Metabolites of caspofungin acetate, a potent antifungal agent, in human plasma and urine.

Caspofungin acetate (MK-0991) is a semisynthetic pneumocandin derivative being developed as a parenteral antifungal agent with broad-spectrum activity against systemic infections such as those caused by Candida and Aspergillus species. Following a 1-h i.v. infusion of 70 mg of [(3)H]MK-0991 to healthy subjects, excretion of drug-related material was very slow, such that 41 and 35% of the dosed radioactivity was recovered in urine and feces, respectively, over 27 days. Plasma and urine samples collected around 24 h postdose contained predominantly unchanged MK-0991, together with trace amounts of a peptide hydrolysis product, M0, a linear peptide. However, at later sampling times, M0 proved to be the major circulating component, whereas corresponding urine specimens contained mainly the hydrolytic metabolites M1 and M2, together with M0 and unchanged MK-0991, whose cumulative urinary excretion over the first 16 days postdose represented 13, 71, 1, and 9%, respectively, of the urinary radioactivity. The major metabolite, M2, was highly polar and extremely unstable under acidic conditions when it was converted to a less polar product identified as N-acetyl-4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine gamma-lactone. Derivatization of M2 in aqueous media led to its identification as the corresponding gamma-hydroxy acid, N-acetyl-4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine. Metabolite M1, which was extremely polar, eluting from HPLC column just after the void volume, was identified by chemical derivatization as des-acetyl-M2. Thus, the major urinary and plasma metabolites of MK-0991 resulted from peptide hydrolysis and/or N-acetylation.

Route-dependent nonlinear pharmacokinetics of a novel HIV protease inhibitor: involvement of enzyme inactivation.

L-754,394, a furanopyridine derivative, is an experimental HIV protease inhibitor. Previous studies from this laboratory have demonstrated that L-754,394 is cleared very rapidly in animals, and that this drug is a potent mechanism-based inactivator (suicide inhibitor) for CYP3A4 in human liver microsomes. Because L-754,394 is a high-clearance drug and an enzyme inactivator, it is expected that this drug will be subject to significant first-pass metabolism, and that the degree of enzyme inactivation will be dependent not only on the dose, but also on the route of administration. The purpose of this study is to examine the effects of dose and route of administration on the kinetics of L-754,394 using rats and dogs as animal models. In both rats and dogs, L-754,394 exhibited marked dose-dependent pharmacokinetics after i.v. and oral administration. Irrespective of i.v. or oral administration, the area under the plasma concentration-time curve from zero to infinity increased with dose in a greater than proportional manner. However, the magnitude of area under the plasma concentration-time curve from zero to infinity increase was much greater after oral dosing than after i.v. administration, indicating route-dependent pharmacokinetics. Data from in vitro and in vivo studies suggested that the dose- and route-dependent pharmacokinetics were due mainly to the inactivation (destruction) of the enzymes responsible for its own metabolism.

Effect of dexamethasone on the intestinal first-pass metabolism of indinavir in rats: evidence of cytochrome P-450 3A [correction of P-450 A] and p-glycoprotein induction .

Indinavir, a potent and specific inhibitor of HIV protease, is a known substrate of cytochrome P-450 (CYP) 3A and p-glycoprotein. The purpose of this study is to investigate and compare the inducing effect of dexamethasone (DEX) on CYP3A and p-glycoprotein in the hepatic and intestinal first-pass metabolism of indinavir in rats. Pretreatment of rats with DEX had little effect on the pharmacokinetics (Cl and T(1/2)) after i.v. administration of indinavir, whereas DEX markedly altered the peak concentration (C(max)) and bioavailability of indinavir after oral dosing. The C(max) decreased from 2.8 microM in control rats to 0.28 microM in DEX-treated rats, and bioavailability decreased from 28 to 12.4%. The decreased bioavailability after DEX pretreatment was due mainly to an increase in first-pass metabolism. Intestinal first-pass metabolism (E(G)) increased from 6% in control rats to 34% in DEX-treated rats, and hepatic first-pass metabolism (E(H)) increased from 65 to 82%. Analysis of in vitro kinetic data revealed that the increased intestinal and hepatic metabolism by DEX was attributed to an increase in the V(max), as a result of CYP3A induction, without a significant change in the K(m) values. DEX pretreatment also induced p-glycoprotein in the intestine and liver of rats. p-Glycoprotein appeared to increase the intestinal metabolism of indinavir whereas it had little effect on the hepatic metabolism of indinavir. Although it has been suggested that the role of intestinal metabolism for some drugs is quantitatively greater than that of hepatic metabolism in the overall first-pass metabolism, the contribution of intestinal metabolism to the overall first-pass metabolism of indinavir in rats is not quantitatively as important as the hepatic metabolism, regardless of DEX induction.

Nonlinear pharmacokinetics of efavirenz (DMP-266), a potent HIV-1 reverse transcriptase inhibitor, in rats and monkeys.

Efavirenz (EFV, Sustiva, Stocrin, DMP-266, L-743,726) is a potent and selective non-nucleoside inhibitor of HIV-1 reverse transcriptase. Pharmacokinetics of EFV was studied in rats and monkeys, the safety assessment species. In rats, after 2 and 5 mg/kg i.v. administrations, the mean CLp, Vdss, and T1/2 were 67 ml/min/kg, 5.0 liters/kg, and 1 h, respectively. EFV was metabolized completely, and the products were excreted almost exclusively via bile. At the higher dose of 15 mg/kg, the CLp was reduced by 36%, implying saturation of metabolism processes. A similar phenomenon occurred in monkeys, where the CLp declined by 60% as the i.v. dose was increased from 5 to 15 mg/kg. After oral dosing, the bioavailability of EFV in rats (10 mg/kg) and monkeys (2 mg/kg) was 16% and 42%, respectively. Higher doses in both species led to disproportionate increases in the AUC and higher Tmax values, suggesting saturation of metabolism and/or prolongation of absorption. The delay in Tmax was more pronounced in monkeys where the plasma concentrations reached plateaus and were sustained for 4 to 20 h. In rats, the prolongation of absorption was due to delayed gastric emptying as demonstrated by >10-fold slower transit of [14C]polyethylene glycol through the stomach of EFV-pretreated animals. The delayed gastric emptying in monkeys also was observed when the animals dosed at 160 mg/kg exhibited emesis, 8 h postdose, which was found to contain a substantial portion of the dose. These results demonstrated that in rats and monkeys, both delayed gastric emptying and saturation of metabolic processes played significant roles in the nonlinear pharmacokinetics of EFV.

On the absorption of alendronate in rats.

Alendronate is an antiosteolytic agent under investigation for the treatment of a number of bone disorders. Since the compound is a zwitterion with five pKa values and is completely ionized in the intestine at the physiological pH, absorption is poor; less than 1% of an oral dose is available systemically in rats. In the present studies, absorption was found to be predominantly in the upper part of the small intestine. Administration of buffered solutions of alendronate (pH 2-11) did not improve absorption. Whereas food markedly impaired the absorption of alendronate, EDTA enhanced absorption in a dose-dependent manner. Pretreatment of rats with ulcerogenic agents, mepirizole, acetylsalicylic acid, or indomethacin, resulted in a 3-7-fold increase in the oral absorption of alendronate. The absorption of phenol red, added as an indicator of intestinal tissue damage, was also increased in rats with experimental peptic ulcers. The enhanced absorption of alendronate observed in rats with experimental peptic ulcers was attributed to the alteration of the integrity of the intestinal membrane.

Nonlinear kinetics of alendronate. Plasma protein binding and bone uptake.

Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate), an antiosteolytic agent, is currently under investigation in the treatment of osteoporosis. The purpose of this study was to examine the plasma protein binding and the ability of bone to bind alendronate, and their effects on the distribution of the drug to bone tissues. In addition, the species differences in plasma protein binding and bone uptake between rats and dogs were studied. Following intravenous administration (0.8 or 1 mg/kg), the apparent uptake clearance (CL,up) by tibia in dogs and rats was approximately 0.075 and 0.18 ml/min/g bone tissue, respectively. The binding of alendronate to plasma protein was species-dependent; the drug was highly bound to rat plasma, but not to dog plasma. The unbound fraction of alendronate was approximately 0.03 for the rat and 0.53 for the dog. Binding studies with purified serum albumin revealed the presence of displacer(s) in dog plasma. This may explain the low binding of alendronate in dog plasma. Like other organs, uptake of drugs by bone tissue is controlled by the plasma flow (Q), the fraction of unbound drug in plasma (fp), and the intrinsic ability of bone to bind the drug (CLin) as described by the equation: CL,up = Q(1-e-tp.CLin/Q). Plasma flow to the tibia of dogs and rats is reported to be approximately 0.09 and 0.25 ml/min/g, respectively. By applying the equation, the CLin was estimated to be approximately 10 ml/min/g for the rat and 0.3 ml/min/g for the dog. These results indicate that both plasma protein binding and bone uptake were species-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of calcium in plasma protein binding and renal handling of alendronate in hypo- and hypercalcemic rats.

Alendronate (4-amino-1-hydroxybutylidine-1,1-bisphosphonate), an antiosteolytic agent, is currently under investigation for the treatment of osteoporosis. Earlier studies in animals from this laboratory disclosed that systemically administered alendronate is rapidly taken up by bone tissues to the extent of 60% to 70% of the dose and excreted by the kidney, 30% to 40% in 24 hr, and that renal excretion is the only route of elimination. This study was designed to explore the effect of calcium on plasma protein binding and the renal handling of alendronate. The binding of alendronate to rat plasma was concentration, pH and calcium dependent. The fraction of unbound drug in rat plasma increased from about 3% to 9% over a drug concentration range of 0.2 to 10 micrograms/ml. Supplementation of calcium strongly augmented the binding to serum albumin. The binding of alendronate in plasma increased with increasing pH from about 50% at pH 6.6 to 98% at pH 8.6. The effects of pH on the binding of calcium and of alendronate to serum albumin were qualitatively similar. Under steady-state conditions, the binding of alendronate was substantially lower in hypocalcemic rats but unchanged in hypercalcemic rats. Although hypocalcemia caused a significant decrease in the renal secretion of alendronate, there was no effect on the renal secretion of tetraethylammonium bromide and p-aminohippuric acid. The differential effect of hypocalcemia suggests that calcium may play an important role in the renal handling of alendronate. However, hypercalcemia resulted in a substantial decrease of renal secretion of all three compounds and the decreased renal secretion was associated with a marked decrease in the glomerular filtration rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Uptake of alendronate by bone tissue in hypocalcemic and hypercalcemic rats.

Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate), an antiosteolytic agent, is currently under investigation in the treatment of osteoporosis. Earlier studies in rats from this laboratory have demonstrated that systemically administered alendronate was taken up by bone tissues to the extent of 60-70% of the dose and excreted by the kidneys, 30-40%, and that renal excretion was the only route of elimination of the drug. In this study, a classic three-compartment model was used to determine the kinetics of bone uptake of alendronate in hypo- and hypercalcemic rats. Following intravenous administration (1 mg/kg), the apparent uptake clearance (CL,up) by tibia was approximately 0.18 ml/min/g of bone for control rats, 0.25 ml/min/g for hypocalcemic rats, and 0.05 ml/min/g for hypercalcemic rats. Like other organs, uptake of drugs by bone tissues would be controlled by the plasma flow rate (Q), the fraction of unbound drugs in plasma (fp), and the intrinsic ability of bone uptake (CLin) as described by the equation: CL,up = Q(1 - e-fp.CLin/Q). The plasma flow rate to the tibia of rats was reported to be approximately 0.25 ml/min/g. The unbound fraction of alendronate in plasma of control, hypo-, and hypercalcemic rats was 0.03, 0.45, and 0.035, respectively. By applying the equation, the intrinsic ability (CLin) of bone uptake was estimated to be approximately 10, 2.3, and 1.6 ml/min/g for control, hypo-, and hypercalcemic rats, respectively, indicating that the intrinsic ability of bone to bind alendronate was decreased in both hypo- and hypercalcemic rats.

Renal handling of alendronate in rats. An uncharacterized renal transport system.

Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate), an antiosteolytic agent, is currently under investigation in the treatment of a variety of bone diseases. Earlier studies from this laboratory have demonstrated that systemically administered alendronate is rapidly either taken up by bone tissues or excreted by the kidney, and that renal excretion is the only route of elimination. The purpose of this study is to characterize the renal handling of alendronate in rats by standard clearance procedures with inulin as a marker of glomerular filtration rate. Alendronate is highly bound to rat serum protein. The excretion of alendronate by the kidney is concentration-and dose-dependent, and saturable, indicating that it is secreted by an active transport mechanism. The secretory mechanism exhibits limitation of transport, with an apparent Tm of approximately 25 micrograms/min/kg. However, high doses of cimetidine, quinine, probenecid, and p-aminohippuric acid had no effect on the renal excretion of alendronate, suggesting that alendronate is not secreted by anionic or cationic transport systems. In contrast, alendronate clearance is inhibited by etidronate, another bisphosphonate, in a dose-dependent manner, implying that these two bisphosphonates compete for an as yet uncharacterized renal transport system. As expected, the renal excretion of alendronate is drastically reduced in rats with acute renal failure. As a consequence of renal impairment, alendronate accumulates in plasma, and the concentration of the drug in bone tissues increases significantly.

Physiological disposition of aerosolized MK-679 in rats.

[14C]MK-679, a potent antagonist of leukotriene D4, was suspended in freon under pressure and sprayed into rat lungs through a tracheal cannula. The particle size of the drug was 1 to 5 microns, and the mean dose was 98.8 +/- 4.46 micrograms/rat. Time course studies indicate that MK-679 was slowly but efficiently absorbed from the lung, with only 6% of the dose remaining in the lung at 6 hr. Biliary excretion, the major route of elimination of aerosolized MK-679, accounted for 48% of the dose in 6 hr. Concentrations of the parent drug plateaued in plasma at 1 to 4 hr, and drug was not detectable in plasma at 6 hr. The parent drug accounted for 94% of the radioactivity in the lung, indicating no significant metabolism by lung tissue. The concentration of MK-679 after aerosol administration was higher in the lung and lower in plasma than after iv administration of the drug at 28 times the aerosol dose. The results of this study suggest that inhalation of MK-679 should be a considered route of administration for the treatment of asthma.

Dose-dependent pharmacokinetics of MK-417, a potent carbonic anhydrase inhibitor, in experimental polycythemic and anemic rats.

MK-417 is a potent carbonic anhydrase inhibitor currently under clinical investigation as a topical ocular hypotensive agent. While present in most of the tissues, carbonic anhydrase predominates in red blood cells. Earlier studies from our laboratory have demonstrated that carbonic anhydrase plays an important role in the elimination kinetics of MK-417 and that the enzyme can be saturated when MK-417 exceeds the stoichiometric concentration of the enzyme. Since carbonic anhydrase is an intracellular enzyme in erythrocytes, conditions which may change the hematocrit can alter the load of MK-417 needed to saturate carbonic anhydrase. It is, therefore, important to determine the effects of anemic and polycythemic states on the pharmacokinetics of MK-417. The anemic state in rats was obtained by replacing whole blood with donor plasma (12-15 ml), while polycythemia was induced by infusion of 12 to 15 ml of whole blood. At low doses (0.05 and 0.1 mg/kg), the pharmacokinetic parameters for MK-417 remained unchanged and there were no significant differences in the pharmacokinetic parameters among the anemic, polycythemic, and normal rats. The total blood clearance and apparent volume of distribution were increased markedly when the dose exceeded 0.2 mg/kg in anemic rats and 0.5 and 1 mg/kg in normal and polycythemic rats, respectively. Clearly, the dose of MK-417 required to saturate the enzyme was different among the three groups of animals. However, the terminal half-life was dose independent and not influenced by hematocrit.(ABSTRACT TRUNCATED AT 250 WORDS)

Interspecies differences in stereoselective protein binding and clearance of MK-571.

(+)-3-(((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)((3-(dimethylamino)- 3-oxopropyl)thio)methyl)thio)propanoic acid (MK-571), is a potent and specific antagonist of leukotriene D4 action in vitro and in vivo. The compound, which is being developed for the treatment of asthma, contains a chiral center at the methine carbon of the dithio side chain and exists in two forms. The binding of MK-571 enantiomers to plasma protein was extensive (greater than 99.5%), stereoselective, and species dependent. The R-(-)-enantiomer was bound to rat plasma to a greater extent than the S-(+)-enantiomer, while in dog and monkey plasma the reverse was the case. The elimination clearance of the enantiomers was inversely related to the stereoselective plasma protein binding, that with the greater unbound fraction being cleared more rapidly. Thus, the pharmacologically more active S-(+)-enantiomer was cleared 3.7 times more rapidly than its antipode in rats following iv administration of the racemate (10 mg/kg), whereas in dogs and monkeys the R-(-)-enantiomer was cleared more rapidly. Kinetic analysis of the data revealed that the intrinsic clearances of the unbound enantiomers were similar within species, suggesting that stereoselectivity in elimination is not attributable to differences in metabolism and biliary excretion. Bioavailabilities of the S-(+)- and R-(-)-enantiomers in the rat were similar (75% and 71%, respectively) suggesting that MK-571 was not stereoselectively absorbed in that species.

Species-dependent enantioselective plasma protein binding of MK-571, a potent leukotriene D4 antagonist.

The plasma protein binding of the enantiomers of MK-571 was stereoselective and the stereoselectivity was species dependent. The 12 mammalian species studied could be classified into three groups: those that bind the S-(+)-enantiomer to a greater extent than the R-(-)-enantiomer (human, baboon, monkey, cow, dog, and cat); those that bind the R-(-)-enantiomer more extensively (rat, guinea pig, and sheep); and those that show no stereoselectivity (rabbit, hamster, and mouse). The stereoselective binding appears to have no phylogenetic relationship. Using serum albumin instead of plasma, a similar degree of stereoselective binding was observed for human, dog, sheep, and rat, suggesting that albumin is the major binding component for MK-571 enantiomers, and that species differences in stereoselective binding are likely due to structural differences in the albumin molecule. Displacement studies with [14C] diazepam, [14C]warfarin, and [3H]digitoxin indicated that the enantioselective differences in protein binding are most likely due to the differences in binding affinity rather than to different binding sites.

Effect of experimental diabetes on elimination kinetics of diflunisal in rats.

The effects of insulin-deficient diabetes on the elimination of diflunisal were investigated in streptozotocin-treated rats. Diflunisal, a fluorinated salicylate with nonsteroidal antiinflammatory properties, is eliminated primarily as the ester and ether glucuronides. After an iv injection of a 10 mg/kg dose, diabetic rats cleared diflunisal more rapidly than control rats; time-averaged total body clearances were 1.96 +/- 0.29 and 1.10 +/- 0.12 ml/min/kg, respectively. For a low clearance drug such as diflunisal, changes in the total body clearance can result from changes in the extent of plasma protein binding and/or drug metabolic rate. To determine whether the pronounced changes in elimination clearance in diabetic rats were due to the changes in plasma protein binding or enzyme activity, diflunisal was infused to obtain steady state kinetics. At steady state, the unbound intrinsic clearance increased from 43.4 +/- 16.4 ml/min/kg in the control rats to 82.5 +/- 21.1 ml/min/kg in diabetic rats at a high infusion rate (72 micrograms/min). When the infusion rate was lowered to 4.5 micrograms/min, the respective values for the unbound intrinsic clearance were 353 +/- 101 ml/min/kg and 561 +/- 112 ml/min/kg. Diabetic rats, however, showed no changes in plasma protein binding of diflunisal. The data suggest that the elimination of diflunisal was increased as a result of increased enzyme activity. Insulin treatment appeared to reverse the diabetic effect, suggesting that the effect on drug metabolism was the result of insulin deficiency and not a secondary or nonspecific effect of streptozotocin.(ABSTRACT TRUNCATED AT 250 WORDS)

The physiological disposition of aerosolized 4-[(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)sulfonyl]-gamma -oxobenzenebutanoate (L-648,051) in rats.

14C-labeled 4-[(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)-sulfonyl]-gamma- oxobenzenebutanoate (L-648,051) was suspended in Freon under pressure and injected into rat lungs via a tracheal cannula. The particle size of the drug was 1 to 5 microns and the mean dose was approximately 0.2 mg/kg. Levels of radioactivity in the lung/trachea declined in a monoexponential manner. Absorption, estimated from radioactivity remaining in the lung and trachea, was 73% in 1 hr and 95% in 4 hr. L-648,051 and its pharmacologically active metabolite L-657,098 (formed by ketoreduction of the butanoic acid moiety of L-648,051) accounted for 96% of the radioactivity in the lung at 10 min after the dose and 91% after 60 min. The lung:plasma concentration ratio of active drug (L-648,051 plus L-657,098) was at least 176:1 at 10 min and 17:1 at 60 min (compared with 1:1 after 2 mg/kg iv) suggesting that aerosol administration of L-648,051 in humans may result in an ideal therapeutic ratio, with high levels of pharmacologically active ingredient in the lung and low levels in the plasma.

Disposition and metabolism of sodium 4-[(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)sulfonyl]-gamma -oxobenzenebutanoate in rats and dogs.

The disposition of sodium 4-[(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)sulfonyl]-gamma-o xo benzenebutanoate (L-648,051) was determined in rats and dogs. L-648,051 is a potent receptor antagonist for leukotriene D4 and is potentially useful in the treatment of asthma and other allergic disorders. After a dosage of 10 mg/kg iv, L-648,051 declined rapidly with a half-life of approximately 2 min in rat and dog plasma. Although the compound was well absorbed, it exhibited poor bioavailability due to efficient first-pass metabolism. In rats receiving 25, 50, and 150 mg/kg po, bioavailabilities were 0.5, 4.8, and 38.7%, respectively. In dogs, bioavailability of 10 and 50 mg/kg po was 0 and 23%, respectively. Two metabolites were identified, 4-[(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)sulfonyl-gamma- hydroxybenzenebutanoic acid (metabolite I), formed by ketoreduction, and 4-[(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)sulfonyl] benzeneacetic acid (metabolite II) formed by catabolic oxidation of the butanoic acid moiety of L-648,051. Ketoreduction resulted in the production of a chiral center and two enantiomers of metabolite I. In vitro studies suggest that rat erythrocytes formed the (+)-enantiomer exclusively. When L-648,051 was administered orally or iv to rats, both the (+)- and (-)-enantiomers were observed in the plasma. The data suggest that either two L-648,051 ketoreductases were present or that inversion of the hydroxyl stereocenter of metabolite I occurred.

The physiological disposition and metabolism of enalapril maleate in laboratory animals.

N-[1-(S)-carboxy-3-phenylpropyl]-L-alanyl-L-proline (MK-422), is a potent angiotensin I-converting enzyme (ACE) inhibitor, but as a diacid is poorly absorbed in laboratory animals. Enalapril maleate, the monoethyl ester of MK-422, proved to be significantly better absorbed in both rats and dogs. Peak levels of radioactivity in plasma occurred in 30 min in rats and 2 hr in dogs after a single dose of 14C-enalapril maleate (1 mg/kg, po). Rats excreted 26% of the dose in the urine and 72% in the feces in 72 hr; dogs excreted 40% of the dose in the urine and 36% in the feces. After the intravenous dose, the presence of radioactivity in the feces of both species suggested that some biliary excretion had occurred. Absorption was estimated to be 34% in the rat and 61% in the dog. The major metabolite of enalapril maleate in dogs, accounting for 86% of the urine radioactivity, was identified as MK-422 by GC/MS. A procedure was developed for the quantitation of MK-422 and enalapril in plasma and urine by their inhibition of purified ACE. The assays showed that enalapril was absorbed intact in dogs and converted to MK-422 after absorption.

Timolol metabolism in man and laboratory anamals.

The two major urinary metabolites of 14C-timolol in man, involving oxidation and hydrolytic cleavage of the morpholine ring, are also observed in both Sprague-Dawley rats and CRCD-1 mice. These are the N-T(4-[3-(1,1-dimethylethyl)amino]-2-hydroxypropoxy)-1,2,5-thiadiazol-3-ylT-N-(2-hydroxyethyl)glycine and 1-(1,1-dimethylethylamino-3-([4-(2-hydroxyethylamino)-1,2,5-thiadiazol-3-yl]oxy)-2-propanol. The former was previously identified erroneously as the isomeric compound 1-(1,1-dimethylethylamino)-3-([4-(N-2-hydroxyethylglycolamido)-1,2,5-thiadiazol-3-yl]oxy)-2-propanol. Rats and mice had two additional metabolites in common, 1-[(1,1-dimethylethyl)amino]-3-([4-(2-hydroxy-4-morpholinyl)-1,2,5-thiadiazol-3-yl]oxy)-2-propanol and a compound now proposed to be the corresponding morpholino lactone 1-[1,1-dimethylethyl)-amino]-3-([4-(2-oxo-4-morpholinyl)-1,2,5-thiadiazol-3-yl]oxy)-2-propanol but for which the corresponding isomeric morpholino lactam structure 1-[(1,1-dimethylenthyl)-amino]-3-([4-(3-oxo-4-morpholinyl)-1,2,5-thiadiazol-3-yl]oxy))-2-propanol was tentatively proposed in an earlier publication. A metabolite observed in the rat, but not in the other species studied, was 4-(4-morpholinyl)-1,2,5-thiadiazol-3-ol-1-oxide. The metabolic pattern in these rodents does not change significantly after repeated doses. A scheme summarizing the metabolic fate of timolol in man and laboratory animals is presented.

Physiological disposition and metabolism of 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride.

MK-447-(14)C [2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride] was well absorbed and metabolized in man, rats, and dogs. Peak plasma levels of radioactivity were observed in these species 1-2 hr after oral administration of 2 mg/kg to rats and dogs and 25 mg to man. At the peak, parent drug represented about 15% of the radioactivity in human plasma and only approximately 5% in rat and dog plasma. The half-life of the parent drug in human plasma was approximately 4 h. Human subjects excreted 96% of the dose, with 76% in the urine and 20% in the feces, in 3 days. Rats excreted 80% of an oral and 82% of an intravenous 2-mg/kg dose in 72 hr, with 66% in the urine and 12-16% in the feces. In dogs given a 2-mg/kg dose intravenously, the recovery of radioactivity in 72 hr was approximately 99%, with 85% in the urine and 14% in the feces. The major metabolite in rat and dog urine, constituting approximately 90% of the urine radioactivity, was the O-sulfate conjugate of MK-447. In man, this metabolite accounted for 17% of the radioactivity in the urine. The major metabolite in human urine, constituting approximately 73% of the urine radioactivity, was tentatively identified as the N-glucuronide of MK-447. Less than 1% of the radioactivity in the urine of the three species was in intact MK-447.