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At least 19 recordsLinked to original sources
PubMed1996

Interaction of sulfaphenazole derivatives with human liver cytochromes P450 2C: molecular origin of the specific inhibitory effects of sulfaphenazole on CYP 2C9 and consequences for the substrate binding site topology of CYP 2C9.

The effects of sulfaphenazole, 1, on typical activities catalyzed by human cytochromes P450 of the 1A, 3A, and 2C subfamilies expressed in yeast were studied. 1 acts as a strong, competitive inhibitor of CYP 2C9 (K(i) = 0.3 +/- 0.1 microM); it is much less potent toward CYP 2C8 and 2C18 (K(i) = 63 and 29 microM, respectively) and fails to inhibit CYP 1A1, 1A2, 3A4, and 2C19. From difference visible spectroscopy experiments using microsomes of yeast expressing various human P450s, 1 selectively interacts only with CYP 2C9 with the appearance of a peak at 429 nm as expected for the formation of a P450 Fe(III)-nitrogenous ligand complex (Ks = 0.4 +/- 0.1 microM). Comparative studies of the spectral interaction and inhibitory effects of twelve compounds related to 1 with CYP 2C9 showed that the aniline function of 1 is responsible for the formation of the iron-nitrogen bond of the 429 nm-absorbing complex and is necessary for the inhibitory effects of 1. The study of two new compounds synthesized during this work, in which the N-phenyl group of 1 was replaced with either an ethyl group or a 3,4-dichlorophenyl group, showed that the presence of an hydrophobic substituent at position 1 of the pyrazole function of 1 is required for a strong interaction with CYP 2C9. A model for the binding of 1 in the CYP 2C9 active site is proposed; that takes into account three major interactions that should be at the origin of the high-affinity and specific inhibitory effects of 1 toward CYP 2C9: (i) the binding of its nitrogen atom to CYP 2C9 iron, (ii) an ionic interaction of its SO2N- anionic site with a cationic residue of CYP 2C9, and (iii) an interaction of its N-phenyl group with an hydrophobic part of the protein active site.

Aryl Hydrocarbon Hydroxylases↗
PubMed1984

Effect of sulfaphenazole on tolbutamide distribution in rabbits: analysis of interspecies differences in tissue distribution of tolbutamide.

The effect of sulfaphenazole on the distribution of tolbutamide was examined by comparing the change in the steady-state volume of distribution (Vdss) determined from in vivo plasma elimination with the tissue-to-plasma concentration ratio of various tissues (Kp) in rabbits; this effect was compared with that previously reported in rats. In rabbits, the Kp values of six tissues studied (i.e., brain, heart, spleen, small intestine, muscle, and skin) increased in the presence of sulfaphenazole ; except for brain, lung, and adipose tissue, the tissue-to-plasma unbound concentration ratio (Kp,f) of other tissues did show a significant decrease. This suggested that both the tissue and plasma protein binding of tolbutamide were affected by sulfaphenazole and that the increase in Kp was due mainly to the displacement of plasma protein binding of tolbutamide by sulfaphenazole , which was greater than that of tissue binding, while no change in Kp was due to a parallel change in both the plasma protein binding and tissue binding of tolbutamide. In both rabbits and rats, the Vdss calculated from plasma concentration versus time curve was very close to that calculated from the Kp values and volumes of various tissues in the presence and absence of sulfaphenazole , respectively. The interspecies difference of the effect of sulfaphenazole on the tissue distribution of tolbutamide between rabbits and rats was elucidated from both in vivo tissue distribution and in vitro plasma protein binding studies.

Animals↗
PubMed1990

Validation of the tolbutamide metabolic ratio for population screening with use of sulfaphenazole to produce model phenotypic poor metabolizers.

The present study has validated kinetically a convenient method to measure tolbutamide hydroxylation capacity in human beings by use of urinary metabolic ratios. The known in vivo and in vitro inhibitory properties of sulfaphenazole were used to convert control phase subjects to phenotypically "poor" metabolizers of tolbutamide. Six healthy subjects were given a single 500 mg oral dose of tolbutamide with and without sulfaphenazole, 500 mg every 12 hours. Tolbutamide, hydroxytolbutamide, and carboxytolbutamide in urine were determined by newly developed HPLC procedures. Plasma tolbutamide clearance and half-life were measured, as were the metabolic ratio (hydroxytolbutamide + carboxytolbutamide/tolbutamide) in successive 6-hour urine collections. The mean tolbutamide plasma clearance decreased from 0.196 +/- 0.026 ml/min/kg without sulfaphenazole to 0.039 +/- 0.009 ml/min kg with sulfaphenazole, and the mean half-life of tolbutamide increased from 7.28 +/- 0.89 hours to 38.76 +/- 13.30 hours. The metabolic ratio determined in the 6 to 12 hour urine collection period decreased from 794.0 +/- 86.6 to 126.0 +/- 79.3, and this collection period also gave the best separation of subjects between phases. There was a good correlation between tolbutamide plasma clearance and metabolic ratio (rs = 0.853, p less than 0.01, n = 12) and between the percentage decrease in plasma tolbutamide clearance and the percentage decrease in metabolic ratio (r = 0.932, p less than 0.01, n = 6). The tolbutamide urinary metabolic ratio therefore effectively distinguishes tolbutamide hydroxylase activity in "normal" subjects and in those converted to model phenotypically "poor" metabolizers by sulfaphenazole.

Administration, Oral↗
PubMed1977

Mechanisms of inhibition of tolbutamide metabolism: phenylbutazone, oxyphenbutazone, sulfaphenazole.

Tolbutamide half-life was increased by chronic administration of sulfaphenazole (9.5 hr to 28.6 hr, n = 2), phenylbutazone (7.9 hr to 23.1 hr, n = 8), and oxyphenbutazone (8.1 hr to 30.2 hr, n = 2). The rate of elimination of tolbutamide was decreased within 1 to 2 hr of a single dose of sulfaphenazole and the tolbutamide half-life was increased from 9.2 hr to 25.7 hr (n = 2). In contrast, phenylbutazone and oxyphenbutazone, administered as single oral doses of 800 mg, had no immediate effect on tolbutamide elimination. At times greater than 20 to 30 hr after the single dose of phenylbutazone or oxyphenbutazone the rate of tolbutamide elimination was decreased. It is suggested that phenylbutazone and oxyphenbutazone act by inducing form of cytochrome P-450 with low activity for tolbutamide hydroxylation, whereas sulfaphenazole acts by direct inhibition of the microsomal mixed function oxidase system.

Adult↗
PubMedDate not supplied

The effect of sulfaphenazole and sulfadoxine on tolbutamide disposition in dwarf goats (Caprus hircus aegagrus).

The aim of the present study was to investigate the effects of intravenously administered sulfadoxine (5 mg kg-1 bodyweight) or sulfaphenazole (5 mg kg-1 bodyweight) on the in vivo elimination of i.v. tolbutamide (5 mg kg-1 bodyweight), as both compounds were shown to inhibit tolbutamide hydroxylation in vitro. It was shown that relative large differences in tolbutamide clearance exist among goats (n = 6). A high correlation was seen between tolbutamide and sulfadoxine clearances. Tolbutamide clearance was significantly reduced by concommitant administration of sulfaphenazole. Sulfadoxine (SDX) had a less consistent effect. Mean tolbutamide plasma clearance was not significantly affected due to the fact that three animals showed an inhibition, whereas three others apparently did not respond. A negative correlation was found between the amount of N4-acetyl SDX in urine and the SDX clearance. Approximately 93 per cent of tolbutamide was bound to plasma proteins. However, there was no evidence for displacement of tolbutamide from its protein binding sites by sulfaphenazole or sulfadoxine. The results described in the present study confirm previous in vitro data obtained with goat hepatocytes. Although quantitative differences in inhibition exist between in vivo and in vitro results, hepatocytes are a good model to study potential drug-drug interactions at the level of biotransformation processes.

Animals↗
PubMed1965

STIMULANT EFFECTS OF A SULFONAMIDE PREPARATION, SULFAPHENAZOLE, ON THE CENTRAL NERVOUS SYSTEM IN RATS.

Sulfaphenazole (Orisul), which had been reported to cause a convulsant syndrome in young European children, lowered the electroshock threshold in rats when administered in the form of tablets or suspension. This effect was not obtained with a sample of sulfaphenazole pure drug or with several other long-acting oral sulfonamide preparations, but was obtained with a mixture of impurities which had been found in the same lot of Orisul that had reportedly caused the convulsant syndrome. A change in the method of manufacture now provides a product which is free from these impurities.

Central Nervous System↗
PubMed1990

High pressure liquid chromatographic analysis and preliminary pharmacokinetics of sulfaphenazole and its N2-glucuronide and N4-acetyl metabolites in plasma and urine of man.

A direct high pressure liquid chromatographic analysis of sulfaphenazole-N2-glucuronide in urine is described. After an oral dose of 439 mg of sulfaphenazole, 0% is excreted unchanged in the urine, less than 1% is excreted as N4-acetylsulfaphenazole. As N2-glucuronide 49.4% is excreted in one slow acetylator and 84.8% in one fast acetylator.

Acetylation↗
PubMed2001

Interaction of new sulfaphenazole derivatives with human liver cytochrome p450 2Cs: structural determinants required for selective recognition by CYP 2C9 and for inhibition of human CYP 2Cs.

A series of new derivatives of sulfaphenazole (SPA), in which the NH(2) and phenyl substituents of SPA are replaced by various groups or in which the sulfonamide function of SPA is N-alkylated, were synthesized in order to further explore CYP 2C9 active site and to determine the structural factors explaining the selectivity of SPA for CYP 2C9 within the human P450 2C subfamily. Compounds in which the NH(2) group of SPA was replaced with R(1) = CH(3), Br, CH = CH(2), CH(2)CH = CH(2), and CH(2)CH(2)OH exhibited a high affinity for CYP 2C9, as shown by the dissociation constant of their CYP 2C9 complexes, K(s), which was determined by difference visible spectroscopy (K(s) between 0.1 and 0.4 microM) and their constant of CYP 2C9 inhibition (K(i) between 0.3 and 0.6 microM). This indicates that the CYP 2C9-iron(III)-NH(2)R bond previously described to exist in the CYP 2C9-SPA complex does not play a key role in the high affinity of SPA for CYP 2C9. Compounds in which the phenyl group of SPA was replaced with various aryl or alkyl R(2) substituents only exhibited a high affinity for CYP 2C9 if R(2) is a freely rotating and sufficiently electron-rich aryl substituent. Finally, compounds resulting from a N-alkylation of the SPA sulfonamide function (R(3) = CH(3), C(2)H(5), or C(3)H(7)) did not retain the selective inhibitory properties of SPA toward CYP 2C9. However, they are reasonably good inhibitors of CYP 2C8 and CYP 2C18 (IC(50) approximately 20 microM). These data allow one to better understand the structural factors that are important for selective binding in the CYP 2C9 active site. They also provide us with clues towards new selective inhibitors of CYP 2C8 and CYP 2C18.

Binding Sites↗
PubMed2001

Relative contributions of CYP2C9 and 2C19 to phenytoin 4-hydroxylation in vitro: inhibition by sulfaphenazole, omeprazole, and ticlopidine.

OBJECTIVES: To determine the relative contribution of cytochromes P450 (CYP) 2C9 and 2C19 to the formation of 5-(-4-hydroxyphenyl)-5-phenylhydantion (HPPH) from phenytoin (PPH). DESIGN: Hydroxylation of PPH to form HPPH was studied in vitro using human liver microsomes and microsomes from cDNA-transfected human lymphoblastoid cells. RESULTS: Formation of HPPH from PPH in liver microsomes had a mean (+/- SEM) apparent Km [substrate concentration corresponding to 50% of maximal reaction velocity (Vmax)] of 23.6 +/- 1.8 mumol/l. Coincubation with the CYP2C9 inhibitor, sulfaphenazole (SPA), at 5 mumol/l reduced reaction velocity to less than 15% of control values. The mean inhibitor concentration at which 50% inhibition is achieved (IC50 value) for SPA versus PPH hydroxylation (0.49 microM) was similar to the SPA IC50 versus flurbiprofen hydroxylation (0.46 microM) and tolbutamide hydroxylation (0.7-1.5 microM). In contrast, the CYP2C19 inhibitor omeprazole (OME) at 10 mumol/l produced only a small degree of inhibition. Incubation of PPH with microsomes from cDNA-transfected human lymphoblastoid cells containing CYP1A2, 2A6, 2B6, 2C8, 2D6, 2E1, or 3A4 yielded no detectable formation of HPPH. Only CYP2C9 and 2C19 had PPH hydroxylation activity, with apparent Km values for the high-affinity component of 14.6 mumol/l and 24.1 mumol/l, respectively. Based on Vmax values in liver microsomes, the Vmax and Km values in expressed CYPs and the relative abundance of the two isoforms in human liver, CYP2C9, and 2C19 were estimated to have relative contributions of 90% and 10%, respectively, to net intrinsic clearance. CONCLUSIONS: Formation of HPPH from PPH is mediated exclusively by CYP2C9 and 2C19, with CYP2C9 playing the major role.

Anti-Infective Agents↗
PubMed2003

Substrate selectivity of human cytochrome P450 2C9: importance of residues 476, 365, and 114 in recognition of diclofenac and sulfaphenazole and in mechanism-based inactivation by tienilic acid.

A series of six site-directed mutants of CYP 2C9 were constructed with the aim to better define the amino acid residues that play a critical role in substrate selectivity of CYP 2C9, particularly in three distinctive properties of this enzyme: (i) its selective mechanism-based inactivation by tienilic acid (TA), (ii) its high affinity and hydroxylation regioselectivity toward diclofenac, and (iii) its high affinity for the competitive inhibitor sulfaphenazole (SPA). The S365A mutant exhibited kinetic characteristics for the 5-hydroxylation of TA very similar to those of CYP 2C9; however, this mutant did not undergo any detectable mechanism-based inactivation by TA, which indicates that the OH group of Ser 365 could be the nucleophile forming a covalent bond with an electrophilic metabolite of TA in TA-dependent inactivation of CYP 2C9. The F114I mutant was inactive toward the hydroxylation of diclofenac; moreover, detailed analyses of its interaction with a series of SPA derivatives by difference visible spectroscopy showed that the high affinity of SPA to CYP 2C9 (K(s)=0.4 microM) was completely lost when the phenyl substituent of Phe 114 was replaced with the alkyl group of Ile (K(s)=190+/-20 microM), or when the phenyl substituent of SPA was replaced with a cyclohexyl group (K(s)=120+/-30 microM). However, this cyclohexyl derivative of SPA interacted well with the F114I mutant (K(s)=1.6+/-0.5 microM). At the opposite end, the F94L and F110I mutants showed properties very similar to those of CYP 2C9 toward TA and diclofenac. Finally, the F476I mutant exhibited at least three main differences compared to CYP 2C9: (i) big changes in the k(cat) and K(m) values for TA and diclofenac hydroxylation, (ii) a 37-fold increase of the K(i) value found for the inhibition of CYP 2C9 by SPA, and (iii) a great change in the regioselectivity of diclofenac hydroxylation, the 5-hydroxylation of this substrate by CYP 2C9 F476I exhibiting a k(cat) of 28min(-1). These data indicate that Phe 114 plays an important role in recognition of aromatic substrates of CYP 2C9, presumably via Pi-stacking interactions. They also provide the first experimental evidence showing that Phe 476 plays a crucial role in substrate recognition and hydroxylation by CYP 2C9.

Amino Acids↗
PubMed2003

Sulfaphenazole derivatives as tools for comparing cytochrome P450 2C5 and human cytochromes P450 2Cs: identification of a new high affinity substrate common to those enzymes.

The inhibitory effects of a series of sulfaphenazole (SPA) derivatives were studied on two modified forms of rabbit liver cytochrome P450 2C5 (CYP2C5), CYP2C5dH, and structurally characterized CYP2C5/3LVdH and compared to the previously described effects of these compounds on human CYP2C8, 2C9, 2C18, and 2C19. SPA and other negatively charged compounds that potently inhibit CYP2C9 had very little effect on CYP2C5dH, whereas neutral, N-alkylated derivatives exhibited IC50 values between 8 and 22 microM. One of the studied compounds, 4, that derives from SPA by replacement of its NH(2) substituent with a methyl group and by N-methylation of its sulfonamide moiety, acted as a good substrate for all CYP2Cs used in this study. Hydroxylation of the benzylic methyl of 4 is the major reaction catalyzed by all of these CYP2C proteins, whereas hydroxylation of the N-phenyl group of 4 was observed as a minor reaction. CYP2C5dH, 2C5/3LVdH, 2C9, 2C18, and 2C19 are efficient catalysts for the benzylic hydroxylation of 4, with K(m) values between 5 and 13 microM and k(cat) values between 16 and 90 min(-1). The regioselectivity observed for oxidation of 4 by CYP2C5/3LVdH was easily interpreted on the basis of the existence of two different binding modes of 4 characterized in the experimentally determined structure of the complexes of CYP2C5/3LVdH with 4 described in the following paper [Wester, M. R. et al. (2003) Biochemistry 42, 6370-6379].

Anti-Infective Agents↗
PubMed1998

Identification of amino acid substitutions that confer a high affinity for sulfaphenazole binding and a high catalytic efficiency for warfarin metabolism to P450 2C19.

Human cytochrome P450s 2C9 and 2C19 metabolize many important drugs including tolbutamide, phenytoin, and (S)-warfarin. Although they differ at only 43 of 490 amino acids, sulfaphenazole (SFZ) is a potent and selective inhibitor of P450 2C9 with an IC50 and a spectrally determined binding constant, KS, of <1 microM. P450 2C19 is not affected by SFZ at concentrations up to 100 microM. A panel of CYP2C9/2C19 chimeric proteins was constructed in order to identify the sequence differences that underlie this difference in SFZ binding. Replacement of amino acids 227-338 in 2C19 with the corresponding region of 2C9 resulted in high-affinity SFZ binding (KS approximately 4 microM) that was not seen when a shorter fragment of 2C9 was substituted (227-282). However, replacement of amino acids 283-338 resulted in extremely low holoenzyme expression levels in Escherichia coli, indicating protein instability. A single mutation, E241K, which homology modeling indicated would restore a favorable charge pair interaction between K241 in helix G and E288 in helix I, led to successful expression of this chimera that exhibited a KS < 10 microM for SFZ. Systematic replacement of the remaining differing amino acids revealed that two amino acid substitutions in 2C19 (N286S, I289N) confer high-affinity SFZ binding (KS < 5 microM). When combined with a third substitution, E241K, the resulting 2C19 triple mutant exhibited a high cataltyic efficiency for warfarin metabolism with the relaxed stereo- and regiospecificity of 2C19 and a lower KM for (S)-warfarin metabolism (<10 microM) typical of 2C9.

Amino Acid Sequence↗
PubMed2001

Synthesis of sulfaphenazole derivatives and their use as inhibitors and tools for comparing the active sites of human liver cytochromes P450 of the 2C subfamily.

Twenty-three new derivatives of sulfaphenazole (SPA) were synthesized to further explore the topology of the active sites of human liver cytochromes P450 of the 2C subfamily and to find new selective inhibitors of these cytochromes. These compounds are derived from SPA by replacement of the NH(2) and H (of the SO(2)NH function) substituents of SPA with various R(1) and R(2) groups, respectively. Their inhibitory effects were studied on recombinant CYP 2C8, 2C9, 2C18, and 2C19 expressed in yeast. High affinities for CYP 2C9 (IC(50) < 1 microM) were only observed for SPA derivatives having the SO(2)NH function and a relatively small R(1) substituent (R(1) = NH(2), CH(3)). Any increase in the size of R(1) led to a moderate decrease of the affinity, and the N-alkylation of the SO(2)NH function of SPA to a greater decrease of this affinity. The same structural changes led to opposite effects on molecular recognition by CYP 2C8 and 2C18, which generally exhibited similar behaviors. Thus, contrary to CYP 2C9, CYP 2C8 and 2C18 generally prefer neutral compounds with relatively large R(1) and R(2) substituents. CYP 2C19 showed an even lower affinity for anionic compounds than CYP 2C8 and 2C18. However, as CYP 2C8 and 2C18, CYP 2C19 showed a much better affinity for neutral compounds derived from N-alkylation of SPA and for anionic compounds bearing a larger R(1) substituent. One of the new compounds (R(1) = methyl, R(2) = propyl) inhibited all human CYP 2Cs with IC(50) values between 10 and 20 microM, while another one (R(1) = allyl, R(2) = methyl) inhibited all CYP 2Cs except CYP 2C9, and a third one (R(1) = R(2) = methyl) inhibited all CYP 2Cs except CYP 2C8. Only 2 compounds of the 25 tested derivatives were highly selective toward one human CYP 2C; these are SPA and compound 1 (R(1) = CH(3), R(2) = H), which acted as selective CYP 2C9 inhibitors. However, some SPA derivatives selectively inhibited CYP 2C8 and 2C18. Since CYP 2C18 is hardly detectable in human liver, these derivatives could be interesting molecules to selectively inhibit CYP 2C8 in human liver microsomes. Thus, compound 11 (R(1) = NH(2), R(2) = (CH(2))(2)CH(CH(3))(2)) appears to be particularly interesting for that purpose as its IC(50) value for CYP 2C8 is low (3 microM) and 20-fold smaller than those found for CYP 2C9 and 2C19.

Aryl Hydrocarbon Hydroxylases↗
PubMed1999

Pharmacokinetic drug interactions between ampiroxicam and sulfaphenazole in rats.

The aim of the present study was to determine the effect of sulfaphenazole (SP) on the pharmacokinetics of ampiroxicam (AM) which is metabolized by cytochrome P-450 (CYP) 2C9, since SP is a potent inhibitor of CYP 2C9, and so a dramatic pharmacokinetic drug interaction between both drugs is assumed after dosing. Single intravenous and oral administrations of AM (5 and 7.5 mg/kg piroxicam equivalent, respectively) and SP (80 and 120 mg/kg, respectively) to rats did not significantly alter the elimination kinetics of AM and piroxicam (PX) converted from AM. When SP was preloaded orally at 2 h before the dosing of AM, and when AM and SP were orally coadministered for 7 d, the elimination of PX from plasma was slightly retarded and the area under the plasma concentration-time curve (AUC) was increased 77 and 53%, respectively, but not significantly, compared with those after AM alone. On the other hand, a significantly decreased metabolic conversion of PX to 5'-hydroxyPX in plasma was observed by these treatments (p<0.05). In order to clarify the mechanism for the interaction, hepatic and intestinal metabolizing enzyme activities, CYP, uridine 5'-diphosphoglucuronyltransferase (UDPGT) and aryl esterase, were assayed after single and multiple oral administrations of AM or AM and SP. The enzyme activities were hardly inhibited by the treatment, indicating that the inhibition of CYP and hydrolytic enzymes by SP was approximately denied. These results suggest that SP does not significantly affect the pharmacokinetics of AM and PX in rats. However, the pharmacokinetic drug interaction between both drugs in man may not always be ignored.

Administration, Oral↗
PubMed1989

Effect of pH and small inorganic ions on binding of sulfadimethoxine and sulfaphenazole to human serum albumin measured by circular dichroism.

The binding of sulfadimethoxine and sulfaphenazole to human serum albumin (HSA) has been shown by circular dichroism measurements to be dependent on the N-B transition. The secondary drug binding sites were found to be optically active in the B conformation form in HSA but optically inactive in the N form. Moreover, the drug-HSA interaction in Tris-HCl buffer seems to be more sensitive to the conformational change in HSA, compared with that in the phosphate buffer.

Circular Dichroism↗