Interaction between antimalarial herbal drugs (AHDs) and complementary antimalarial drugs (CAMDs) revealed 8 antagonism, 16 synergism, 5 non-effects and 1 of both effects, making up a total of 30 studies reviewed. The three broad categories of such studies evaluated include interaction between AHDs and CAMDs using P. berghei and P. yoelii nigerense model, interaction between AHDs and CAMDs in normal animals (mice, rats and rabbits), and interaction between AHDs and CAMDs in human volunteers and in-vitro model. Vernonia amygdalina was the most studied herbal remedy compared to others. Frequencies of CAMDs used include chloroquine (14, 48.28%), artesunate (9, 30.00%), amodiaquine (4, 13.79%), quinine (2, 6.90%) and halofantrine (1, 3.45%).
Synopsis of studies on herbal-antimalarial drugs interactions in P. berghei model
Studies in this category involved
Plasmodium berghei (
P. berghei) infected mice model which is an acceptable and a reproducible experimental model for screening potential antimalarial candidates. The outcomes of these studies are summarized in Tables
1 and
2.
Table 1
Summary of studies on herbal-antimalarial drugs interactions using P. berghei model
1 | Methanol leaf extract of VA (125 mg/kg) | ART (2.86 and 35.14 mg/kg | High dose of ART antagonized VA | |
2 | Gynostemma pentaphyllum and Moringa oleifera (500, 1000 and 2000 mg/kg) | ART (6 mg/kg) | Greater antimalarial activity was recorded. | |
3 | Kaempferol (20 mg/kg) | CQ (10 mg/kg) | ↓ in parasitemia | |
4 | Aqueous root extract of Cryptolepis sanguinolenta (36 mg/kg) | ART (2.5 mg/kg) | Extract ↓effectiveness of ART. | |
5 | Hydroalcoholic fruit extract of Balanites aegyptiaca and leaf latex of Aloe camperi | CQ (12.5 mg/kg) | ↑ in parasitemia suppression ability of CQ | |
6 | Aqueous fresh leaf extract of A. indica (100, 500, and 1000 mg/kg) | ART (6, 15, and 20 mg/kg) | A significant reduction in parasitemia | |
7 | Methanol extracts of 15 Kenya medicinal plants, from 11 families | CQ (Dose not specified) | Improved suppressions of parasitemia | |
8 | Hot water extract of 18 Kenya medicinal plants | CQ (Dose not specified) | Improved suppressions of parasitemia | |
9 | Aqueous extracts of Morinda morindiodes (Mm) root, Morinda (Ml) lucida leaf and VA leaf | ART (10 mg/kg) | Mm and Ml extract ↓effectiveness of ART, but ART ↑effectiveness of VA | |
10 | 216 extracts from 50 Western Ghats plants | CQ (Dose not specified) | Moderate to high in vivo antimalarial activity | |
11 | Carica papaya leaf (50 mg/kg) | ART (15 mg/kg) | Antagonism | |
Table 2
Summary of studies on herbal-antimalarial drugs interactions using P. berghei and P. yoelii nigerense model
12 | Aqueous leaf extract of TO (200 mg/kg) | ART (2 mg/kg) | Synergistic effect | |
13 | VA (100–500 mg/kg) | AQ (2–10 mg/kg) and ART (0.8–4 mg/kg) | Synergistic effect | |
14 | Aqueous leaf extract of Ageratum conyzoides (100 mg/kg) | CQ (5 mg/kg), ART | Extract potentiated activities of CQ and ART | |
15 | MAMA herbal antimalarial decoction (120 mg/kg) | AQ (10 mg/kg) | Synergistic effect against CQ sensitive (except resistant) | |
16 | Methanol leaf extract Uvaria chamae (100–400 mg/kg) | AQ (10 mg/kg) | Low dose of extract + AQ produced better antimalarial activity | |
17 | Aqueous leaf extract of VA (31.25, 62.5, 125 mg/kg) | CQ (5 mg/kg) | Extract ↑ antimalarial effects of CQ | |
18 | Ethanol stem bark extract of Khaya grandifolia (50–400 mg/kg) | CQ (2.5 mg/kg) Halofantrine, 6.25 mg/kg) | Enhanced antiplasmodial activity and mean survival time | |
Recently, Ihekwereme et al [
25] did a study on the interaction between artemisinin combination-based therapies; ART and
Vernonia amygdalina (VA) methanol leaf extract. The study revealed dose dependent antagonism of ART on the antimalarial efficacy of VA (125 mg/kg) using Rane’s curative test in
P. berghei. Concomitant administration of 125 mg/kg of VA and of 35.14 and 2.86 mg/kg of ART produced parasitemia clearance of 80.49% and 97.05% respectively. The authors postulated that people should discourage the combination of the higher dose of ART and VA, and also encouraged the combination of low dose of ART (2.86 mg/kg) and 125 mg/kg of VA in malaria patients.
In a separate study, the chemotherapeutic interaction between VA (100–500 mg/kg) and Amodiaquine, AQ (2–10 mg/kg) and ART (0.8–4 mg/kg) was investigated in
P. berghei infected swiss albino mice. Sub-therapeutic doses of 100, 2 and 2.4 mg/kg were obtained for VA, AQ and AR respectively. The study revealed a significant increase in the chemosuppressive effect of AQ and ART, as well as parasite clearance when co-administered with VA extract. Also, the mean survival period was higher in animals that received the three combinations, VA, AQ, AR compared to placebo [
3].
An investigation was carried out on the antimalarial activity of kaempferol (20 mg/kg) when combined with CQ (10 mg/kg). A reasonable antimalarial activity with prolonged survival time of
P. berghei strain infected mice was recorded for Kaempferol alone and in combination with CQ. Notably, the effect produced by kaempferol was not significantly different from that of the CQ treated group. Suppression at the combined doses (20 and 10 mg/kg) ranged from 70 to 95.98% in suppressive, prophylactics and curative tests [
5].
In a 4-day suppressive test using
P. berghei on the extract of
Gynostemma pentaphyllum and
Moringa oleifera at 500, 1000 and 2000 mg/kg produced dose dependent suppression of 45, 50, and 55% and 35, 40, and 50% respectively. Greater antimalarial activities with suppression of 78, 91, and 96% for
G. pentaphyllum leaf extract and 73, 82, and 91% of
Moringa oleifera leaf extract were observed when they were combined with ART (6 mg/kg). The authors recommended that their combination with ART showed a strong prospect for development as antimalarial combination therapy [
10].
The outcome of co-administration of the hydroalcoholic fruit extract of
Balanites aegyptiaca and leaf latex of
Aloe camperi on the antimalarial effect of CQ was investigated by Sibhat and Hiben [
23] using peters four day suppressive method in
P. berghie infected mice. The study revealed that
Balanites aegyptiaca and leaf latex of
Aloe camperi increased the parasitemia suppression ability of CQ.
Adepiti et al., [
33] investigated the effect of concomitant administration of AQ and MAMA herbal antimalarial decoction, comprising leaves of
Mangifera indica,
Alstonia boonei,
Morinda lucida and
Azadirachta indica in CQ-sensitive
P. berghei. There was a complete parasite clearance in the therapeutic combination dose (MAMA, 120 mg/kg and Amodiaquine, 10 mg/kg) against CQ -sensitive
P. berghei. Conversely, remarkable activity was not recorded at these doses against CQ-resistant
P. berghei.
Adepiti and Iwalewa [
34] also investigated possible herbal interaction of
Uvaria chamae methanol leaf extract (100–400 mg/kg) with AQ (10 mg/kg) in mice infected with CQ-sensitive
P. berghei in in four -day, curative and prophylactic antimalarial test models. CQ -resistant
P. berghei mice were also treated with extract at 400 mg/kg and AQ in the four-day prophylactic and curative test models. The interaction study revealed that low-dose combination of the leaf extract and AQ produced a better antimalarial activity in the CQ-sensitive murine malaria, but not in CQ-resistant murine malaria.
In other to evaluate the interaction effect between ART and
Cryptolepis sanguinolenta, Ocloo and co-workers administered aqueous root extract of
Cryptolepis sanguinolenta (36 mg/kg) and ART (2.5 mg/kg) in
P. berghei infected male Sprague-Dawley rats. The study revealed that the extract reduced the effectiveness of ART following concurrent administration. It was recommended that this combination could lead to ART inactivity against malaria. Thus, patients who practice the use of the combination should take caution [
13].
In vivo schizontocidal activity in swiss albino mice infected with malaria parasite using the aqueous fresh leaf extract of
Azadirachta indica at 100, 500, and 1000 mg/kg and 6, 15, and 20 mg/kg of artesunic acid alone and in combination were investigated. A significant reduction in parasitemia at 96.87% was recorded at 1000 mg/kg of the extract combined with 15 mg/kg of artesunic acid when compared to 68.14% reduction produced by 20 mg/kg of artesunic acid alone. The artesunic acid did not produce a cure on day 30, except the combinations of both the extract with artesunic acid [
26].
Adegbolagun et al [
16] investigated the effect of aqueous leaf extract of
Telfaria occidentalis on the biological activities of ART using a curative model in
P. berghei infected mice. The study revealed that the extract, ART and the combination of both produced 72.17±4.07%, 70.43± 4.27% and 85.43± 3.65% reduction in parasitaemia respectively, after 48 h of administration, demonstrating a synergistic effect of the combination on parasite clearance of
P. berghei infection.
A total of 216 extracts from 50 Western Ghats traditionally used to treat malaria were tested for in vivo antiplasmodial activity alone as well as in combination with CQ against CQ-tolerant
P. berghei strain. The study revealed that more than 70% of the plant extracts displayed moderate to high
in- vivo antimalarial activity when used separately as well as in combination with CQ [
30].
Antimalarial properties of fresh
Carica papaya leaf (50 mg/kg) alone and in combination with artesunic acid (15 mg/kg) were determined by using the Peter’s 4-day suppressive test in
P. berghei -infected mice. From the study, the combination of
Carica papaya with artesunic acid was antagonistic. The authors concluded that combinations of artemisinins and
Carica papaya show little promise for combination therapy development [
31].
In four-day suppressive and curative tests, the effect of aqueous leaf extract of
Ageratum conyzoides in combination with CQ and ART was investigated using
P. berghei infection in mice. There were greater suppressive activities in both extract-drug combinations, with extract-CQ (100 mg/kg: 5 mg/kg) having the highest suppressive effect (98%) than individual drugs. Absolute survival was recorded in the two extract-drug combinations than individual drugs. The authors concluded that aqueous extract of
Ageratum conyzoides potentiates the antimalarial activity of CQ and ART [
32].
Chemotherapeutic interaction between ethanol stem bark extract of
Khaya grandifolia (50–400 mg/kg) and two antimalarial drugs (CQ, 2.5 mg/kg and halofantrine, 6.25 mg/kg) in mice infected with
Plasmodium yoelii nigerense was carried out. The study revealed enhanced antiplasmodial activity and mean survival time when the extract was combined with CQ or halofantrine compared to individual drugs. The authors posited that reduced therapeutic doses of halofantrine may be needed to enhance parasite clearance when used together with
Khaya grandifolia, thereby yielding a great advantage to halofantrine which produces cardiotoxicity at high doses [
11].
Aqueous leaf extract of VA was found to enhance the antimalarial effects of CQ in CQ sensitive and resistant
P. berghe. CQ at 5 mg/kg was administered in combination with 31.25, 62.5, 125 mg/kg of the extract. At 30 mg/kg of CQ for 3 days in combination with the extract, there was a decrease in parasite clearance times from 4.8 to 2.6–4.4 days for CQ-VA 62.5/125 combination, prolonged recrudescent times (from 7.2 to 8.9–18.9) and also improved cure rate (from 58.3% to 66.7–100%) in the treated
P. berghei - infected mice on day 14 compared to CQ monotherapy [
15].
Methanol extracts of 15 medicinal plants, from 11 families traditionally used for malaria treatment in Kenya were screened for their in vivo antimalarial activity against a CQ (CQ)-tolerant
P. berghei. Following combination of the extract with CQ,
Albizia gummifera,
Ficus sur,
Rhamnus prinoides and
Rhamnus staddo,
Caesalpinia volkensii,
Maytenus senegalensis,
Withania somnifera,
Ekebergia capensis,
Toddalia asiatica and
Vernonia lasiopus produced statistically significant and improved suppressions of parasitemia which ranged from 45.5 to 85.1% compared to when they were used alone (31.7–59.3%). Remarkable parasitemia suppression by the extracts when used alongside CQ produced longer mouse survival than the control [
27].
As a follow up study, hot water extracts of 18 medicinal plants representing five families of plants used in Kenya for treatment of malaria were screened against CQ resistant
P. berghei either alone or in combination with CQ. A similar result was recorded, as there was outstanding parasitemia suppression by extracts when administered in combination with CQ, which gave rise to longer survival of mice relative to the controls [
28].
In the year 2020, Idowu and co-workers evaluated the interaction effects of
Morindamorindiodes (Mm) root,
Morindalucida (ML) leaf and
Vernonia amygdalina (VA) leaf on the efficacy of artemisinin derivatives. From the study, artesunate produced a total parasite clearance (100.00%). Although the single administration of Mm and ML extracts produced considerable antiplasmodial effects (86.83 and 84.20%), their combination with artesunate (10 mg/kg) did not produce complete parasite clearance (89.93 and 89.43%). VA in the presence of artesunate produced a better chemosupression (86.93%) than when it was administered alone (48.10%). The authors emphasized the need to educate the public on the likely limitations associated with concomitant use of antimalarial plants alongside conventional antimalarial drugs [
29].
Synopsis of studies on herbal-antimalarial drugs interactions with normal animals
This section is made of pharmacokinetic studies that involved normal animals that were not subjected to
P. berghei or other forms of malaria infections. Concentrations of standard antimalarial drugs were measured following their co-administration with herbal remedies. The outcome of these studies is summarized in Table
3.
Table 3
Summary of studies on herbal-antimalarial drug interactions in normal animals (mice, rats and rabbits)
1 | Aqueous root extract of Cryptolepis sanguinolenta (36 g/kg) | ART (150 mg/kg) | Rats | Cryptolepis sanguinolenta decreases the effectiveness of ART | |
2 | VA (250 and 500 mg/kg) | Dihydroartemisinin (2 mg/kg) | Rats | ↓in AUC; ↑in Ka | |
3 | Leaf of Heinsia crinata (200 mg/kg) | CQ (15 mg/kg) | Rats | Extract ↓ bioavailability of CQ | |
4 | Aqueous leaf extract of Azadirachta indica | CQ (Dose not specified) | Rabbit | Extract ↑ & ↓ in pharmacokinetic parameters | |
5 | MAMA herbal antimalarial decoction (120 mg/kg) | AQ (10 mg/kg) | Mice | Decoction ↑ the activity of AQ and its metabolites | |
6 | Ethanolic leaf extract of Lasianthera Africana (200 mg/kg) | CQ (15 mg/kg) | Rats. | Extract ↑ & ↓ in pharmacokinetic parameters | |
7 | Ethanolic leaf extract of Vernonia amygdalina | CQ (10 mg/kg) | Rats | Extract ↑ & ↓ in pharmacokinetic parameters | |
8 | Grapefruit juice (4 ml/kg) | CQ (100 mg/kg) | Mice | ↑ plasma concentration of CQ | |
9 | Gnetum africana (200 mg/kg) | CQ (15 mg/kg) | Rats | ↑ & ↓ in some pharmacokinetic parameters | |
Adepiti and co-researchers explored the influence of MAMA antimalarial decoction (125 mg/kg) on the pharmacokinetics of AQ (10 mg/kg) in mice. Using a validated high-performance liquid chromatography (HPLC) approach, blood samples were collected between 0 and 96 h for quantification of AQ and its major metabolite (desethylamodiaquine). In the presence of the decoction, there was a 12% increase in the maximum concentrations of AQ, while the 85% increase was recorded in mice pretreated for 3 days. An increase was also recorded in the active metabolites. The authors concluded that the decoction influenced the pharmacokinetics of AQ and desethylamodiaquine [
39].
Eseyin et al [
25] evaluated the effect of
Gnetum africana on the pharmacokinetic parameters of CQ phosphate in overnight fasted albino rats. The study revealed a significant decrease in C
max (9.17%), Ka (3.06%), Ke (45.38%), Cl (48.46%) and AUC (0–8) (16.90%) of CQ (15 mg/kg) by the extract (200 mg/kg). The t
1/2 (83.11%) and t
max (100.00%) of CQ phosphate was increased by the extract. The authors remarked that since the pharmacokinetic parameters of CQ were altered by the extract
, malaria patients on CQ treatment should beware of consuming
Gnetum africana alongside CQ, as such, could lead to a decreased therapeutic effect of the drug thereby leading to resistance.
Eseyin et al [
36] did another study on the effects of the leaf extract of VA (250 and 500 mg/kg) on the pharmacokinetics of dihydroartemisinin (2 mg/kg) in rats. UV spectrophotometer was used to measure the serum level of dihydroartemisinin at 0, 0.25, 0.5, 0.75, 1.0, 2.0, and 5 h on the last day (day 7th) of concurrent dihydroartemisinin and extract administration. There was a reduction in bioavailability (F), absorption constant (Ka), peak concentration (C
max) as well as elevation in the apparent volume of distribution (V
d). Administration of the extract at a single dose (250 and 500 mg/kg) caused a reduction in AUC, as well as an elevation in elimination constant. The authors posited the need for patients receiving VA alongside dihydroartemisinin to exercise caution.
The effect of the aqueous root extract of
Cryptolepis sanguinolenta on the pharmacokinetics of ART in male Sprague-Dawley rats was investigated. A single oral dose of ART (150 mg/kg) was administered after the exposure of animals to 36 g/kg of the extract for two weeks. There was an increase of 233 and 62.1% in the elimination rate constant and clearance of dihydroartemisinin (the most potent metabolite of ART) respectively, when ART was concurrently administered with
Cryptolepis sanguinolenta when compared with ART alone. A significant reduction was recorded in bioavailability (40.1%), volume of distribution (68.1%) and half-life (52.1%) of dihydroartemesinin, indicating that
Cryptolepis sanguinolenta could produce decrease in effectiveness due to herb-drug interactions. They suggested the need to inform patients on the serious implication of using
Cryptolepis sanguinolenta and ART concomitantly [
35].
Effect of ethanol leaf extract of
Lasianthera africana on the pharmacokinetic parameters of CQ was investigated. The first group of rats received only CQ (15 mg/kg), while the second group received the extract (200 mg/kg) and CQ (15 mg/kg) at the same time. Using UV-Vis spectrophotometer, the serum was analyzed for CQ and protein. The extract significantly altered the pharmacokinetic parameters of CQ as follows; relative increase in t
½ (115%), t
max (100%), V
d (14%) and AUC (0-∞) (59%) and reduction in K
a (54%), K
el (53%), C
max (38%) and CL (47) [
40].
In 2010, Eseyin and co-workers studied the effects of the leaf of
Heinsia crinata on the pharmacokinetics of CQ in rats. CQ (15 mg/kg) was administered at the same time with the extract (200 mg/kg) to group one, while only CQ (15 mg/kg) was administered to the second group. Serum of blood collected via cardiac puncture under chloroform anesthesia in 0.25, 0.50, 1.00, 2.00, 4.00 and 8.00 h was analyzed spectrophotometrically at 344 and 260/280 nm. The study revealed that concomitant oral administration of CQ and
Heinsia crinata extract produced significant (
p< 0.05) reduction in most as well as a significant increase in few pharmacokinetic parameters of CQ. As suggested by the authors, reduced bioavailability of CQ produced by the vegetable extract indicates that a higher dose of CQ may be required whenever the vegetable meal is taken with CQ [
37].
The pharmacokinetics interaction effect between ethanolic leaf extract of VA and CQ was studied in rats. The extract was administered before and at the same time with CQ. The study revealed AUC of 297.52 ± 8.45 and 333.22 ± 24.99, C
max of 74.60 ± 1.02 and 76.60 ± 3.07 for test and control groups. Elimination rate (Ke) in the test group (0.088 ± 0.035) was higher than the control group (0.027 ± 0.017). The authors recommended the avoidance of concomitant administration of VA and CQ to avoid the development of resistance [
41].
Ali et al [
42] investigated the effect of grapefruit juice (GFJ) on plasma CQ kinetics in mice. Grapefruit juice (4 mL/kg) was orally administered to mice before oral administration of CQ (100 mg/kg). Measurement of CQ plasma concentration was done fluorometrically at 0, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 18 and 24 h subsequent to its administration. Mean AUC, C
max, and T
max for control (distilled water) and test (GFJ) were 5.34 ± 0.38 and 7.01 ± 0.66 mg·h/L; 763.4 ± 39.1 and 859.2 ± 45.2 mg/L and 2.65 and 2.95 h respectively. The authors concluded that concomitant administration of GFJ with CQ enhances the plasma concentration of CQ,
Synopsis of studies on herbal-antimalarial drugs interactions in-vitro and in human volunteers
Studies involving in-vitro model as well as human volunteers made up this section and the outcome of these studies are summarized in Table
4.
Table 4
Summary of studies on herbal-antimalarial drugs interactions in human volunteers and in-vitro studies
1 | Garcinia kola seed (12.5 g) | Quinine sulphate (600 mg/kg) | ↓ in peak plasma concentration of quinine and its metabolites | |
2 | Kola nut (12.5 g) | Halofantrine (500 mg) | ↓ in plasma concentrations of halofantrine and its active metabolite | |
3 | Garcinia kola seed | Quinine: HPLC quantitative study | Quinine was adsorbed on G. kola (indicating antagonism) | |
Igbinoba et al [
19] evaluated the interaction between quinine and
Garcinia kola (
G. kola) using an in vitro adsorption method at 37 ± 0.1 °C. HPLC was used to quantify the amount of quinine adsorbed and desorbed. From the study, Quinine was adsorbed on
G. kola, suggesting the need to circumvent the simultaneous administration of quinine and
G. kola. This would aid in preventing potential drug interaction and decreased drug bioavailability.
In a follow-up study, a randomized crossover study was carried out in 24 healthy Nigerian volunteers to investigate the effect of concurrent ingestion of
G. kola seed on the pharmacokinetics of quinine. One group of participants received 600 mg quinine sulphate per subject before and after the administration of
G. kola (12.5 g) daily for seven days, while another group received 12.5 g twice daily for six days and once on day seventh. There was a reduction in the peak plasma concentration of quinine and its metabolites (3 hydroxyquinine) following the Co-administration of oral quinine and
G. kola seeds. The authors posited the need for caution to be exercised when oral quinine is given concurrently with
G. kola [
43].
Kolade et al [
44] investigated the effect of kola nut on the pharmacokinetics of halofantrine using 15 healthy male volunteers who received 12.5 g of kola nut alongside 500 mg of halofantrine. Collected blood samples were analyzed by HPLC. The study revealed a significant decrease in the plasma concentrations of halofantrine and the active metabolite (desbutylhalofantrine). Authors submitted that caution should be exerted whenever halofantrine is taken together with caffeine-containing nutrients.
An interaction study between CQ and aqueous leaf extract of
Azadirachta indica was investigated in rabbits. There was a significant decrease in serum concentration of CQ following concurrent administration of both drugs. There was a slower absorption and elimination as well as longer half-life of CQ. Significant reduction in the area under the curve (71.9%), maximum serum concentration (69.8%), absorption rate constant (37.3%), elimination rate constant (53.9%), clearance rate (76.5%) and volume of distribution (47.2%) as well as pronounced elevation in the half-life of the drug (125.7%) were observed [
38].
Postulated interaction mechanism(s) between medicinal plants and conventional antimalarial drugs
A combination of two or more drugs would either produce a none effect, especially when both drugs do not have interaction. Also, such combination could result to a less effect (antagonism), usually when one of the drugs decreases or abolishes the action of the other. In synergism, the action of one drug is expedited or enhanced by the other drug, resulting in an additive or potentiation effect [
45].
It is interesting to note that, the three interaction effects stated above were observed from the above highlighted studies. But what mechanism(s) or process could have underlain such interactions?
Medicinal plants contain various bioactive compounds such as tannins, terpenoids, saponins, alkaloids, coumarins, kaempferol, quinines, flavonoids, chalcones, sesquiterpene lactones, quercetin, sesquiterpenes, polyphenols [
10] among others, which are responsible for their antimalarial activities as a well as interaction effects with conventional antimalarial drugs. The presence of plant secondary metabolites could pose significant alterations in pharmacokinetics parameters of the combination [
2]. Diminution in pharmacological activity could also result when plant chemicals combine and interact with drug transporters [
46]. For instance, zinc can stimulate intestinal proteins that bind drugs and hinder their absorption from the lumen of the intestine into the blood circulation [
24]. Also, the half-life of CQ was found prolonged following inhibition of Cytochrome P
450 enzymes by flavonoids [
24]. Green leafy vegetables have been reported to be among foods which alkalinize urine, which in turn increases tubular reabsorption, leading to a reduction in Ke of CQ [
24,
47]. Iwalokun [
15] proposed the synergistic action of VA on CQ to be due to the ability of VA to prolong the elimination half-life of CQ. In the same vein, Sibhat and Hiben, [
23], suggested that some herbal products could alter some pharmacokinetic parameters of CQ by blocking its absorption, distribution and elimination [
23].
Igbinoba and co-researchers in their in vitro study suggested that the interaction of quinine with
G. kola could have occurred due to capacity-limited adsorption of quinine unto
G. kola, which contains flavonoids that possesses functional groups that promote formation of complexes with other compounds. The presence of trace elements (sodium, magnesium, calcium, copper, aluminum, potassium and zinc) in
G. kola was suggested to have the capacity of producing drug interactions via chelation [
19].
Medicinal plants that are rich in fat and dietary fiber have the capacity of delaying the entry of orally administered drugs [
24,
48]. Thus, concomitant administration of plant based food with conventional antimalarial drugs would go a long way increasing or decreasing their therapeutic or adverse effects.
From the review, chloroquine (14, 48.28%) appeared to have the highest frequency of combination with medicinal plants, which substantiates its affordability and preference of use with herbal medicines by the locals.
Pharmacokinetic parameters such as elimination rate constant (Kel), absorption rate, peak serum concentration, elimination half-life (T
1/2), area under the curve (AUC), volume of distribution (Vd), absorption rate constant (Ka), maximum whole blood concentration (C
max), time for maximum concentration to be attained (T
max) and clearance (Cl), of a drug can be affected by food and phytoconstituents [
13]. Case in point, the activity of cytochrome P450
1A isozyme was enhanced following simultaneous administration of
C. sanguinolenta and ART, which resulted to decrease in bioavailability, half-life, clearance, volume of distribution, increase elimination rate constant of dihyhroartemisinin, the active metabolite of ART [
13,
35].