Ans. A. Lipophilic. (Ref KDT 6th/pg. 19; Harrison's 17th edition, page 29)APPARENT VOLUME OF DISTRIBUTION (Theoretical volume occupied by the total absorbed drug amount at the plasma concentration.)# Vd = amount of drug in the body / plasma drug concentrationFactors governing the volume of drug distribution:# Lipid: Water partition Co-efficient of the drug: Lipid insoluble drugs do not enter cells - V approximates extracellular fluid volume, e.g. streptomycin, gentamicin 0.25L/kg.# pKa value of the drug.# Degree of plasma protein binding: The volume of distribution of drugs extensively bound to plasma proteins but not to tissue components approaches plasma volume (are largely restricted to the vascular compartment) and hence have low V values e.g. diclofenac and warfarin (99% bound) V = 0.15L/kg.# Affinity for different tissues: By contrast, for drugs highly bound to tissues, the volume of distribution can be far greater than any physiologic space. Thus, drugs sequestrated in tissues may have, V much more than total body water or even body mass, e.g. digoxin 6 L/kg, propranolol 4L/kg, morphine 3.5 L/kg, because most of the drug is present in other tissues and plasma concentration is low. Thus, in case of poisoning, drugs with large volume of distribution are not easily removed by hemodialysis.# Fat: lean body mass ratio, which can very with age, sex, obesity, etc.# Diseases like CHF, uremia, cirrhosisVd COMPARTMENT DRUG TYPESLowBlood (4-8 L)Large/charged molecules; plasma protein boundMediumECFSmall hydrophilic moleculesHighAll tissues including fatSmall lipophilic molecules, especially if bound to tissue proteinHarrison's 17th edition, page 29.............DRUG DISTRIBUTIONIn a typical 70-kg human, plasma volume is ~3 L, blood volume is ~5.5 L, and extracellular water outside the vasculature is ~42 L. The volume of distribution of drugs extensively bound to plasma proteins but not to tissue components approaches plasma volume; warfarin is an example. By contrast, for drugs highly bound to tissues, the volume of distribution can be far greater than any physiologic space. For example, the volume of distribution of digoxin and tricyclic antidepressants is hundreds of liters, obviously exceeding total-body volume. Such drugs are not readily removed by dialysis, an important consideration in overdose.Only when distribution is near-complete does the concentration of digoxin in plasma reflect pharmacologic effect. For this reason, there should be a 6-8 h wait after administration before plasma levels of digoxin are measured as a guide to therapy.Educational pointsClinical Implications of Altered Protein BindingThe acute-phase reactant ?l-acid glycoprotein binds to basic drugs, such as lidocaine or quinidine, and is increased in a range of common conditions, including myocardial infarction, surgery, neoplastic disease, rheumatoid arthritis, and burns. This increased binding can lead to reduced pharmacologic effects at therapeutic concentrations of total drug. Conversely, conditions such as hypoalbuminemia, liver disease, and renal disease can decrease the extent of drug binding, particularly of acidic and neutral drugs, such as phenytoin. Here, plasma concentration of free drug is increased, so drug efficacy and toxicity are enhanced if total (free + bound) drug concentration is used to monitor therapy.