EVALUATION OF POSSIBLE INTERACTION AMONG DRUGS CONTEMPLATED FOR USE DURING MANNED SPACE FLIGHTS Progress Report For The Period July 1972 To September 1973 prepared for MANNED SPACECRAFT CENTER NATIONAL AERONAUTICS AND SPACE ADMINISTRATION HOUSTON, TEXAS by ARTHUR D. LITTLE, INC. CAMBRIDGE, MASSACHUSETTS 02140 L CONTRACT NAS 9-12970 OCTOBER 31, 1973 3 l161) EVALUATION OF POSSIBLE NASA-CF=1 FOR INTERACTION AMONG DRUGS CONTEMPLATED USE DURING MNANE SPACE FLIGHTS Unclas Progress Report, Jul, (Little (Arthur 2378 Do), Inc,) 2-7-p HC CSCL ,60 G3/4 23 I/z Fni CES SUBJELT TW : EVALUATION OF POSSIBLE INTERACTION AMONG DRUGS CONTEMPLATED FOR USE DURING MANNED SPACE FLIGHTS PROGRESS REPORT FOR THE PERIOD JULY 1972 TO SEPTEMBER 1973 PREPARED FOR MANNED SPACECRAFT CENTER NATIONAL AERONAUTICS AND SPACE ADMINISTRATION HOUSTON, TEXAS CONTRACT NAS 9-12970 Arthur D Little, Inc. October 31, 1973 C-74804 I TABLE OF CONTENTS Page No. LIST OF TABLES v LIST OF FIGURES Vii FOREWORD 1 SUMMARY 3 I. INTRODUCTION 5 II. BACKGROUND 7 A. Studies of Potential Interactions between Nitrofurantoin and Chloral Hydrate, Barbiturate, or Flurazepam In Vitro and In Vivo 7 Nitrofurantoin 7 Chloral Hydrate 8 Barbiturate 8 Flurazepam 10 B. Studies of Potential Interactions of Enzyme Inducers with Phenazopyridine 14 Phenobarbital 16 Flurazepam 17 C. Study of the Effect of Diphenoxylate on the Bioavailability of Nitrofurantoin 17 Nitrofurantoin 19 III. RESULTS 25 A. Studies of Potential Interaction between Nitro- furantoin and Chloral Hydrate, Barbiturates, or Flurazepam In Vitro and In Vivo 25 1. Summary 25 2. Introduction 25 3. Materials and Methods 26 4. Results and Discussion (a) Microsomal Studies 33 (b) Pharmacological Studies 44 PRECEDING PAGE BLANK NOT FILMED iii Arthur D Little, Inc TABLE OF CONTENTS - CONTINUED B. Studies of Potential Interactions of Enzyme Inducers with Phenazopyridine 47 1. Summary 47 2. Introduction 47 3. Materials and Methods 48 4. Results and Discussion (a) Induction of Azoreductase 50 (b) Methemoglobin Production by Phenazo- pyridine 53 C. Studies on the Effects of Diphenoxylate on the Bioavailability of Nitrofurantoin 77 1. Summary 77 2. Introduction 78 3. Materials and Methods 79 4. Results and Discussion (a) Studies in Dogs 85 (b) Studies in Man 102 IV. REFERENCES 112 V. APPENDIX 117 VI. DISTRIBUTION LIST 120 iv Arthur D Little, Inc LIST OF TABLES No. Page No. 1 Effect of chronic treatment with nitrofurantoin 34 on total body and liver weight and yield of microsomal protein 2 Effect of chronic treatment with nitrofurantoin on 35 rat liver cytochrome 3 Microsomal hexobarbital oxidase activity after 36 chronic nitrofurantoin premedication 4 Metabolic rates of meperidine in vitro using liver 39 microsomes from control and nitrofurantoin-treated rats 5 Microsomal nitroreductase activity after chronic 42 nitrofurantoin premedication 6 Effect of chronic dosing with nitrofurantoin on 45 hexobarbital- and chloral hydrate-induced sleeping times in rats 7 Measurement of azoreductase induction in control 52 and phenobarbital-treated rats 8 Effect of phenobarbital pretreatment on liver weights 54 and protein levels of rats 9 Measurement of azoreductase induction in control and 55 flurazepam-treated rats 10 Effect of flurazepam treatment in rats on liver weights 56 and protein levels 11 Effect of chronic dosing with flurazepam on cytochrome 57 enzyme levels in rat liver microsomes 12 Levels of methemoglobin in control and phenobarbital- 61 treated rats following multiple doses of phenazopyridine 13 Levels of methemoglobin in control and phenobarbital- 63 treated rats following a single dose of phenazo- pyridine 14 Level of methemoglobin in control and phenobarbital- 65 .treated rats following multiple doses of phenazo- pyridine v Arthur D Little, Inc No. Page 15 Levels of methemoglobin in control and flurazepam- 71 treated rats following multiple doses of phenazo- pyridine 16 Levels of methemoglobin in control and flurazepam- 73 treated rats following a single dose of phenazopyridine 17 Levels of methemoglobin in control and flurazepam- 75 treated rats following multiple doses of phenazo- pyridine 18 The sequence of administering diphenoxylate and 84 nitrofurantoin in six human subjects 19 Cumulative percent of Macrodantin and Furadantin 102 excreted by dogs with/without diphenoxylate pretreatment 20 Cumulative percent of Macrodantin and Furandantin® 110 excreted by man with/without diphenoxylate pretreatment vi Arthur D Little, Inc LIST OF FIGURES No. Page 1 Metabolism of chloral hydrate 9 2 Proposed metabolism of flurazepam 11 3 Model for rate of appearance of unchanged drug in urine 21 4 Typical cumulative excretion of drug in urine 22 5 Difference spectra of cytochrome b 5 31 6 Difference spectra of cytochrome P-450 32 7 Lineweaver-Burk plot of hexobarbital oxidase activity 37 in control and nitrofurantoin-treated rats 8 Lineweaver-Burk plot of N-demethylase activity in 40 control and nitrofurantoin-treated rats 9 Rate of production of p-aminobenzoic acid from 41 p-nitrobenzoic acid at several substrate concentrations 10 Lineweaver-Burk plot of nitroreductase activity in 43 control and nitrofurantoin-treated rats 11 Standard curve for methemoglobin determination 51 12 Concentration of methemoglobin following a single 58 dose of aniline (500 mg/kg) in control and pheno- barbital-treated rats 13 Concentration of methemoglobin following a single dose 59 of aniline (1 g/kg) in control and phenobarbital- treated rats 14 Level of MHb found in the blood of a dog following 69 a single dose (200 mg/kg) of aniline 15 Standard curve of nitrofurantoin in urine 81 16 Cumulative excretion of Macrodantin in the urine 86 of all the dogs. 17 Cumulative excretion of Furadantin ®in the urine of 87 all the dogs 18 Cumulative excretion of Macrodantin and Furadantin® 88 in the urine of Dog 100 vii Arthur D Little, lnc LIST OF FIGURES - CONTINUED No. Page 19 Cumulative excretion of Macrodantin and Furadantin 89 in the urine of Dog 101 20 Cumulative excretion of Macrodantin and Furadantin 90 in the urine of Dog 102 21 Cumulative excretion of Macrodantin and Furadantin 92 in the urine of Dog 103 22 Cumulative excretion of Macrodantin in the urine 93 of Dog 100 with/without diphenoxylate 23 Cumulative excretion of Macrodantin in the urine 94 of Dog 101 with/without diphenoxylate 24 Cumulative excretion of Macrodantin in the urine 95 of Dog 102 with/without diphenoxylate 25 Cumulative excretion of Macrodantin in the urine 96 of Dog 103 with/without diphenoxylate 26 Cumulative excretion of Furadantin in the urine 97 of Dog 100 with/without diphenoxylate 27 Cumulative excretion of Furadantin in the urine 98 of Dog 101 with/without diphenoxylate 28 Cumulative excretion of Furadantin ©in the urine 99 of Dog 102 with/without diphenoxylate 29 Cumulative excretion of Furadantin in the urine 100 of Dog 103 with/without diphenoxylate 30 Cumulative excretion of Macrodantin and Furadantin® 104 with/without diphenoxylate in the urine of subject No. 1 31 Cumulative excretion of Macrodantin and Furadantin® 105 with/without diphenoxylate in the urine of subject No. 2 32 Cumulative excretion of Macrodantin and Furadantin 106 with/without diphenoxylate in the urine of subject No. 3 33 Cumulative excretion of Macrodantin® and Furadantin 107 with/without diphenoxylate in the urine of subject No. 4 34 Cumulative excretion of Macrodantin® and Furadantin® 108 with/without diphenoxylate in the urine of subject No. 5 35 Cumulative excretion of Macrodantin and Furadantin® 109 with/without diphenoxylate in the urine of subject No. 6 viii Arthur D Little, Inc FOREWORD This program was undertaken to evaluate possible interactions among drugs contemplated for use during manned space flights. It was carried out during the period July 1, 1972 to September 30, 1973 and was the subject of our proposals dated March 10, 1972 and May 14, 1973, in response to RFP No. 9-13B32-79-2-185P and RFP No. 9-13B631-4-3177P. The program will continue until June 30, 1974. Dr. Vernon Carter of the NASA Manned Spacecraft Center is Technical Officer for this agency. Dr. David W. Yesair, Dr. Francis J. Bullock (former Arthur D. Little, Inc. staff member), Dr. Philip S. Thayer, Mrs. Marianne Callahan, and Mr. James Braun comprise the Arthur D. Little, Inc., project team. 1 Arthur D Little, Inc SUMMARY Possible interactions among drugs contemplated for use during manned spaceflights have been studied in several animal species. The following seven drugs were investigated: nitrofurantoin, chloral hydrate, hexobarbital, phenobarbital, flurazepam, diphenoxylate, and phenazopyridine. Particular combinations included: chloral hydrate, hexobarbital or flurazepam with nitrofurantoin; phenobarbital or flurazepam with phenazo- pyridine; and diphenoxylate with two dose formulations of nitrofurantoin. Specifically, rat liver microsomes were used to determine whether chronic dosage with nitrofurantoin would inhibit rates of oxidative drug metabolism. Rates of hexobarbital oxidation, N-demethylation of meperidine, and reduction of p-nitrobenzoic acid were studied in control and nitro- furantoin-treated rats. No difference in oxidative metabolic rates were found between control and nitrofurantoin-treated rats. Pharmacological studies were carried out to determine whether premedication of rats with nitrofurantoin would result in potentiation of activity of hexobarbital, chloral hydrate, or flurazepam. This was determined for chloral hydrate and hexobarbital by studies of sleeping times determined by loss of the righting reflex. Flurazepam