Pathways of Drug Metabolism in Man

lndiddualization of Drug Therapy Symposium on Individualization

Pathways of Drug Metabolism in Man Dennis E. Drayer, Ph.D.*

The metabolism of drugs usually takes place in two phases:

l

Oxidation ) Phase I {Reduction Phase 11 Conjugated D ) Dr u g ) enzymes lHydrOlYSis. Hydrolysis enzymes metabolites Metabolites In phase I, groups such as OH, C0 2 H, and NH2 NH 2 are introduced into the drug molecule. In phase 11, the phase I metabolite reacts with an endogenous substrate, such as amino acids or glucuronic acid, to yield what is referred to as a conjugated metabolite which is usually excreted from the body. Drugs are usually lipid-soluble compounds and are therefore able to penetrate cell membranes, which are lipoprotein barriers. In general, the more lipid-soluble the drug, the greater is the proportion reabsorbed in the kidney by diffusion into the tubule cells. The driving force is the concentration gradient produced during reabsorption of water and solutes. The majority of the drug biotransformation reactions are carried out in the liver by enzymes which are located mainly in the smooth endoplasmic reticulum of the hepatic cells. The result of metabolic transformation of drugs is metabolites that are more polar and less lipidsoluble (therefore, more easily excreted) than the parent drug. Phase I pathways of drug metabolism and the organic chemistry involved are summarized below. Subsequently, each pathway is described in detail.

OXIDATIONS Biological oxidations include a wide range of reactions, many of which may be ascribed to a common mechanism, hydroxylation. Pharmacology. Temple University School of Medicine, Philadelphia, ':'Fellow in Clinical Pharmacology, Pennsylvania Medical Clinics of North America- Vole Vol. 58, No. 5, September 1974

927

928

DENNIS

E.

DRAYER DRA YER

1. Aromatic hydroxylation to phenols.

OH

o~6

Aromatic ring

Phenol

2. Aliphatic hydroxylation to alcohols.

Examples of aliphatic groups are the following: CH 3 -

CH a3 CH 22 -

(methyl),

(ethyl), and VCYclOheXYI)o VCYclOheXYl). An alcohol (ROH) is a com-

pound containing a hydroxyl group (OH) attached to an alkyl or aromatic group (in which case the compound is called a phenol). A primary (1 0) (10) alcohol occurs when a hydroxyl group is attached to a carbon with at least 2 hydrogens. In this case further oxidation to a carboxylic acid is possible. RCH 2 0H (1 °0 alcohol)

~ ------>

RC0 2 H (Carboxylic acid)

3. O-Dealkylation (carbon hydroxylation) of ethers to alcohols and formaldehyde. ROCH 33 Ether

------> ~

(RO-CH 22 -OH) Not isolated

ROH Alcohol

------> ~

+

HCHO Formaldehyde

An ether (R-O-R') is a compound containing oxygen attached to one of the following: 2 alkyl groups, 2 aromatic groups, or an alkyl and aromatic group. An example of a drug containing an aromatic ether group is tetrabenazine.

Ether

------>

H:lCOno Ha CO

/~ I

N

11

o Tetrabenazine 4. N-Dealkylation (carbon hydroxylation) of secondary (2°) or tertiary (3°) amines to new amines with 1 less alkyl substituent and aldehydes.

RNHCH RNHCH:3~ (RNHCH~-OH)~ RNH~ + HCHO a------> (RNHCH 2-OH) ~ RNH2 2 ° Amine Not isolated 1 ° .A.mine Amine

929 929

PATHWAYS OF DRUG METABOLISM IN MAN

Amines are compounds of the general formulas: RNH NH RNH22 (1 ° amine), R R2NH 2 R3N (2° amine), R 3 N (3° amine), where R can be an alkyl or an aromatic group. 5. N -Oxidation of 33°° amines to amine oxides. N-Oxidation

R3N (3° Amine)

----?

R3N+-O- (Amine oxide)

6. N-Oxidation of 1° 1 ° and 2° amines to hydroxylamines.

RNH22 (1 ° Amine) RNH

----? ~

RNHOH (Hydroxylamine)

7. Oxidative deamination of 1 ° amines to aldehydes (which can be further oxidized to carboxylic acids) or ketones.

0

OH 1I

RCH 22 -NH 2 ----? (RCH-NH 2 2)) 2 ~ Not isolated

11

RCH ----? ~ RC0 22 H Aldehyde Carboxylic acid 8. S-Oxidation of sulfides to sulfoxides. ~ ----?

oo RSR' (Sulfide)

~ ----?

RSR' (Sulfoxide)

~ ----?

oo 11

11

RSR' (Sulfone) 11

0

REDUCTIONS Several types of bioreduction reactions can occur in the body. The most frequently encountered are the following: 1. Reduction of nitrobenzenes to amines.

Nitrobenzene

2. Reduction of ketones to alcohols. RCR' (Ketone)

----? ~

o o 1111

RCR' (Alcohol) 1I

OH

HYDROLYSES The most common types of hydrolysis reactions which occur in the body are those of esters and amides. 1. Rapid hydrolysis of esters to carboxylic acids and alcohols. RCOR' (Ester)

oo 1111

----? ~

RC0 22 H

+ R'OH

930

DENNIS

E.

DRAYER

2. Slow hydrolysis of amides to carboxylic acids and amines.

RCNHR' (Amide)

lo"

~

RC0 2 2H

+ R'NH 22

R or R' can be an alkyl or an aromatic substituent. An example of a drug containing many of the functional groups previously mentioned is the local anesthetic procaine.

o o

3 0 Amine 0

0 y

~

Ester ACH,CH,N(CH,CH'::: ~ COCH " 2 CH 2 N(CH 2 CH 3 )2 E"er 11

'\.

"'"

~)

Aromatic ~

I

NH 2 NH2

Ethyl group

~ 1 Amine Procaine 0 0

A detailed analysis of each phase I pathway as well as examples of drugs metabolized in man by each pathway is given below.

AROMATIC HYDROXYLATION Drugs containing an aromatic ring are hydroxylated via an epoxide intermediate to phenols (usually the predominant metabolite), diols, catechols, and mercapturic acids. An epoxide is a very reactive 3-membered cyclic ether. Focusing on one of the aromatic groups in 5,5diphenylhydantoin (Dilantin), the following metabolites have been observed: OH 28 Phenolic28 Phenolic 22 I (m-Isomer)

1_ /

O~ .6'

tH

Q~Q~QOH R

R

Epoxide (not isolated)

DioP5 Diol35

R

OH

6 Y

0H ~OH

R = Remainder of molecule

(p-Isomer)

I

R

CatechoF

931

PATHWAYS OF DRUG METABOLISM IN MAN

Mercapturic acids arise from epoxides as follows:

0

Glutathione

0 0

)

Epoxide -H 2 0

1

Acetylase

, a o

C0 2 H

I

SCH2CHNHCOCH3 ~SCH2CHNHCOCH3

-:7'1

Mercapturic acid This pathway is demonstrated in man by the isolation of

and its acetylated derivative as phenacetin metabolites.37 Epoxides have also been" been implicated as the metabolites responsible for polycyclic hydrocarbon carcinogenesis. Polycyclic

~ ------>

hydrocarbon

Epoxide

~ ------>

Reaction with nucleic acids, proteins, etc etc..

.,/' /

Altered cellular macromolecules

~~ ------>------>

Neoplasm

Evidence supporting this mechanism is as follows: epoxides have been detected as microsomal metabolites of carcinogenic polycyclic hydrocarbons;31 they react with DNA and RNA upon incubation;32 and they are more active in the production of malignant transformation in hamster embryo cells than the parent hydrocarbons.33 Benzo(a)pyrene, a carcinogenic polycyclic hydrocarbon, is a major ingredient of cigarette smoke.

Benzo(a)pyrene

932

DENNIS

E.

DRA YER DRAYER

Aromatic hydroxylation is also a major metabolic pathway for '4 phenobarbital phenobarbita1 48 and phenylbutazone. 14

HNLi:;CH_:~ ______~ HN~::;CH_" oo~N~Y H

~NJ,Y

Phenobarbital

Phenylbutazone

chlorpromazine/o Drugs such as acetaminofluorene,72 acetanilid,9 chlorpromazine,7° 21 (Tofranil), nitrobenzene,36 phenacetin,44 quinidine,60 and imipramine 21 warfarin 46 are likewise metabolized by this pathway in man.

ALIPHATIC HYDROXYLATION The alkyl side chain of many drugs is hydroxylated at either the terminal carbon (w-oxidation) to yield a primary alcohol or at other carbons in the chain to yield secondary or tertiary alcohols. If w-oxidation occurs, subsequent oxidation to the corresponding carboxylic acid is 24 possible, as evidenced in the metabolism of probenecid.24

w-Oxidation

933

PATHWAYS OF DRUG METABOLISM IN MAN

With compounds containing both alicyclic and aromatic rings, the saturated ring is more readily hydroxylated, as evidenced by the metabotetralin.2255 lism of tetralin. OH II 0H

CX) (X) ~ (X) CX)---7 CX) ++ (DOH , I Tetralin

Barbiturates 52 are usually metabolized by alkyl side chain hydroxylation.

The following drugs are also metabolized by this pathway in man: amobarbital,52 imipramine,21 imipramine,tl methamphetamine,16 methamphetamine/ 6 pentazocine,62 phenylbutazone,14 butazone/ 4 quinidine,60 spironolactone 42 (Aldactone), and tetrabenazine. 65

O-DEALKYLATION OF ETHERS O-Dealkylation involves the removal of a methyl or another alkyl group from an ether oxygen atom to yield an alcohol, as demonstrated by fi6 the formation of acetaminophen (Tylenol) from phenacetin. 66

o o

o o

11

11

66

NHCCH 3

I

~ #

Aromatic

Acetanilid

11

)

hydroxylation

o

NHCCH 3 I O-De-

6 O~

N~CCH~_De_ or / /'

I

ethylation

OH Acetaminophen

o

11

NHCCH;)3 NHCCH II

I

OCH 2CH CH;)3 Phenacetin

Hydrolysis (minor)

o(s---~ o NH 2 1

NHOH

I

--~)O

---~) ---~)

Methemoglobinemia

The analgesic action of acetanilid is exerted mainly through its hyacetaminophenY9 In this case biotransformation, droxylated metabolite, acetaminophen. rather than being an inactivation process as it is usually thought of, pro-

934

DENNIS

E.

DRAYER DRA YER

duces a metabolite that is pharmacologically active and therapeutically useful. Biotransformation can also produce toxic metabolites, as shown by the minor metabolic pathway for acetanilid 99 ,63 ,63 (see diagram above) and epoxide formation from polycyclic carcinogenic hydrocarbons (previously discussed). Interestingly, O-demethylation of codeine, a minor metabolic pathway for this drug, produces a significant amount of morphine in the body.4 CH 33

CH 33

N h

I

I

~ yoJY OH

CH 33 0

N

0-

)

demethylation (minor)

~ HO

OH

Morphine

Codeine

Other drugs are metabolized by O-dealkylation in man, such as 64 griseofulvin,t8 mescaline,t7 papaverine,3 tetrabenazine,65 and versidyne. 64 griseofulvin,18

N-DEALKYLATION N -DEALKYLATION Secondary or 3 ° amines undergo N -dealkylation to yield new amines with one less alkyl substituent and aldehydes as evidenced by the formation of amphetamine and amphetamine derivatives from metham16 (2° amine). phetamine 16 CH 3

I

CH 22CHNHCH 6HNHCH 33

9

Methamphetamine

1

OH

CH 33

1

OH

CH 33

6o --~'QQ I

I

CH-CHNH CH-CHNH22 I

I

I

CH-CHNH 22

----->,

Amphetamine

OH Norephedrine (NE) p-Hydroxy-NE

PATHWAYS OF DRUG METABOLISM IN MAN

935

Metabolism of methamphetamine in man involves, in addition to Ndemethylation, de methylation, aromatic hydroxylation (major metabolic pathway) and side chain hydroxylation (minor pathway which yields norephedrine and p-hydroxynorephedrine). At high doses the guinea pig excretes much more norephedrine than at low doses. This means that at the higher dose metabolic pathways become saturated and the drug is therefore channeled through metabolic routes that are minor at lower doses. Hence in large doses one is dealing with a different drug from that in low doses. If this were true in man, chronic intake of methamphetamine would cause an increased conversion of the drug into the false neurological transmitter, p-hydroxynorephedrine, which could be related to habituation. The 3° amines lidocaine 55 and propoxyphene 53 are N-dealkylated to the corresponding 2° amines. N-dealkylation is a major metabolic pathway for these drugs.

Lidocaine

Additional examples of drugs metabolized by N -dealkylation in man are the following: aminopyrine,lO aminopyrine,lo chlorcyclizine,45 chlorcyc1izine;5 chlorpromazine 70 (Thorazine), codeine,4 imipramine,21 methopholine,64 meperidine 12 (Demerol), probenecid,24 and thioridazine 74 (Mellaril).

N-OXIDATION OF TERTIARY AMINES N-Oxidation of 3° amines to amine-oxides is generally thought of as a minor route of drug elimination. Exceptions are the biotransforma39 and guanethidine,54 tion of dimethylampbetamine 39 guanethidine,"4 where N-oxides are major urinary metabolites. Since guanethidine N-oxide has much less antihypertensive activity than the parent drug, metabolism in this instance is an inactivation process.

936 936

DENNIS

O

0

N-Oxide

Dimethylamphetamine

iH

NCH 2CH 2NHCNH 2 ~

Guanethidine

1+

E. DRAYER DRAYER

iH

fCH2CH2NHCNH2

0N-Oxide N -Oxide

Other drugs, such as chlorcyclizine,45 chlorpromazine,70 diphen39 (Benadryl), imipramine,21 nicotine,39 and nicotinamide,67 are hydramine 39 metabolized in man by this pathway.

OXIDATIVE DEAMINATION Oxidative deamination of 1 0 amines yields the corresponding aldehydes (which can be further metabolized to carboxylic acids) or ketones and ammonia. Oxidative deamination, catalyzed by monoamine oxidase, is a major metabolic pathway for mescaline 17 and tyramine,69 yielding the corresponding carboxylic acids. 0

CH 22 C0 22 H

~

H3C0--Y0CH3 H 3 C0---Y0CH 3

o Q y

OCH OCHa3

Mescaline

CH 22 CH 22 NH 22

I

#

OH Tyramine

Q 0Y

Monoamin~) I

Monoamine oxidase

CH 22 C0 22 H #

OH

Tyramine is thought to be responsible for the severe hypertensive reactions sometimes seen in patients taking monoamine oxidase inhibitors who also ingest tyramine-containing foods such as cheese, yeast extracts, and red wine. Epinephrine,1 histamine,58 imipramine,21 imipramine,2! and methamphetamine 16 Epinephrine,l are also metabolized in man by this pathway.

937

PATHWAYS OF DRUG METABOLISM IN MAN

N -HYDROXYLATION

N-Hydroxylation of certain aromatic amines and amides is viewed as the first step in the metabolic activation of these compounds into potent carcinogens, as evidenced by the metabolism of 2-acetamidofluorene 72 (AAF). In the mechanism of 2-acetamidofluorene carcinogenesis, the ultimate carcinogen is viewed as the electrophilic (electron deficient) metabolite, resulting from the loss of sulfate from the Nhydroxysulfate ester intermediate, which then combines with cellular macromolecules. How these altered macromolecules lead to tumors is yet unknown.

0c0 OCO 1

~

~

N) .#-NHCCH;~ Hydroxylation "",-NHCCH"

~

Sulfate formation

"'"

"'"

11 11

AAF

0 0

-SO,,2

11

------->

NCCR, 1

o

~ ~ .# NCCH

~ I~

11 11

NCCH 3 11

OH

~ .# NCCH o

~ / ' / 11

"'"

NCCH 3

+

Carcinogenic electrophile

OS03-

Cells with AAF bound to nucleic acids, proteins, etc. ~

t~

Neoplasm

Evidence supporting this mechanism is as follows: first, AAF induces tumors only at sites distant to the point of entry, whereas Nhydroxy-AAF induces tumors at local sites, indicating that AAF requires metabolic activation;19 second, the inability of guinea pigs to N-hydroxylate AAF is considered the reason that AAF is not carcinogenic in this species;56 and finally, synthetic esters of N-hydroxy-AAF combine with cellular macromolecules in vitro, whereas N-hydroxy-AAF is unable to, indicating that further metabolic activation of N-hydroxy-AAF is necessary.19 necessary.!!' N -hydroxy amines or The ultimate carcinogen, not only for certain N-hydroxy amides but for most and perhaps all chemical carcinogens, is a strong electrophilic reactant frequently produced by in vivo biotransformation. 56 Aromatic amines have methemoglobin formation as an important toxic side effect. The N-hydroxy metabolite of these amines is viewed as 43 the methemoglobin forming agent in red cells. 43 Aniline

11N-hydroxylation

O~) Cl) O H-~-OH

HemoglObin)

o? 0.,

-

Methemoglobin

(

I

C

.:

Q)

~ ~

~CG_6_P

Q) NADP 0 ) / 0 0 Q) %b(G-6-P E '" 0~ rn ro ~ "'d '"0 0 ~ >-

0

aa

NO"& NO ~

NADPH

~

~

oCl

6-PGA

938

DENNIS

E.

DRA YER DRAYER

Owing to the cyclic nature of this mechanism, 1 molecule of hydroxylamine transforms many equivalents of hemoglobin into methemoglobin. Support for this mechanism is the detection of N-hydroxydapsone as an in vivo human metabolite 68 and the observation that the conversion of dapsone to N-hydroxydapsone, in the presence of normal human red cells and rat-liver microsomes, correlates with methemoglobin for22 mation. 22 Additional compounds that are N-hydroxylated in man are the following: acetanilid,6 benzidine,6 I-naphthylamine,6 2-naphthylamine,6 phenacetin,'; and urethane. urethane."8 phenacetin,6

S-OXIDATION The heterocyclic sulfur atom in many of the phenothiazine-type tranquilizers undergoes oxidation to the corresponding sulfoxide. Thioridazine (Mellaril), containing a chain sulfide group in addition to the heterocyclic sulfur atom, forms 2 sulfoxide metabolites. 74

R

I

(X ~ I I CX ~ sA/ I

~

/

1

N~SCH3 NyYSCH3 S

~

· ·daZIne . Th10rI Ion aZlne

R

0

R

1I

11

(JC ~ sA/ ~S~

(X ,~ I CX

N~SCH3 N O SCH 3

~ "

#

S

I

##

I 1

I NyYSCH3 ~N'(YSCH3 o o 11

Chain sulfoxide Heterocyclic sulfoxide R = Substituted piperidine The biotransformation of chlorpromazine (Thorazine) provides an interesting example of the metabolism of a drug that contains many functional groups. Metabolism involves S-oxidation, N -oxidation, Ndemethylation, aromatic hydroxylation, and combinations of these pathways.7o

939

PATHWAYS OF DRUG METABOLISM IN MAN

HO~ H0Y'l

o

V

1\11

S /~ /""

+

(S-Oxidation)

N(CH 33)2 )2 f(CH

NHCH3~ NH 2 NHCH3~NH2

0- (N-Oxidation)

(N -Demethylation)

I

Of the 168 theoretical metabolites possible involving just these pathways, 34 have been identified and 42 have been detected but not identified. Dimethyl sulfoxide,73 perphenazine,71 spironolactone,42 and G-2567l G-25671 113:l (uricosuric agent) are additional drugs metabolized by S-oxidation in man.

KETONE REDUCTION A variety of steroids and other drugs are metabolized by ketone reduction to the corresponding alcohols. It is reduction of the carbonyl group at the 1ll-position I-position in the steroids cortisone and prednisone that 38 activeYs renders them biologically active. CH 2 0H I1 O=C ... " . OH

CH 22 0H I1 O=C I OH 1

Activation

o o

o Cortisone

Hydrocortisone (cortisol)

Similarly, prednisone is activated by reduction to prednisolone. The other carbonyl groups and the double bond in these steroids are subject to 15 toO.15 bioreduction, toO.

940

DENNIS

E.

DRAYER DRAYER

34 and warfarin,46 are also readily reKetones, such as metyrapone 34 duced to alcoholic metabolites.

N

OH

CH 3

N

Q-6H-{-O CH 3

Metyrapone OH 1

Reduced metyrapone

0

0

1

11

~CHCH2CCH3 ~

~OAO Warfarin alcohol

Warfarin

5 ! are Aldosterone,27 chloral hydrate,50 tetrabenazine,65 and testosterone 51 likewise metabolized by this pathway in man.

NITRO-REDUCTION Aromatic nitrocompounds, such as nitrobenzene 36 and nitrazepam,57 are reduced in the body to the corresponding amines.

Q NH 2

Nitrobenzene

OH p-Aminophenol p- Aminophenol

Nitrazepam

Dantrolene,20 niclosamide,57 and p-nitrobenzoic acid40 are also metabolized by this pathway in man.

HYDROLYSIS ll procaine!! Esters such as procaine are rapidly hydrolyzed, whereas amides 49 are slowly hydrolyzed to the corresponding such as procainamide 49 carboxylic acid.

941

PATHWAYS OF DRUG METABOLISM IN MAN

o

o 11

?OCH 2CH 2N (C 2H,J2

1

Proc~~~ \

INH~rocainamide

Fast

Slow

o

COOH

I1

I1

NH 2 NH2

Chloramphenicol is not suitable for oral administration because of its bitter taste. The drug is therefore administered as a tasteless ester which 29 On the other hand, is rapidly activated by hydrolysis to the free drug. 29 succinylcholine is normally inactivated by rapid hydrolysis by serum cholinesterase. 41

o o 1I11

0 +

CH CH2COCH2CH2N(CH3);~ 2 COCH 2CH 2 N(CHJa

I

+

1

~

CH 2COCH 2CH 2N (CHa),l (CH3);~

o 11

Succinylcholine S ucciny lcholine

11

CH 22 COH

I 1

+

CH 2COCH 2CH 2N (CH 3)3

+ Choline

11

0

Therefore, depending upon the drug, hydrolysis, as well as other metabolic pathways, can be an activation or inactivation process. The presence of an "atypical esterase" in a small percentage of the population causes a prolonged action of succinylcholine in these people. This is due to a decrease in succinylcholine hydrolysis rate caused by a decrease in the affinity of the "atypical" enzyme for this muscle relaxant. Other drugs which are metabolized in the human body by hydrolysis 26 (which yields morare esters: aspirin 23 (acetylsalicylic acid), heroin 26 phine as a major metabolite), meperidine,12 prednisolone-21-phosphate,55 and reserpine;47 and amides: acetanilid,f) acetanilid,rJ acetyldapsone,3o acetyldapsone,ao isoniazid,61 59 (antimicrobial agent). lidocaine,5 lidocaine,s and NF-124 59 The biotransformation of phase I metabolites is discussed on pages 945 to 949.

REFERENCES Alton. H., and McGoodall, C.: Metabolic products of adrenaline (epinephrine) during long1. Alton,

term constant rate intravenous infusion in the human. Biochem. Pharmacol., 17: 2163-2169, 1968.

942

DENNIS

E.

DRA YER DRAYER

2. Atkinson, A. J., MacGee, J., Strong, J., et al.: Identification of 5-meta-hydroxyphenyl-5phenylhydantoin as a metabolite of diphenylhydantoin. Biochem. Pharmacol., 19: 2483-2491, 1970. K, and Sjoerdsma, A.: Fate of papaverine in man and 3. Axelrod, J., Shofer, R., Inscoe, J. K., 124:9-15, 1958. other mammals. J. Pharmacol. Exper. Ther., 124:9-15,1958. 4. Baker, E. M.: The metabolic fate of codeine in man. J. Pharmacol. Exper. Ther., 114: 251-261, 1955. 5. Beckett, A. H., Boyes, R. N., and Appleton, P. J.: The metabolism and excretion of lignocaine in man. J. Pharm. Pharmacol., 18:Suppl., 76S-81S, 1966. 6. Belman, S., Troll, W., Teebor, G., and Mukai, F.: Carcinogenic and mutagenic properties of N-hydroxy-aminonaphthalenes. Cancer Res., 28 :535-542, 1968. 7. Borga, 0., Garle, M., and Gutova, M.: Identification of 5-(3,4-dihydroxyphenyl)-5-phenylhydantoin as a metabolite of 5,5-diphenylhydantoin (phenytoin) in rats and man. Pharmacology, 7:129-137, 1972. K S., and Williams, K.: K: Metabolism and possible mode of 8. Boyland, E., Nery, R., Peggie, K. action of urethane. Biochem. J., 89:113P-114P (No. 3), 1963. ofurethane. 9. Brodie, B. B., and Axelrod, J.: Fate of acetanilide in man. J. Pharmacol. Exper. Ther., 94:29-38,1948. 10. Brodie, B. B., and Axelrod, J.: Fate of aminopyrene in man and methods for the estimation of aminopyrene and its metabolites in biological material. J. Pharmacol. Exper. Ther., 99:171-184, 99:171-184,1950. 1950. 11. Brodie, B. B., Lief, P. A., and Poet, R.: Fate of procaine in man following its intravenous administration and methods for the estimation of procaine and diethylaminoethanol. 94:359-366,1948. J. Pharmacol. Exper. Ther., 94:359-366, 1948. 12. Burns, J. J., Berger, B. L., Lief, P. A., et al.: Physiological disposition and fate of meperidine in man and a method for its estimation in plasma. J. Pharmacol. Exper. 114:289-298,1955. Ther., 114 :289-298, 1955. 13. Burns, J. J., Ritterband, A., Perel, J. M., and Brodie, B. B.: A potent new uricosuric agent, the sulfoxide metabolite of the phenylbutazone analogue G-25671. J. Pharmacol. Exper. Ther., 119:418-426,1957. 119 :418-426, 1957. 14. Burns, J. J., Rose, R. K., Goodwin, S., et al.: The metabolic fate of phenylbutazone in man. J. Pharmacol. Exper. Ther., 113 :481-489, 1955. 15. Burstein, S., Savard, K., K, and Dorfman, R. 1.: In vivo metabolism of cortisone. Endocrinology, 52 :448-452, 1953. (I4C) methamphetamine in 16. Caldwell, J., Dring, L. G., and Williams, R. T.: Metabolism of (l4C) 129:11-22, 1972. man, guinea pig and rat. Biochem. J., 129:11-22,1972. 17. Charalampous, K. K D.: Comparison of metabolism of mescaline and 3,4-dimethoxyphenethylamine in humans. Behav. Neuropsychiat., 2 :26-29, 1971. 18. Chiou, W. L., and Riegelman, S.: Absorption characteristics of solid, dispersed and 60:1376-1380,1971. micronized griseofulvin in man. J. Pharm. Sci., 60:1376-1380, 1971. K M., and Dean, H. G.: Aromatic amine carcinogenesis: The im19. Clayson, D. B., Dawson, K. portance of N-hydroxylation. Xenobiotica, 1 :539-542, 1971. 20. Cox, P. L., Heotis, J. P., Polin, D., and Rose, G. M.: Quantitative determination of dantrolene sodium and its metabolites by differential pulse polarography. J. Pharm. Sci., 58:987-989,1969. Sci.,58:987-989, 196~ H. Urinary 21. Crammer, J. L., Scott, B., and Rolfe, B.: Metabolism of 14C-imipramine. 11. metabolites in man. Psychopharmacologia, 15 :207-225, 1969. Day ton, P. G.: Microsomal N-oxidation of dapsone as a 22. Cucinell, S. A., Israili, Z. H., and Dayton, cause of methemoglobin formation in human red cells. Amer. J. Trop. Med. Hyg., 21 :322-331, 1972. N.Y. 23. Davison, C.: Salicylate metabolism in man. Ann. N .Y. Acad. Sci., 179:249-268, 179 :249-268, 1971. 24. Dayton, Day ton, P. G., and Perel, J. M.': M.: Metabolism of probenecid in man. Ann. N.Y. Acad. Sci., 179:399-402,1971. 179 :399-402, 1971. 25. Drayer, D. E., and Reidenberg, M. M.: Metabolism of tetralin and toxicity of cuprex in man. Drug Metab. Disposit., 1 :577-579, 1973. 26. Elliott, H. W., Parker, K. K D., Crim, M., et al.: Actions and metabolism of heroin administered by continuous intravenous infusion to man. Clin. Pharmacol. Ther., 12 12:806-814, :806-814, 1971. 27. Flood, C., Pincus, G., Tart, J. F., and Willoughby, S.: A comparison of the metabolism of radioactive 17-isoaldosterone and aldosterone administered intravenously and orally to normal human subjects. J. Clin. Invest., 46:717-727,1967. 46:717-727, 1967. 28. Glazko, A. J., Chang, T., Baukema, J., and Buchanan, R. A.: Metabolic disposition of diphenylhydantoin in normal human subjects following intravenous administration. Clin. Pharmacol. Ther., 10:498-504, 1969. 29. Glazko, A. J., Edgerton, W. H., Dill, W. A., and Lenz, W. R.: Chloromycetin palmitate-a synthetic ester of chloromycetin. Antibiot. Chemother., 2 :234-242, 1952. 30. Gordon, G. R., Peters, J. H., Gelber, R., and Levy, L.: Metabolic disposition of dapsone (4,4'-diaminodiphenyl sulfone) in animals and man. Proc. Western Pharmacol. Soc., 13:17-24,1970. 13: 17-24, 1970.

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