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Abstract
Essentials of Biopharmaceutics and Pharmacokinetics
Kar’s Essentials of Biopharmaceutics and Pharmacokinetics deals with how a drug exerts its action in the human body through the fundamentals of absorption, distribution, metabolism and excretion. The book adopts a growth-oriented format and design that is developed systematically and methodically.
The book interrelates five different sections:
Section 1 Biopharmaceutics and Pharmacokinetics: What Do They Mean?
Section 2 Biopharmaceutics
Section 3 Pharmacokinetics
Section 4 Clinical Pharmacokinetics
Section 5 Bioavailability and Bioequivalence
Each section starts with a basic theory and fields of application, focuses on model-independent pharmacokinetic analyses, expatiates various biopharmaceutical aspects of dosage form and evaluation, provides an altogether new approach in understanding both dosage regimen design and individualization, and explains modification in drug molecules related to the pharmacokinetics.
Undoubtedly, the unique blend of fundamental principles and latest breakthroughs in the field will certainly provide sufficient subject matter to the students of pharmacy, pharmacology, medicinal chemistry scientists, who need a simple as well as detailed introduction in theory and application.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Front Cover\r | Front Cover | ||
| Front Matter\r | iii | ||
| Copyright\r | iv | ||
| Dedication\r | v | ||
| PREFACE | vii | ||
| CONTENTS | ix | ||
| SECTION 1 \rBiopharmaceutics andPharmacokinetics:What Do They Mean? | 1 | ||
| 1 - Introduction to Biopharmaceutics and Pharmacokinetics | 3 | ||
| Introduction | 3 | ||
| Historical Perspective of Biopharmaceutics | 3 | ||
| Extravascular Administration of a Drug | 6 | ||
| Scope of Biopharmaceutics | 7 | ||
| Variants in Biopharmaceutics | 7 | ||
| Pharmacokinetics | 8 | ||
| Modus Operandi | 8 | ||
| Salient Features of Pharmacokinetics | 8 | ||
| Clinical Pharmacokinetics | 10 | ||
| Therapeutic Drug Monitoring and Pharmacokinetics | 11 | ||
| Pharmacodynamics | 12 | ||
| Toxicokinetics and Clinical Toxicology | 13 | ||
| Bioavailability | 13 | ||
| Absolute Bioavailability | 14 | ||
| Relative Bioavailability | 14 | ||
| Quantifying Absolute Availability | 14 | ||
| Quantifying Relative Availability | 16 | ||
| Bioequivalence | 17 | ||
| Bioequivalence: The Canadian Regularly Perspective | 17 | ||
| Uncomplicated Drugs | 19 | ||
| Guidelines for Equivalence Studies | 19 | ||
| Plasma& | 19 | ||
| Modus Operandi | 19 | ||
| SECTION 2 \rBiopharmaceutics | 23 | ||
| 2 - Biopharmaceutics | 25 | ||
| 1. Introduction | 25 | ||
| 1.1. Alternative Distinctness of Biopharmaceutics | 26 | ||
| 1.1.1. Important Modalities Encountered by a Drug | 26 | ||
| 1.2. Pharmacokinetics | 27 | ||
| 1.3. Clinical Pharmacokinetics | 27 | ||
| 2. Biopharmaceutics Classification System (BCS) | 29 | ||
| 3. In Vitro& | 30 | ||
| 3.1. Genesis of IVIVC | 31 | ||
| 3.2. FDA Definition for IVIVC | 31 | ||
| 3.3. Important Factors for Development of IVIVC | 31 | ||
| 3.4. IVIVC Utilization in Novel Dosage Forms | 32 | ||
| 3.5. Applications of IVIVC | 32 | ||
| 4. Passage of Drugs across Biological Barrier | 33 | ||
| 4.1. Simple Capillary Endothelial Barrier (CEB) | 33 | ||
| 4.2. Cell Membrane Barrier (CMB) | 34 | ||
| 4.3. Blood& | 36 | ||
| 4.3.1. Permeability of Cell and Capillary Membranes | 36 | ||
| 4.3.2. Highlights of BBB as a Lipoidal Barrier | 38 | ||
| 4.4. Blood& | 39 | ||
| 4.5. Placental Barrier (PB) | 40 | ||
| 4.6. Blood& | 42 | ||
| 5. Factors Influencing Drug Absorption | 43 | ||
| 5.1. Rate-Limited Stages in Oral Drug Absorption | 43 | ||
| 5.2. Drug Absorption via Gastrointestinal Tract (GIT) | 45 | ||
| 5.2.1. Cell Membrane Structure | 45 | ||
| Routes Adopted by Small Drug Molecules in Crossing Cell Membranes | 46 | ||
| 5.2.2. Pathways of Drug Absorption | 47 | ||
| Important Points | 47 | ||
| 5.2.3. Gastrointestinal (GI) Physiology | 47 | ||
| 5.3. Fluid-Mosaic Model for Transcellular Diffusion of Polar Molecules | 50 | ||
| 5.4. Gastrointestinal Physiology | 51 | ||
| 5.4.1. Gastrointestinal Blood Flow | 51 | ||
| 5.4.2. Gastrointestinal pH | 52 | ||
| 5.5. Gastric Emptying | 54 | ||
| 5.5.1. Mechanism of Gastric Emptying | 54 | ||
| Gastric Emptying& | 54 | ||
| Gastric Emptying of Liquids vs. Solid Drug Products or Foods | 55 | ||
| Gastric Emptying Designates a Simple Mono-Exponential Process | 55 | ||
| 5.6. Gastrointestinal Motility | 57 | ||
| 6. Mechanisms of Drug Absorption | 58 | ||
| 6.1. Passive Diffusion | 59 | ||
| 6.1.1. Fick& | 60 | ||
| 6.1.2. Characteristic Features of Passive Diffusion | 60 | ||
| 6.1.3. Fate of Lipophilic and Hydrophilic Substituted Drugs | 61 | ||
| 6.1.4. Implication of Henderson and Hasselbalch Equation | 62 | ||
| 6.2. Pore Transport (Convective Transport) | 62 | ||
| 6.2.1. Highlights of Pore Transport | 63 | ||
| 6.3. Carrier-Mediated Transport | 63 | ||
| 6.3.1. Important Characteristic Features of Carrier-Mediated Transport | 64 | ||
| 6.4. Active Transport | 66 | ||
| 6.5. Facilitated Diffusion | 67 | ||
| 6.6. Carrier-Mediated Intestinal Transport | 68 | ||
| 6.7. Ionic Diffusion (or Electrochemical Diffusion) | 69 | ||
| 6.7.1. Permeation Profile of Cationic Drug Molecules | 69 | ||
| 6.8. Ion-Pair Transport | 69 | ||
| 6.9. Endocytosis | 70 | ||
| 6.10. Summary of Important Transport Processes vis-& | 71 | ||
| 7. Drug Absorption vs. Bioavailability | 72 | ||
| 7.1. Preamble | 72 | ||
| 7.2. Pharmaceutical Factors (or Biopharmaceutic Considerations) Affecting Drug Bioavailability | 73 | ||
| 7.2.1. Rate-Determining Step (RDS) | 73 | ||
| Disintegration | 74 | ||
| Dissolution | 75 | ||
| Various Absorption Steps Immediately after Oral Ingestion of Coated Tablets or Capsules | 75 | ||
| Rate-Limiting Steps vis-& | 76 | ||
| 7.2.2. Noyes& | 78 | ||
| Preamble | 78 | ||
| 7.3. Factor Influencing GI Absorption of a Drug from Its Respective Dosage Forms | 79 | ||
| 7.3.1. Pharmaceutical Factors | 79 | ||
| Physicochemical Characteristic Features of Drug Substances | 79 | ||
| Dosage Form Characteristics Features and Pharmaceutic Ingredient | 80 | ||
| 7.3.2. Patient-Related Factors | 80 | ||
| 7.4. Physicochemical Nature of the Drug vis-& | 80 | ||
| 7.4.1. Drug Solubility and Dissolution Rate | 81 | ||
| 7.4.2. Theories of Drug Dissolution | 83 | ||
| Diffusion Layer Model (or Film Theory) | 83 | ||
| Danckwert& | 83 | ||
| Interfacial Barrier Model (or Double Barrier or Limited Solvation Theory) | 84 | ||
| Important Points | 85 | ||
| 7.4.3. Particle Size and Drug Absorption | 86 | ||
| 7.4.4. Polymorphic Crystals, Solvates and Drug Absorption | 88 | ||
| 7.4.5. Drug pKa, Lipophilicity and GI pH (or pH-Partition Hypothesis) | 89 | ||
| Drug pKa and Gastrointestinal pH (or GI-pH) | 91 | ||
| Important Points | 92 | ||
| Lipophilicity and Absorption of Drug | 96 | ||
| 7.4.6. Limitations of pH-Partition Hypothesis | 97 | ||
| Specific Presence of Virtual Membrane pH | 98 | ||
| Critical Absorption of Ionized (Polar) Drugs | 98 | ||
| Influence of GI Surface Area vis-& | 99 | ||
| Crucial Presence of Aqueous Unstirred Diffusion Layer | 99 | ||
| 7.4.7. Deviations from the pH-Partition Hypothesis | 101 | ||
| Microclimate pH | 101 | ||
| A Unifying Hypothesis | 101 | ||
| 7.5. Product Form (Dosage Form) Characteristics vis-& | 102 | ||
| 7.5.1. Product Form Characteristics | 103 | ||
| Formulati on Factors | 103 | ||
| Disintegration Time | 106 | ||
| Exempted Disintegration Tests for Certain Drug Products | 106 | ||
| Processing Variants | 108 | ||
| Granulation Variables | 108 | ||
| Wet Granulation Method | 108 | ||
| Precompression Method | 109 | ||
| Applied Compression Force | 109 | ||
| Packing of Capsule Contents | 111 | ||
| 7.5.2. Pharmaceutic Ingredients | 111 | ||
| Diluents (or Fillers) | 112 | ||
| Binders and Granulating Agents | 112 | ||
| Vehicles | 113 | ||
| Lubricants (or Anti-frictional Agents) | 114 | ||
| Disintegrants (or Disintegrating Agents) | 114 | ||
| Important Points | 114 | ||
| Coatings | 115 | ||
| Surfactants | 115 | ||
| Buffers | 116 | ||
| Colorants | 116 | ||
| Complexing Agents | 117 | ||
| Crystal Growth Inhibitors | 117 | ||
| 7.6. Drug Absorption vis-& | 117 | ||
| SECTION 3 \rPharmacokinetics | 121 | ||
| 3 - Pharmacokinetics\r | 123 | ||
| 1. Introduction | 123 | ||
| 2. Clinical Significance of Plasma Protein Drug Concentration Measurement | 124 | ||
| 2.1. Significance of Drug–Protein Binding Complex | 124 | ||
| 2.1.1. Serum Albumin | 126 | ||
| 2.1.2. a1-Acid Glycoprotein (or a1-AGP or AAG) | 128 | ||
| 2.1.3. Lipoproteins | 129 | ||
| 2.1.4. Globulins (α-, β-, γ-Globulins) | 131 | ||
| 2.1.5. Erythrocytes [or Red Blood Cells (RBCs)] | 131 | ||
| 3. Pharmacokinetic Models | 133 | ||
| 3.1. Pharmacokinetic Models vis-à-vis Mathematical Models | 135 | ||
| Preferred Model for Analysis of Data | 135 | ||
| 3.2. Classification of Pharmacokinetic Models | 136 | ||
| 3.2.1. Compartment Models | 136 | ||
| Mammillary Model | 137 | ||
| 3.2.2. Flow Models (or Physiologic–Pharmacokinetic Models) | 147 | ||
| Salient Features | 148 | ||
| Merits of Physiologic–Pharmacokinetic Models | 151 | ||
| 3.2.3. Non-Compartmental Pharmacokinetics | 151 | ||
| Important Applications | 153 | ||
| Merits of Non-Compartmental Pharmacokinetics | 153 | ||
| 3.2.4. Non-Linear Pharmacokinetics | 154 | ||
| Time-Dependent Pharmacokinetics | 154 | ||
| 4. Pharmacokinetics of Drug Absorption | 154 | ||
| 4.1. Zero-Order Absorption Rate Constant | 155 | ||
| 4.1.1. Plasma Drug Level–Time Curve for a Drug Administered in Single Oral Dose | 156 | ||
| 4.2. First-Order Absorption Rate Constant | 158 | ||
| 4.3. The Loo–Riegelman and Wagner–Nelson Equations | 160 | ||
| 4.3.1. Loo–Riegelman Equation | 160 | ||
| 4.3.2. Wagner–Nelson Equation | 164 | ||
| 4.3.3. Estimation of Cmax and tmax | 168 | ||
| 4.3.4. Influence of Ka and KE upon Cmax, tmax and AUC | 169 | ||
| 5. Volume of Distribution and Distribution Coefficient | 170 | ||
| 5.1. Volume of Distribution (Vd) | 170 | ||
| 5.2. Presence of a Fraction of Drug Both Inside and Outside Plasma | 171 | ||
| 5.3. Determination of Plasma Volume | 171 | ||
| 5.4. Volume of Total Body Water (or Fluid) | 172 | ||
| 5.5. Volume of Distribution (Vd) vs. Protein/Tissue Binding of Drugs | 172 | ||
| 6. Organ-Specific Clearance | 173 | ||
| 6.1. Concept of Organ-Specific Clearance | 174 | ||
| 6.2. Renal Clearance | 175 | ||
| 6.2.1. Two Substances Used to Determine GFR | 176 | ||
| 6.2.2. Active Tubular Secretion (ATS) | 176 | ||
| 6.2.3. Kinetics of Urinary Excretion | 177 | ||
| 6.3. Hepatic Clearance | 187 | ||
| 6.3.1. Venous Equilibrium Model of Hepatic Clearance | 187 | ||
| 6.4. Extra Hepatic/Non-Renal Elimination | 189 | ||
| 6.4.1. Biliary Excretion | 189 | ||
| 6.4.2. Exhalation47 | 193 | ||
| 6.4.3. Foecal Excretion | 193 | ||
| 6.4.4. Intestinal Excretion | 194 | ||
| 6.4.5. Excretion via Saliva/Skin | 194 | ||
| 6.4.6. Excretion via Milk | 195 | ||
| 7. Non-Linear Pharmacokinetics | 195 | ||
| 7.1. Preamble | 195 | ||
| 7.2. Michaelis–Menten Equation | 196 | ||
| 7.2.1. Accounting for Deviation of Michaelis–Menten Equation | 196 | ||
| 7.2.2. Graphical Representation of Michaelis–Menten Equation | 199 | ||
| 7.3. Drug Elimination by Capacity-Limited Process | 201 | ||
| 7.4. Important Recognized Plot Variants in Non-Linear Pharmacokinetics | 202 | ||
| 7.4.1. Lineweaver–Burk Plot (or Doubled-Reciprocal Plot) | 202 | ||
| 7.4.2. Hanes–Woolf Plot | 204 | ||
| 7.4.3. Woolf–Augustinsson–Hofstee Plot | 205 | ||
| 7.4.4. Direct Linear Plot | 205 | ||
| 8. Pharmacokinetic Profiles of Some Specific Examplesfrom Various Classes of Drugs | 206 | ||
| 8.1. Antihypertensives | 207 | ||
| 8.2. Antiarrythmics | 208 | ||
| 8.3. Antianginal Drugs | 209 | ||
| 8.4. Pharmacokinetics of Nitroglycerin after Intravenous Infusion in Normal Subjects | 210 | ||
| 8.4.1. Experimental Procedure | 210 | ||
| 8.5. Antineoplastic Agents | 211 | ||
| 8.6. Pharmacokinetics of Oral and Intravenous Fluorouracil in Humans | 211 | ||
| 8.6.1. Experimental Procedure | 211 | ||
| 8.7. Antibiotics | 212 | ||
| 8.8. Pharmacokinetics of Piperacillin and Gentamicin FollowingIntravenous Administration to Dogs | 213 | ||
| 8.8.1. Experimental Procedure | 213 | ||
| Suggested Readings | 214 | ||
| SECTION 4 \rClinical Pharmacokinetics | 215 | ||
| 4 - Clinical Pharmacokinetics\r | 217 | ||
| Introduction | 217 | ||
| Scope of Pharmacokinetics | 219 | ||
| Therapeutic Objective | 220 | ||
| Dosage Regimens: Design, Modalities and Implementation | 221 | ||
| Design of Dosage Regimens | 221 | ||
| Optimal Single Dosage Regimen | 221 | ||
| Optimal Multiple Dosage Regimen | 221 | ||
| Accumulation of Drug in Multiple Dosing | 225 | ||
| Reachable Time for Achieving Steady State in Multiple Dosing | 227 | ||
| Average Drug Concentration vs. Body Content from Multiple Dosing to Steady State | 229 | ||
| Preamble | 229 | ||
| Loading and Maintenance Doses | 230 | ||
| Maintenance of Drug Level Within the Therapeutic Range | 231 | ||
| Perfect Design of Dosage Regimen Based Upon the Plasma–Drug Concentrations | 233 | ||
| Individualization | 235 | ||
| Objectives of Individualization | 235 | ||
| Important Steps for Individualization | 235 | ||
| Individualization: Clinical Experience and Optimization Based uponPlasma–Drug Concentration (C) | 243 | ||
| Drug Monitoring and Drug Therapy | 245 | ||
| Preamble | 245 | ||
| Therapeutic Endpoint | 245 | ||
| Toxic Endpoint | 246 | ||
| Importance of Monitoring Drug Therapy | 246 | ||
| Variants in Drug Monitoring and Drug Therapy | 246 | ||
| Single Dose Bioequivalence Study: Design and Relevant Statistics | 248 | ||
| Preamble | 248 | ||
| Bioequivalence Study Parameters | 251 | ||
| Bioequivalence Study Protocol | 258 | ||
| Bioequivalence Study Design | 259 | ||
| Parallel Design | 259 | ||
| Cross-Over Design | 259 | ||
| Statistical Methods in Bioequivalence Study | 261 | ||
| Statistical Method Variants | 261 | ||
| Bioequivalence Data: Statistical Interpretation | 263 | ||
| US-FDA/EMEA Regulatory Requirements for Bioequivalence Studies | 264 | ||
| Good Clinical Practices (GCPs) in Bioequivalence | 265 | ||
| Commonly Observed Non-Compliances in Bioequivalence Study | 267 | ||
| Exemptions in Bioequivalence Study | 267 | ||
| Bioequivalence Studies: Not Necessary | 268 | ||
| Absolute Bioavailable Dosage | 268 | ||
| Practice Problems | 274 | ||
| Pharmacokinetic Drug Interaction: Significance in Combination Therapy | 275 | ||
| Pharmacokinetic Interactions | 275 | ||
| Drug Absorption | 275 | ||
| Case Study 1 | 276 | ||
| Interactions Changing Drug Distribution | 278 | ||
| Interactions Affecting Metabolism | 278 | ||
| Interactions Affecting Renal Excretion | 281 | ||
| Pharmacodynamic Interactions | 281 | ||
| Pharmacological Synergism | 282 | ||
| Pharmacological Antagonism | 282 | ||
| Suggested Readings | 282 | ||
| SECTION\r 5 Bioavailability andBioequivalence | 283 | ||
| Section 5: - Bioavailability and Bioequivalence | 285 | ||
| 1. Introduction | 285 | ||
| 1.1. Preamble | 285 | ||
| 1.2. Definitions | 286 | ||
| 2. Bioavailability | 291 | ||
| 2.1. Preamble | 291 | ||
| Important Points | 291 | ||
| 2.2 Absolute Bioavailability | 292 | ||
| 2.3 Relative Bioavailability | 292 | ||
| 2.4 Bioequivalance Assessment and Data Evaluation (or Importance of Bioequivalence) | 293 | ||
| 2.4.1 Bioequivalence Assessment | 293 | ||
| 2.4.2. Urinary Drug Amount& | 294 | ||
| 2.4.3. Peak-Height Concentration | 295 | ||
| Example of a cardiac glycoside (e.g., Digoxin and Digitoxin): | 296 | ||
| 2.5. Bioavailability Studies in Human: Pharmacokinetic Profiles | 296 | ||
| 2.5.1 Comparison with a Reference Drug/Formulation | 297 | ||
| 2.5.2 Bioavailability Studies as per the Helsinki Declaration66Azarnoff DL: Clin. Pharmacol. Ther., 13: 796& | 297 | ||
| 2.5.3 Drug Dissolution Rate and Bioavailability | 298 | ||
| Testing Models: For In Vitro Dissolution Technique | 299 | ||
| Important Factors Governing the In Vitro Dissolution Technique | 299 | ||
| The Drug Dissolution Estimation Apparatus | 300 | ||
| 2.6. Statistical Methods for Bioavailability Studies | 306 | ||
| 2.6.1 Methods of Data Analysis | 307 | ||
| 2.6.2 Statistical Analysis | 307 | ||
| 2.6.3. Statistical Interpretation of Bioequivalence Data | 308 | ||
| 2.7. Factors that Decrease Bioavailability | 308 | ||
| 2.7.1 Presystemic Metabolism | 308 | ||
| 2.7.2 Instability | 311 | ||
| Hydrolysis of Weak Acidic Drugs (Penicillins) in Gastric Fluids | 312 | ||
| Delaying Absorption until Reaching Intestines | 313 | ||
| Important Points | 314 | ||
| Complexation | 314 | ||
| 2.8. Factors that Increase Bioavailability | 315 | ||
| 2.8.1. Overcoming Acute Bioavailability Issues | 315 | ||
| 2.8.2. Physicochemical Characteristics of a Drug | 317 | ||
| Micronization | 317 | ||
| Surfactants (or Surface-Active Agents) | 318 | ||
| Salts of Drugs | 319 | ||
| Metastable Polymorphs | 319 | ||
| Change in pH of Drugs Microenvironment | 319 | ||
| Pseudopolymorphism (or Solute& | 319 | ||
| Preferential Adsorption on Insoluble Carriers | 320 | ||
| Solvent Deposition | 320 | ||
| Solid Solutions | 320 | ||
| Eutectic Mixtures | 322 | ||
| Important Points | 323 | ||
| Solid Dispersions | 324 | ||
| Molecular Encapsulation (with Cyclodextrins) | 326 | ||
| 3. Bioequivalence | 327 | ||
| 3.1. Preamble | 327 | ||
| 3.2. Design and Conduct of Bioequivalence Studies | 327 | ||
| Important Points | 327 | ||
| 3.2.1. Criteria for the Design of Bioequivalence Study | 328 | ||
| Multiple-Dose Study vs. Single-Dose Study | 328 | ||
| Demerits of Multiple-Dose Bioequivalence Studies | 329 | ||
| 3.2.2. Design | 329 | ||
| 3.2.3. Subjects (or Volunteers) | 330 | ||
| 3.2.4. Reference and Test Product | 331 | ||
| Important Points | 331 | ||
| 3.2.5. Analytical Methods | 331 | ||
| Bioanalytical Methods | 332 | ||
| Assay of Biotransformation Product | 332 | ||
| Use of Radioactive Labelled Molecules | 333 | ||
| 3.2.6. Investigation of Characteristic Features | 333 | ||
| 3.2.7. Generalized Approach: Single-Dose Pharmacokinetic Bioequivalence Studies | 334 | ||
| Study Conduct | 334 | ||
| Collection of Sample and Sampling Times | 335 | ||
| 4. Bioanalytical Method Development and Validation for Bioavailability and Bioequivalence Studies | 336 | ||
| 4.1. Preamble | 336 | ||
| Important Points | 336 | ||
| 4.1.1. Bioanalytical Instruments | 337 | ||
| 4.2. Factors Governing Retention Time& | 338 | ||
| 4.2.1. Instrument to Be Used | 338 | ||
| 4.3. Selection of GC/HPLC Column | 339 | ||
| 4.3.1. pH of Mobile-Phase Buffer | 341 | ||
| Important Points | 341 | ||
| 4.3.2. Specific Composition of & | 342 | ||
| 4.3.3. Column-Oven Temperature | 342 | ||
| 4.3.4. Sample Injection Volume | 343 | ||
| 4.3.5. Extra Column Volume | 343 | ||
| 4.4. Method Validation | 344 | ||
| Index | 347 | ||
| A | 347 | ||
| B | 347 | ||
| C | 348 | ||
| D | 349 | ||
| E | 350 | ||
| F | 350 | ||
| G | 351 | ||
| H | 351 | ||
| I | 352 | ||
| K | 352 | ||
| L | 352 | ||
| M | 353 | ||
| N | 353 | ||
| O | 353 | ||
| P | 354 | ||
| Q | 355 | ||
| R | 355 | ||
| S | 355 | ||
| T | 356 | ||
| U | 357 | ||
| V | 357 | ||
| W | 357 | ||
| X | 357 | ||
| Y | 357 | ||
| Z | 357 |