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PHARMACOKINETICS Introduction The following data has been generated following a number of DMPK investigations on the New Chemical Entity Compound A (RMM 380) (Figure 1). Figure 1: Structure of Compound A Pharmacokinetic Studies 1. IV Administration Single Bolus Dose: A solution of Compound A hydrochloride in saline was administered at a dose of 1 mg/kg body weight (equivalent of the free base) to rats, dogs and monkeys. Blood samples were obtained at set time intervals (data obtained following the study in rats being presented in Table 1), urine was collected for 48h post dosing and analysed for the parent compound and selected metabolites (Table 3; Figure 2). 2. Oral Administration Single Dose: An aqueous solution of Compound A hydrochloride was administered to overnight fasted animals, rats, dogs and monkeys, at a dose of 10mg/kg body weight (equivalent of the free base) by gastric intubation. Blood and urine samples were collected from all three species, plasma data following administration to the rat are presented in Table 2 and the urine data from all three species are presented in Table 3. Three healthy volunteers (weight 60-65kg) were each given an experimental tablet formulation containing Compound A hydrochloride equivalent to 50mg of the free base and urine samples were collected and analysed for the parent drug and metabolites (Table 3; Figure 2). 3. Metabolic Investigations: Urine samples were collected from the above studies in order to identify the metabolites formed and to compare between species (Table 3; Figure 2). Results & Questions Table 1: Plasma Concentrations following IV Bolus Administration of Compound A. Time Post Dose (h) Plasma Concentration (ng/mL) Rat Dog Monkey 0.5 60.9 127.0 396.0 1.0 53.1 108.0 327.0 2.0 40.2 77.5 222.0 3.0 30.4 55.7 151.0 5.0 17.5 28.8 70.0 7.0 10.1 - - 8.0 - 10.7 22.0 Questions Plot the data from all three species using two cycle semilog graph paper. Using information derived from an examination of the plots calculate the following parameters following drug administration to the three species: • Elimination rate constant; • Half-life; • Volume of distribution; • Area under the plasma concentration versus time curve; • Clearance. Tabulate the values for all pharmacokinetic parameters for drug A in the three species.   Table 2: Plasma Concentrations following Single Oral Administration of Compound A. Time Post Dose (h) Plasma Concentration (ng/mL) Rat Dog Monkey 0.2 40.2 317.0 610.0 0.4 69.4 509.0 1080.0 0.6 90.1 618.0 1420.0 0.8 104.0 673.0 1670.0 1.0 113.0 693.0 1840.0 2.0 118.0 591.0 1980.0 3.0 97.2 437.0 1620.0 5.0 56.3 227.0 826.0 6.0 41.9 164.0 560.0 8.0 23.0 84.5 243.0 Questions Plot the data obtained following drug administration to the three species using three cycle semilog graph paper. Using the information derived from an examination of the plots determine the following for each species: • Maximum plasma concentration (Cmax) and the time (tmax) to attain it; • Elimination rate constant and half-life; • Absorption rate constant and absorption half-life; • Area under the plasma concentration versus time curve by both calculation and using the trapezoidal method. Using the data provided determine the Absolute Bioavailability of Compound A in all three species. Tabulate the pharmacokinetic data for the three species. Comment of the values of Cmax and AUCoral of Compound A in each species.   Table 3: Urinary Excretion, following 48h sample collection, of Compound A and total metabolites following Oral and IV administration to animals and man. Urinary Excretion (% dose) Compound A (Unchanged) Metabolites(Total) Route of Administration IV Oral IV Oral Species Rat 17.1 5.6 28.2 20.6 Dog 13.4 6.4 34.7 38.8 Monkey 14.8 10.3 - 35.8 Man - 30.1 - 12.8 Questions Calculate the bioavailability Compound A using the urinary excretion data following drug administration to each of the three animal species. Compare and comment on the values obtained with those calculated from the plasma data. Comment on the urinary excretion in relation to the half-life of the drug in the three species. Figure 2: Metabolic Profile of Compound A The metabolic pathways shown are the major routes in the four species examined. In monkeys the metabolites found were those found in man and dog, the former being more important. Questions 1. For the metabolic pathways indicated in Figure 2 name the type of transformation that drug A has undergone to produce the individual metabolites, draw any intermediate compounds which may be involved in the pathway(s), indicate the enzyme systems likely to be involved in the reactions, together with their cofactor requirements and subcellular location. 2. What tentative conclusions can be drawn concerning the Phase I Functionalisation metabolism of Compound A in the four species? 3. What significance does this knowledge of metabolism have in interpretation of the pharmacokinetic data? 4. Does the metabolic data have any significance in the interpretation of animal toxicity studies?

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2. What tentative conclusions can be drawn concerning the Phase I Functionalisation metabolism of Compound A in the four species?
Answer
Phase I Functionalisation metabolism of Compound A in all species causes its conversion into a relatively inactive and more polar metabolite by introduction of new polar functional groups. In dog phase-I reaction is enough to make compound A polar for excretion but in man and rat phase-II reaction (sulphate conjugation) is also required to make compound A more polar for excretion. In man and rat aromatic –OH group is generated by aromatic hydroxylation and O-dealkylation respectively. In dog carboxylic polar group generated by oxidative deamination and oxidation of aldehyde group. These metabolites will be successively excreted easily from urine. Every species having different Phase I functionalization reactions for same compound A. So metabolic studies of drug separately in human being are very important. Metabolism of compound A in man is more similar to rat rather than dog.

3. What significance does this knowledge of metabolism have in interpretation of the pharmacokinetic data?
Answer
Knowledge of metabolism is important in interpretation of number of different important pharmacokinetic parameters. Drug and metabolite excretion data can be used to calculate the various pharmacokinetic parameters of drug. Inter species differences in metabolism of a drug is also an important factor for interpretation of pharmacokinetic data. E.g. in some cases, metabolism of a drug lead to formation of more potent therapeutically...
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