilol can enhance the toxicity risks due to drug accumulation. However, moderate consumption of garlic may be useful for blood pressure control, especially in myocardial stress, by minimizing potassium excretion. Further studies are required to verify these observations and determine safe dosing regimens in clinical settings.