VALUATION OF THE PHARMACOKINETIC PROFILE OF 3 HERBAL FORMULATIONS AND PHARMACOKINETIC PROFILE OF SMALL MOLECULES CO-ADMINISTERED WITH HERBAL FORMULATIONS

EVALUATION OF THE PHARMACOKINETIC PROFILE OF 3 HERBAL FORMULATIONS AND PHARMACOKINETIC PROFILE OF SMALL MOLECULES CO-ADMINISTERED WITH HERBAL FORMULATIONS

1.0 TEST SYSTEM DETAILS:

Species : Rattus norvegicus (Rats)

Strain: Sprague Dawley

Age: 6-7 weeks

Sex: Male and Female

No. of animals: Study 1: 8 (4M+4F) animals per group.

: Study 2: 8 (4M+4F)

No. of groups: Study 1: 3 and Study 2: 3

Total animals: Study 1: Twenty-Four animals for 3 compounds – HF1, HF2, HF3

Study 2: Twenty-four animals for pharmacokinetic drug interaction study between HF1 and Amoxicillin

 2.0 TEST ARTICLE DETAILS:

HF1: Curcuma longa-based herbal formulation.
HF2: Withania somnifera-based herbal formulation.
HF3: Tinospora cordifolia and Withania somnifera-based herbal formulation.

3.0 ALLOCATION OF GROUPS:


Study 1, Compounds: HF1, HF2, HF3

Groups	Treatment	Dose; ROA	Dose Volume
G1	Low Dose	10-30 mg/kg, once only, p.o. in 0.5% MC	5 mL/kg
G2	Mid Dose	30-100 mg/kg, once only, p.o. in 0.5% MC
G3	High Dose	100-300 mg/kg, once only, p.o. in 0.5% MC

STUDY 2, Compounds: HF1 + Amoxicillin

Group No.	Group Description	Treatment administered	Dose Volume and Route
G1	HF1 + Amoxicillin Low Dose	HF1: 100-300 mg/kg + Amoxicillin: 50 mg/kg in 0.5% MC	5 ml/kg, p.o.
G2	HF1 + Amoxicillin Mid Dose	HF1: 100-300 mg/kg + Amoxicillin: 100 mg/kg in 0.5% MC
G3	HF1 + Amoxicillin High Dose	HF1: 100-300 mg/kg + Amoxicillin: 200 mg/kg in 0.5% MC

Abbreviations: MC-Methyl Cellulose, p.o.-per os.

1.0 METHOD FOR STUDY 1:

· Animals will be randomized based on their body weights into three groups.

· Rats will be fasted overnight before the conduct of the experiment.

· Before the administration of the test articles blood will be withdrawn from the retro-orbital plexus of the rats (0-hour sample) under transient isoflurane anesthesia.

· Subsequently, animals of groups G1, G2, and G3 will receive HF1 by oral route in a dose range of 10-300 mg/kg.

· Blood (0.2 mL) will again be withdrawn from the retro-orbital plexus of the animals at 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours after compound administration.

· Plasma will be separated and submitted for bioanalysis.

· After a 15-day wash-out period, the animals will again be used for the determination of the pharmacokinetic profile of HF2 as mentioned above, and after a further wash-out period of 15 days, the animals will be re-utilized for the evaluation of the pharmacokinetic profile of HF3.


METHOD FOR STUDY 2

· Animals will be randomized based on their body weights into three groups.

· On Day 1, blood will be withdrawn from the animals from the retro-orbital plexus under transient isoflurane anesthesia.

· Subsequently, rats allocated to groups G1-G3 will receive the HF1 formulation orally in the dose range of 100-300 mg/kg and they will concomitantly receive the small molecule in three escalating doses as mentioned in the tables for each study.

· The animals will be administered both test articles for fourteen days.

· On Day 15, from overnight fasted animals, blood will be withdrawn and then they will be orally administered the Ayurvedic formulation along with the small molecule.

· Blood (0.2 mL) will again be withdrawn from the retro-orbital plexus of the animals at 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours after compound administration.

· Plasma will be separated and submitted for bioanalysis.

2.0 PARAMETERS TO BE EVALUATED:

· Plasma concentrations of the test articles and derived pharmacokinetic parameters.

3.0 REFERENCE(S):

1. Alnaqeeb, M. et al. Critical pharmacokinetic and pharmacodynamic drug-herb interactions in rats between warfarin and pomegranate peel or guava leaves extracts. BMC Complement. Altern. Med. 19, 1–12 (2019).

2. Li, Y., Liu, C., Zhang, Y., Mi, S. & Wang, N. Pharmacokinetics of ferulic acid and potential interactions with Honghua and clopidogrel in rats. J. Ethnopharmacol. 137, 562–567 (2011).

3. Balap, A., Atre, B., Lohidasan, S., Sinnathambi, A. & Mahadik, K. Pharmacokinetic and pharmacodynamic herb-drug interaction of Andrographis paniculata (Nees) extract and andrographolide with etoricoxib after oral administration in rats. J. Ethnopharmacol. 183, 9–17 (2016).

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