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Ramesh Jayaraman, Founder-Director, DoseQuantics Consulting Pvt Ltd, India The cytochrome P450 (CYP450) family of enzymes is responsible for the metabolic clearance of a majority of small molecule drugs. Some of the major CYP450 enzymes are CYP3A, CYP2D6, CYP1A, CYP2C9, CYP2C19, CYP2B6 and CYP2E1. For many drugs a single CYP450 can be contribute to the metabolic…

Ramesh Jayaraman, DoseQuantics Consulting Pharmacokinetic parameters estimated in blood, serum and plasma are normally used for interpreting efficacy (pharmacodynamics) and safety of a drug and to establish pharmacokinetic/pharmacodynamic (PK/PD) relationships for identifying the optimum dose and regimen.  However, ethical and methodological reasons make it difficult to measure drug concentrations in tissues. As blood or serum…

Ramesh Jayaraman, DoseQuantics Consulting The KRAS (Kirsten Rat Sarcoma) gene is a rat oncogene homolog in humans that drives myriad cell functions through a network of signaling pathways. Cell growth-factors, which signal through receptor tyrosine kinases (RTKs), activate guanine nucleotide exchange factors (GEFs) that accelerate intrinsic RAS exchange activity and the formation of RAS-GTP which…

The male genital tract (MGT) is a site for infection (HIV), cancer (testicular) and disorders (erectile dysfunction). Since it is part of the male excretory and reproductive system it is also vulnerable to toxic effects of drugs. The MGT is a physiological pharmacokinetic compartment consisting of anatomical (blood-testes barrier) and physiological barriers (expression of drug…

Amiodarone is an antiarrhythmic drug indicated for treatment and prophylaxis of ventricular fibrillation (VF)* and hemodynamically unstable congestive ventricular tachycardia (VT)* Pharmacology: Amiodarone is a class III antiarrhythmic drug. Mechanism : Inhibition of potassium rectifier currents responsible for repolarizing the heart during phase 3 of cardiac action potential. K+ channel-blocking effect results in increased action…

Ramesh Jayaraman, DoseQuantics Consulting In anti-bacterial drug discovery and development, preclinical animal models of infection have played a pivotal role in evaluating the translational potential of drug candidates. Drug regulatory agencies review pharmacology data from preclinical animal models of infection for understanding the pharmacokinetic/pharmacodynamic (PK/PD) basis for setting efficacious dose and regimens for phase 2…

In drug discovery, in vitro pharmacology studies are fundamental in assessing a drug candidate’s intrinsic efficacy (Emax,activation or Imax,inhibition) and potency (EC50activation or IC50inhibition) on its pharmacological (drug) target outside the cells (binding and inhibiting or activating the target’s activity e.g. enzyme and receptor assays) and inside the cells (functional assays such as cell division, growth, inhibition,…

As the saying goes health is wealth. As long as people are healthy, physically and mentally, all is well. This is the ideal situation. However, the reality is far from this. Many people, unfortunately, are struck by illnesses that are life threatening or chronically debilitating, such as infection, cancer, diabetes, arthritis, hypertension, neurological, liver or…

An in vivo study, be it pharmacokinetics (PK), pharmacodynamics (PD), or pharmacokinetic/pharmacodynamic (PK/PD), should be designed to yield data that enables a decision to be made in drug discovery projects. This is particularly important as in vivo studies can be lengthy and often expensive. Poorly designed experiments may yield data that can be un-interpretable, incomplete…

Physiologically based pharmacokinetics (PBPK) describes the pharmacokinetics (PK) of a drug by integrating its physicochemical and in vitro ADME properties (drug specific) with physiological parameters (system specific) of the body. This is known as the” bottom up” approach (mechanistic), the opposite of empirical description of PK (sum of exponentials/compartments) known as “top down” approach. The mechanistic…