contrast to truly human DMEs, bacterial enzymes originating from the intestinal
microflora possess a higher inherent ability to catalyzing reductive reactions of
drugs. The outcome of this drug-gut bacteria interaction can manifest in various
ways and can have significant effects on pharmacokinetic and safety profiles:
metabolism of the active may reduce its oral bioavailability (e.g., nizatidine),
enzymatic breakdown may release a pharmacologically active metabolite from the
inactive parent compound (e.g., sulfasalazine), ester hydrolysis of acyl glucuronides
may recycle the acidic drug and facilitate enterohepatic recirculation (e.g., DCF)
thereby extending its elimination half-life, and formation of reactive metabolites
may cause toxicity (e.g., metronidazole) [14].
2.2 Phase II Reactions
As for conjugative phase II reactions, they rely on the presence of specific functional
groups to accommodate the moiety transferred from the cofactor to the substrate. By
far the most prominent DME in this class is uridine 5
0 -diphosphoglucuronosyltransferase (UGT) which in a nucleophilic substitution attaches
glucuronic acid to carboxyl, aliphatic and aromatic hydroxyl, and amino groups or
to N-heterocycles to yield the glucuronide conjugate [15]. Given the critical function
of glucuronidation in human drug metabolism, the UGT family has been characterized to an extent comparable to that of CYPs with respect to identification of the
human isoforms (belonging to the families UGTA1 and UGT2B), tissue expression,
substrate selectivity, and polymorphic variants. It is worth stressing that certain
UGTs involved in the conjugation of drugs are exclusively expressed in extrahepatic
tissues [16]. Consequently, a liver-centered approach in assessing the extent of
glucuronidation is likely to fail in accurately predicting the overall contribution of
this phase II reaction to the overall metabolic clearance [17]. One aspect of particular
interest to the environmental scientist dealing with the fate of glucuronide conjugates
of acidic drugs carrying a carboxyl group (e.g., DCF and IBU) resides in the
susceptibility of the resulting ester towards enzymatic hydrolysis (Fig. 6). This
reaction, which can already be catalyzed prior to excretion by intestinal bacteria
exposed to bile secretions, may regenerate the parent drug if no preceding phase I
reaction took place.
Second to glucuronidation is the sulfotransferase-mediated (SULT) conjugation
of a sulfo group (SO 3 ) to an alcohol, phenol, or amine [18]. In this sulfation reaction,
the resulting metabolite is a sulfate and a sulfamate, respectively. Although human
cytosolic SULTs are high-affinity enzymes, their quantitative relevance is limited
owing to their low capacity. Accordingly, sulfation is usually a minor pathway in the
metabolic scheme of synthetic drugs. Sulfate and glucuronide conjugations share the
pharmacokinetically relevant characteristic of greatly lowering the lipophilicity of
drug molecules and thus are usually the final metabolic step before efficient metabolite secretion into bile or excretion into urine takes place.
Metabolism of Pharmaceuticals in Plants and Their Associated Microbiota
229
microflora possess a higher inherent ability to catalyzing reductive reactions of
drugs. The outcome of this drug-gut bacteria interaction can manifest in various
ways and can have significant effects on pharmacokinetic and safety profiles:
metabolism of the active may reduce its oral bioavailability (e.g., nizatidine),
enzymatic breakdown may release a pharmacologically active metabolite from the
inactive parent compound (e.g., sulfasalazine), ester hydrolysis of acyl glucuronides
may recycle the acidic drug and facilitate enterohepatic recirculation (e.g., DCF)
thereby extending its elimination half-life, and formation of reactive metabolites
may cause toxicity (e.g., metronidazole) [14].
2.2 Phase II Reactions
As for conjugative phase II reactions, they rely on the presence of specific functional
groups to accommodate the moiety transferred from the cofactor to the substrate. By
far the most prominent DME in this class is uridine 5
0 -diphosphoglucuronosyltransferase (UGT) which in a nucleophilic substitution attaches
glucuronic acid to carboxyl, aliphatic and aromatic hydroxyl, and amino groups or
to N-heterocycles to yield the glucuronide conjugate [15]. Given the critical function
of glucuronidation in human drug metabolism, the UGT family has been characterized to an extent comparable to that of CYPs with respect to identification of the
human isoforms (belonging to the families UGTA1 and UGT2B), tissue expression,
substrate selectivity, and polymorphic variants. It is worth stressing that certain
UGTs involved in the conjugation of drugs are exclusively expressed in extrahepatic
tissues [16]. Consequently, a liver-centered approach in assessing the extent of
glucuronidation is likely to fail in accurately predicting the overall contribution of
this phase II reaction to the overall metabolic clearance [17]. One aspect of particular
interest to the environmental scientist dealing with the fate of glucuronide conjugates
of acidic drugs carrying a carboxyl group (e.g., DCF and IBU) resides in the
susceptibility of the resulting ester towards enzymatic hydrolysis (Fig. 6). This
reaction, which can already be catalyzed prior to excretion by intestinal bacteria
exposed to bile secretions, may regenerate the parent drug if no preceding phase I
reaction took place.
Second to glucuronidation is the sulfotransferase-mediated (SULT) conjugation
of a sulfo group (SO 3 ) to an alcohol, phenol, or amine [18]. In this sulfation reaction,
the resulting metabolite is a sulfate and a sulfamate, respectively. Although human
cytosolic SULTs are high-affinity enzymes, their quantitative relevance is limited
owing to their low capacity. Accordingly, sulfation is usually a minor pathway in the
metabolic scheme of synthetic drugs. Sulfate and glucuronide conjugations share the
pharmacokinetically relevant characteristic of greatly lowering the lipophilicity of
drug molecules and thus are usually the final metabolic step before efficient metabolite secretion into bile or excretion into urine takes place.
Metabolism of Pharmaceuticals in Plants and Their Associated Microbiota
229