Computational pharmacokinetics and in vitro-in vivo correlation of anti-diabetic synergistic phyto-composite blend

Table 1 Possible therapeutic molecular targets for type 2 anti-diabetic therapy

Type	Target for action	Nature of action	Effect produced
Protein kinases	Protein kinase C	Inhibitory	Block receptor desensitization
	AMP activated kinase	Activator	Enhance glucose transport
	GSK-3	Inhibitory	Activate glycogen synthase
	MAP kinase	Inhibitory	Block receptor desensitization
Protein phosphatases	PTP-1b	Inhibitory	Block receptor dephosphorylation
	PP1	Activator	Activate glycogen synthase
	LAR	Inhibitory	Block receptor dephosphorylation
Lipid phosphatases	PTEN	Inhibitor	Increase PIP3-stimulated glucose transport
Cell surface receptors	Insulin receptor	Agonist	Insulin mimetic
	Glucagon receptor	Antagonist	Low fasting glucose
	GLP receptor	Agonist	Increase insulin secretion
	β-3 adrenergic receptor	Agonist	Increase lipolysis
Ion channels	Sulphonyl urea receptor	Inhibit K channel	Increase insulin secretion
Transcription factors	PPAR-γ	Selective modulator	Insulin sensitizer
	HNF4	Selective modulator	Increase insulin secretion

AMP: Adenosine monophosphate activated kinase; GSK-3: Glycogen synthase kinase 3; MAP: Mitogen activated protein; PTP-1b: Protein tyrosine phosphatase-1b; PP1: Protein phosphatase 1; LAR: Leukocyte antigen related; PTEN: Phosphatase and tensin homolog; PPAR-γ: Peroxisome proliferator-activated receptor; GLP: Glucagon-like peptide.

Table 2 Types of in vitro-in vivo correlation and the parameters used

Level	In vitro parameters	In vivo parameters	Utility
Level A: direct relationship with in vivo data based on in vitro measurement alone	Dissolution curves	Absorption curves	Highest level of correlation depicting point to point relation between in vitro dissolution rate and in vivo input rate of drug from dosage form. Marks in vitro dissolution as the surrogate of in vivo performance
Level B: relation based on statistical moments analysis	MDT	MAT; MRT	Mean in vitro dissolution time of the product compared to mean in vivo residence time or mean in vivo dissolution time
Level C: relates one dissolution time point (t50%, t90%, etc.) to one mean pharmacokinetic parameter (AUC, Cmax, tmax)	Disintegration time, time to have 10%, 50%, 90% dissolved, dissolution rate, dissolution efficiency	Cmax, Tmax, Ka, time to have 10%, 50%, 90% absorbed, AUC (total or cumulative)	Single point weak correlation showing a partial relation between absorption and dissolution. Used in early stages of formulation development before pilot production

MDT: In vivo measurement of the dissolution rate in the digestive tract; MRT: The mean time that the drug resides in the body, MRT may also be the mean transit time; MAT: The mean time required for drug to reach systemic circulation from the time of drug administration. It is actually the mean time involved in the in vivo release and absorption processes as they occur in the input compartment and is estimated as MAT = MRT - MRToral/i.v.; AUC: In pharmacokinetics, AUC is the area under the curve (mathematically known as definite integral) in plot of concentration of drug in blood plasma against time, it reflects the actual body exposure to drug after administration of a dose of the drug and expressed in mg × h/L; Ka: It is the absorption rate constant which is a proportionality constant that relates the rate of drug absorbed in the body; Cmax: It refers to peak serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered and prior to the administration of a second dose; Tmax: It is the time after administration of a drug when the maximum plasma concentration, Cmax is reached and during which rate of absorption is equal to the rate of elimination. MDT: Mean dissolution time; MAT: Mean absorption time; MRT: Mean residence time.