Pharmacokinetics and metabolism of E-5-(2-[131I]iodovinyl)-2'-deoxyuridine in dogs

Abstract

E-5-(2-lodovinyl)-2'-deoxyuridine (IVdU) is a potent inhibitor of herpes simplex virus type 1 replication in vitro. The selective antiviral activity of IVdU is due to pireferential phosphorylation by the herpes simplex virus type 1-encoded thymidine kinase. This selective sequesteration provided the rationale for the development of radioiodinated IVdU as a potential radiopharmaceutical compound for use in noninvasive diagnosis of herpes simplex virus encephalitis. We studied the pharimacokinetics and the in vivo metabolism of [131 ]IVdU in dogs.The radioactive components in plasma were characterized and quantitated by radio high-pressure liquid chromatography. During incubation with dog blood, [13'IJIVdU was metabolized to the corresponding base (E)-5-(2-iodovinyl)uracil. '311-labeled (E)-5-(2-iodovinyl)uracil accounted for 73% of the total radioactivity present in plasma after 2 h of incubation, suggesting that phosphorilysis of the nucleoside is the major degradation pathway of IVdU in blood. The in vivo studies showed that there was an initial rapid clearance of the tracer from blood, followvd by a second very slow clearance phase, Evaluation of the renal excretion of the radiotracer showed that only 8% of the injected dose was excreted by kidneys over an 8-h period. IVdU was rapidly metabolized to three radioactive compounds. Two of these metabQlites, the base (E)-5-(2-iodovinyl)uracil and iodide, were characterized. The radioactivity associated with these metabolites was responsible for the slow clearance phase. Our results suggest that the development of [1311]IVdU as a radiopharmaceutical compound will require measures to prevent its rapid degradation in vivo.

Synthesis and Cellular Uptake of 2‘-Substituted Analogues of (E)-5-(2-[125I]Iodovinyl)-2‘-deoxyuridine in Tumor Cells Transduced with the Herpes Simplex Type-1 Thymidine Kinase Gene. Evaluation as Probes for Monitoring Gene Therapy

“…In HSV-1 TK gene-transduced tumor cells (KBALB-STK), the order of cellular uptake is [ 125 I]IVDU > [ 125 I]IVFRU > [ 125 I]IVFAU > [ 125 I]IVAU. Although [ 125 I]IVDU displayed the highest uptake in KBALB-STK cells at all time periods examined, it is considered unsuitable as an imaging agent due to its susceptibility to rapid, phosphorylase-mediated deglycosylation …”

“…Previous studies with radiolabeled IVDU have demonstrated that, despite rapid accumulation in cells expressing HSV-1 TK in vitro , it is an unsuitable agent for in vivo detection of HSV-1 TK expressing tissue due to rapid phosphorylase-mediated deglycosylation …”

Specific neuro-radiological diagnosis of Herpes encephalitis in an animal model

“…However, post-mortem autoradiographic studies of rat brain showed that this was not a problem in the present model presumably because of the rapid clearance of radio-IVDU from the peripheral circulation [22]. Whilst rapid drug clearance is a useful parameter in the overall design of an imaging programme sufficient time must be allowed, post administration of radio-IVDU, for both clearance of nonmetabolized drug and for active sequestration into infected cells to take place.…”

“…Delivery of radio-IVDU to the anatomical site of interest in sufficient quantity and unaltered form is a significant problem. Radio-IVDU is rapidly cleared from peripheral circulation via renal excretion [22], the drug has poor lipid solubility [12] and the blood brain barrier (BBB) remains intact in this animal model of HSVE [12]. Following intravenous or intra-arterial injection, radio-IVDU is almost completely excluded from the brain.…”

A Novel Synthesis of 2‘-Modified 2‘-Deoxy-4‘-thiocytidines from d-Glucose1

“…On the basis of these investigations, 2‘-deoxy-4‘-thionucleosides have been shown to have potent anti-herpes virus activities, and some analogues, especially 4‘-thiothymidine and 2‘-deoxy-4‘-thiocytidine ( 9 ), have been shown to possess potent cytotoxicity. ,, Notably, the 4‘-thionucleosides are resistant to hydrolytic cleavage of glycosyl linkage catalyzed by nucleoside phosphorylase . This is a major advantage of 4‘-thionucleosides, since several “4‘-oxy” antivirals have fatal drawbacks with regard to their metabolic stability caused by nucleoside phosphorylase . In addition, the potent antiviral activity and cytotoxicity of 4‘-thionucleosides suggest that they are well-recognized as substrates by both viral and host cells kinases.…”